Article

A study of twins and stroke

March 1992
Stroke 23(2):221-3

March 1992
23(2):221-3

DOI:10.1161/01.STR.23.2.221

Source
PubMed

Authors:

Kathleen R Merikangas

National Institutes of Health

Although there are strong genetic contributions to coronary artery disease, only a few studies have considered heritable influences on stroke. We investigated the role of genetic factors in stroke using the Twin Registry maintained by the National Academy of Sciences-National Research Council. The registry includes 15,948 male twin pairs born between 1917 and 1927. In 1985, 9,475 twins responded to a mailed questionnaire, which covered vascular risk factors, cardiac events, and stroke. Analysis of twin pairs in which both responded to the questionnaire, and a question on stroke, indicated proband concordance rates of 17.7% for monozygotic pairs and 3.6% for dizygotic pairs (relative risk = 4.3; chi 2 = 4.94, df = 1; p less than 0.05). This nearly fivefold increase in the prevalence of stroke among the monozygotic compared with the dizygotic twin pairs suggests that genetic factors are involved in the etiology of stroke. The twin study paradigm holds considerable promise for identifying both genetic and environmental influences on stroke.

Heritability for stroke: Essential for taking family history

Article

Full-text available

May 2020

Background: There are many well-established factors that influence the risk of stroke including blood pressure, diabetes, low socioeconomic status and smoking, however, the shared genetic resource in members of a family effect on stroke predisposition. Genome-wide association studies (GWAS) have demonstrated evidence of a shared genetic source in stroke risk. This review considered the influence of family history as one of the main risk factors in stroke according to the literature. Methods: Literature review was obtained by searching for the key words "stroke", "family history" and "stroke gene" in PubMed. An overview has been made on the topics: relevance of stroke family history, family history assessment tools and specific candidate genes for stroke. Results: Family history of stroke is an important risk factor for the development of cerebrovascular diseases in addition to stroke subtypes in relatives who have reached the questionnaire and pedigree. While variation in a small number of loci showed Mendelian inheritance of stroke phenotypes, the genetic variations in several stroke risk loci are shared with multiple related vascular traits. Conclusion: This study highlighted the importance of family history in stroke phenotypes and current related genetics information. Increasing awareness of the importance of family history in stroke has the advantage of preventing exposure to stroke with health care.

Recent Advances in Stroke Genetics

Chapter

Jun 2017

Stroke Research in GenomEUtwin

Article

Full-text available

Oct 2003
Twin Res

Stroke is one of the leading causes of severe disability and death in the world. In the present article we outline possibilities and limitations for future stroke research within the GenomEUtwin. The combined sample of twins born before 1958 from Denmark, Finland, and Sweden, and available for follow-up into the second millennium for non-fatal and fatal stroke events through national inpatient and death registers exceeds 70,000 twin pairs. This sample size will enable the study of genetic influences on stroke and major stroke subtypes. Large samples of twins in GenomEUtwin have been followed up repeatedly through interviews and questionnaires concerning a variety of exposures and potential risk factors for stroke. We briefly outline how this information can be combined with the health register information for epidemiologic and genetic epidemiologic studies of stroke. We also present the number of twin pairs concordant and discordant for stroke in Denmark, Finland and Sweden, and time lags between events for twins concordant for stroke. This information illustrates that the number of affected sib pairs for linkage studies is relatively limited, but the sample sizes are promising for association studies.

Functional polymorphism in miR-208 is associated with increased risk for ischemic stroke

Article

Full-text available

Jul 2023
BMC MED GENOMICS

Background The miR-208 gene is one of the microRNAs now under active studies, and has been found to play significant roles in an array of cardiovascular diseases. Nevertheless, until now, no studies have examined the relationship between the susceptibility to ischemic stroke (IS) and genetic variations in miR-208. This study explored the association between the miR-208 polymorphisms (rs178642, rs8022522, and rs12894524) and the risk of IS. Methods A total of 205 cases of IS and 211 control subjects were included. The SNPscans genotyping test was employed to determine the genotypes of the three polymorphisms. Results Significant correlation was observed between rs8022522 polymorphism and risk of IS on the basis of analyses of genotypes, models and alleles (GA vs. GG: adjusted OR = 2.159, 95% CI: 1.052–4.430, P = 0. 036; AA vs. GG: adjusted OR = 5.154, 95% CI: 1.123–23.660, P = 0.035; dominant model: adjusted OR = 1.746, 95% CI, 1.075–2.838, P = 0.025; G vs. A: adjusted OR = 2.451, 95% CI: 1.374–4.370, P = 0.002). Conclusions The rs8022522 polymorphism of the miR-208 gene is significantly associated with an elevated risk of ischemic stroke in Chinese.

TRENDS-IN-INTERPROFESSIONAL-CARE-MANAGEMENT-IN-HEALTHCAR

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Mar 2022

Hüseyin Gürbüz

TRENDS-IN-INTERPROFESSIONAL-CARE-MANAGEMENT-IN-HEALTHCAR

Chapter

Full-text available

Mar 2022

Hülya Kanbur Çiçek

The World Health Organization (WHO) defines ischemic stroke as neurological dysfunction, which occurs due to focal cerebral spinal or retinal infarction, and this is the definition of ischemic stroke proposed in the 20th century. Stroke is divided into two groups in the form of "ischemic stroke or intracerebral hemorrhage" and "hemorrhagic stroke due to subarachnoid hemorrhage." Before the ischemic stroke, transient ischemic attacks (TIA) may be observed, and a temporary ischemic attack is defined as temporary neurological dysfunction that emerged due to cerebral spinal or retinal ischemia without acute infarction. It has the same pathogenesis as ischemic stroke, with an early risk of recurrence similar to ischemic stroke. In some cases, this risk is higher depending on etiology. Some recent studies have reported brain damage using diffusion-weighted magnetic resonance imaging in about 30-50% of cases defined as TIA, with treatable causes identified in its pathology.

COVID-19, NURSING CARE AND ETHICS

Chapter

Dec 2021

A premier Journal for Neurosurgery, Neurology & Allied Sciences Impact Factor of 2.128 (Clarivate Analytics @ 2020) 686 Endothelial Nitric Oxide Synthase (Glu298Asp) Polymorphism is Associated Significantly with Ischemic Stroke Presenting with Seizures and Altered Sensorium

Article

Full-text available

Jun 2021

Background: Endothelial nitric oxide synthase (eNOS) is an enzymatic marker whose genetic polymorphism might predispose to acute ischemic stroke (AIS) via vascular endothelial dysfunction. It has a potential role in atherosclerosis, making it a plausible risk factor for stroke. Prior studies have failed to prove a conclusive relationship between eNOS polymorphism and AIS. Objective: The aim of this study is to find an association between the presence of eNOS polymorphism (Glu298Asp) and the risk of developing AIS. Materials and Methods: We recruited 307 subjects including 153 AIS cases and 154 healthy controls. The eNOS (Glu298Asp) polymorphism was identified in EDTA blood by PCR amplification of the target region followed by restriction enzyme digestion, and genotyping on Agarose gel. GG, GT and TT genotypes were obtained. Statistical analysis was done using SPSS software version 20. Results: A significant association was found between the presence of TT genotype and the risk of AIS (Odd’s ratio (OR): 2.43, P-value = 0.038). There was no significant association between the TT genotype and the traditional stroke risk factors. However, the TT genotype was significantly associated with the presence of altered consciousness (OR: 5.27, 95% CI: 1.59–17.04, P-value = 0.003) and with the occurrence of seizures at presentation (OR: 7.98, 95% CI: 1.99–32.09, P-value = 0.007). Conclusions: There is a significant association between the presence of eNOSpolymorphism (Glu298Asp) and the risk of AIS, and the TT genotype may predispose to a more severe initial presentation of ischemic stroke. Key Words: Endothelial nitric oxide synthase (eNOS), gene polymorphism, ischemic stroke, genotype

Levels of Lipid Parameters in Children with Arterial Ischemic Stroke and Headache: Case-Control Study and Meta-Analysis

Article

Full-text available

Mar 2021
BSRCCS

Background: Abnormalities in levels of lipid parameters are one of the main causes of cardiovascular and cerebrovascular disease in adults. There are limited data on the role of disturbances of lipid metabolism in the etiopathogenesis of arterial ischemic stroke (AIS) in children and the results provided are ambiguous. The aim of the study was to compare the levels of lipid parameters (total cholesterol [TC], triglycerides [TG], high-density lipoprotein [HDL] and low-density lipoprotein [LDL]) between children with AIS, children with headache and healthy children. In addition, we performed meta-analysis of available data on lipid parameters in young patients with AIS. Methods: We retrospectively analyzed 218 children hospitalized between 2002 and 2018 in the Upper-Silesian Child’s Health Center (n = 82 children with AIS, n = 45 children with headache, n = 91 healthy children) with available data on lipid levels, i.e., TC, TG, and HDL. The levels of LDL, non-HDL cholesterol, and a very-low density lipoprotein (VLDL) were calculated. The ratios of TC/HDL, TG/HDL and LDL/HDL were also assessed. Data between cases and controls were analyzed using STATISTICA 13.0 whereas meta-analysis was performed with RevMan version 5.4 software. Results: Children with headache were significantly older than children with AIS (p = 0.001). Ten percent of children with AIS had posterior stroke. The mean TC level was significantly higher in the AIS children than in controls or in children with headache. Mean TG and VLDL levels were significantly different between all groups (p < 0.001 each). The hypertriglyceridemia was more prevalent in AIS children than in children with headache (39% vs. 13%, OR = 4.16 95% CI 1.58–10.94, p = 0.004). Similarly, the frequency of dyslipidemia was higher in children with AIS compared to children with headache (38% vs. 22%, OR = 2.13 95% CI 0.93–4.89, p = 0.078). The meta-analysis was conducted based on data from 4 studies (3 studies published previously plus the results we obtained in the present case-control analysis) with total number of 236 young patients with AIS and 272 healthy controls. Significant Standard Mean Difference (SMD) was found in triglycerides level between young patients with AIS and controls (0.78 95%CI 0.30–1.26 p = 0.002). Conclusions: Lipid abnormalities, especially levels of triglycerides, seem to be of particular importance in children with AIS, as confirmed in meta-analysis. The results of the present study may be a significant contribution to the further research on the role of lipid metabolism disorders in the development of childhood stroke.

Natural genetic variation in Stim1 creates stroke in the spontaneously hypertensive rat

Article

Full-text available

May 2020

Similar to humans, the risk of cerebrovascular disease in stroke-prone spontaneously hypertensive rats (SHR-A3/SHRSP) arises from naturally occurring genetic variation. In the present study, we show the involvement of genetic variation affecting the store-operated calcium signaling gene, Stim1, in the pathogenesis of stroke in SHR. Stim1 is a key lymphocyte activation signaling molecule and contains functional variation in SHR-A3 that diverges from stroke-resistant SHR-B2. We created a SHR-A3 congenic line in which Stim1 was substituted with the corresponding genomic segment from SHR-B2. Compared with SHR-A3 rats, Stim1 congenic SHR-A3 (SHR-A3(Stim1-B2)) have reduced cerebrovascular disease in response to salt loading including lower neurological deficit scores and cerebral edema. Microbleeds and major hemorrhages occurred in over half of SHR-A3 rats. These lesions were absent in SHR-A3(Stim1-B2) rats. Loss of Stim1 function in mice and humans is associated with antibody-mediated autoimmunity due to defects in T lymphocyte helper function to B cells. We investigated autoantibody formation using a high-density protein array to detect the presence of IgG and IgM autoantibodies in SHR-A3. Autoantibodies to key cerebrovascular stress proteins were detected that were reduced in the congenic line.

A functional polymorphism in the promoter of miR-17-92 cluster is associated with decreased risk of ischemic stroke

Article

Full-text available

Nov 2019
BMC MED GENOMICS

Abstract Background The microRNA-17-92 (miR-17-92) cluster is one of the most extensively studied miRNA clusters. Abnormal expression of the cluster has been found to play important role in different kinds of human diseases, including ischemic stroke (IS). The aim of our study was to investigate the association between three polymorphisms (rs1491034, rs9301654 and rs982873) in the promoter of the miR-17-92 cluster and risk of IS. Methods Three hundred and ninety-eight patients with IS and 397 control subjects were included. The genotypes of the three polymorphisms were determined by Snapshot SNP genotyping assay. Relative expression of the cluster in peripheral blood mononuclear cells (PBMCs) of cases and controls were examined by quantitative real-time PCR. Results Significant association between rs9301654 polymorphism and risk of IS were observed basing on genotype, model and allele analyses (GA vs. AA: adjusted OR = 0.63, 95% CI: 0.41~0.97, P = 0.037; GG vs. AA: adjusted OR = 0.23, 95% CI: 0.07~0.78, P = 0.018; GA + GG vs. AA: adjusted OR = 0.57, 95% CI: 0.38~0.87, P = 0.009; GA + AA vs. GG: adjusted OR = 0.27, 95% CI: 0.08~0.89, P = 0.032; G vs. A: adjusted OR = 0.58, 95% CI: 0.40~0.83). Haplotype analysis showed that TGC and TGT haplotypes were associated with decreased risk of IS (OR = 0.59, 95% CI: 0.40~0.87, P = 0.007 for TGC haplotype; OR = 0.21, 95% CI: 0.06~0.75, P = 0.009 for TGT haplotype). Importantly, we found the expression of miR-17-5p was significant higher while miR-19a-3p was significant lower in patient with IS compared with the control group (P

Association Between Endothelial Nitric Oxide Synthase Polymorphisms T786C and G894T and Ischaemic Stroke

Article

Full-text available

Jan 2019

A functional polymorphism in the promoter of TUG1 is associated with an increased risk of ischaemic stroke

Article

Full-text available

Jul 2019
J CELL MOL MED

Taurine‐upregulated gene 1 (TUG1), a kind of long non‐coding RNAs (lncRNAs), was up‐regulated in ischaemic stroke (IS) with the function of promoting neuron apoptosis. In this study, we aimed to investigate the association of TUG1 polymorphisms with IS risk. The TUG1 polymorphisms were genotyped using a custom‐by‐design 48‐Plex SNPscan kit. The promoter activity was measured using the dual luciferase reporter assay. Relative expression of TUG1 in IS patients was analysed using quantitative PCR and the binding of TUG1 rs2240183 polymorphism to transcription factor was analysed using chromatin immunoprecipitation (ChIP) assay. The rs2240183 CT/CC genotypes and C allele in the promoter of TUG1 were associated with an increased risk of IS (CT/CC vs. TT: adjusted OR = 1.70, 95% CI, 1.16‐2.49, P = 0.006; C vs. T: adjusted OR = 1.47, 95% CI, 1.12‐1.93, P = 0.005). Logistic regression analysis showed that the rs2240183 was a risk factor of IS besides TC, TG, HDL‐C, LDL‐C, VLDL‐C, Apo‐A1, Apo‐B and NEFA. Further functional analysis revealed that the TUG1 rs2240183 C allele exhibited higher transcriptional activity and TUG1 expression levels (P < 0.01). The ChIP assay showed that the rs2240183 C allele binds to transcriptional factor GATA‐1. These findings indicate that the rs2240183 C allele was associated with a higher risk of IS possibly by binding to GATA‐1 and elevating TUG1 levels.

Type 2 diabetes in midlife and risk of cerebrovascular disease in late life: a prospective nested case−control study in a nationwide Swedish twin cohort

Article

Full-text available

Aug 2019
DIABETOLOGIA

Aims/hypothesis: We aimed to examine the association between midlife type 2 diabetes mellitus and cerebrovascular disease (CBD) in late life, and further to explore whether genetic and early-life familial environmental factors (such as shared childhood socioeconomic status and adolescent environment) play a role in this association. Methods: In this prospective nested case-control study based on the Swedish Twin Registry, 33,086 twin individuals who were born in 1958 or earlier and were CBD-free before the age of 60 were included. Midlife (40-59 years) type 2 diabetes was ascertained from self-report, the National Patient Registry (NPR) and glucose-lowering medication use. CBD diagnosis (cerebral infarction, occlusion of cerebral arteries, subarachnoid haemorrhage, intracerebral haemorrhage and unspecified CBD) and onset age were identified from the NPR. Late-life CBD was defined as CBD onset age ≥60 years. Generalised estimating equation (GEE) models were used to analyse unmatched case-control data (adjusted for the clustering of twins within a pair). Conditional logistic regression was used in co-twin matched case-control analyses in CBD-discordant twin pairs. Results: Of all the participants, 1248 (3.8%) had midlife type 2 diabetes and 3121 (9.4%) had CBD in late life. In GEE models adjusted for age, sex, education, BMI, smoking, alcohol consumption, marital status, hypertension and heart disease, the ORs (95% CIs) of type 2 diabetes were 1.29 (1.03, 1.61) for cerebral infarction, 2.03 (1.20, 3.44) for occlusion of cerebral arteries, 0.52 (0.12, 2.21) for subarachnoid haemorrhage and 0.78 (0.45, 1.36) for intracerebral haemorrhage. In multi-adjusted conditional logistic regression, the OR of the type 2 diabetes-cerebral infarction association was 0.96 (0.51, 1.80). The differences in ORs from the GEE and co-twin control analyses were not statistically significant (p = 0.780). Conclusions/interpretation: Midlife type 2 diabetes is significantly associated with increased risk of cerebral infarction and occlusion of cerebral arteries, but not intracerebral haemorrhage or subarachnoid haemorrhage in late life. Genetic and early-life familial environmental factors do not appear to account for the type 2 diabetes-cerebral infarction association, but further clarification is needed.

De la genética a la prevención del ictus

Article

Jan 1999
REV NEUROLOGIA

José Berciano

Genetic testing for Mendelian stroke due to cerebrovascular anomalies and other syndromes

Article

Full-text available

Sep 2018

Stroke is defined as a focal or at times global neurological impairment of sudden onset and presumed vascular origin. 85% of strokes are due to cerebral ischemia and the other 15% to primary intracerebral hemorrhage. Ischemic stroke (IS) is characterized by complete or partial obstruction of a vessel in the brain, resulting in lack of blood supply and death of brain tissue. The most common causes of IS are atherosclerosis, cardioembolism and small-vessel disease (lacunar stroke). Genetic factors play important role. Incidence rates for IS in the 15- to 45-year age range are ≈10 per 100,000 person years. Hemorrhagic stroke (HS) is the least treatable and the most fatal form of cerebrovascular disease. Genetic mechanisms play a role in its development. Occurrence depends on many risk factors, including hypertension, heavy alcohol intake and anticoagulant treatment. According to the World Health Organization, 15 million people suffer stroke worldwide each year. The overall incidence of spontaneous HS worldwide is 24.6 per 100,000 person years. Strokes are the third most common cause of death and the most common cause of disability in developed countries. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Genetics of stroke recovery: BDNF val66met polymorphism in stroke recovery and its interaction with aging

Article

Aug 2018

Stroke leads to long term sensory, motor and cognitive impairments. Most patients experience some degree of spontaneous recovery which is mostly incomplete and varying greatly among individuals. The variation in recovery outcomes has been attributed to numerous factors including lesion size, corticospinal tract integrity, age, gender and race. It is well accepted that genetics play a crucial role in stroke incidence and accumulating evidence suggests that it is also a significant determinant in recovery. Among the number of genes and variations implicated in stroke recovery the val66met single nucleotide polymorphism (SNP) in the BDNF gene influences post-stroke plasticity in the most significant ways. Val66met is the most well characterized BDNF SNP and is common (40-50 % in Asian and 25-32% in Caucasian populations) in humans. It reduces activity-dependent BDNF release, dampens cortical plasticity and is implicated in numerous diseases. Earlier studies on the effects of val66met on stroke outcome and recovery presented primarily a maladaptive role. Novel findings however indicate a much more intricate interaction between val66met and stroke recovery which appears to be influenced by lesion location, post-stroke stage and age. This review will focus on the role of BDNF and val66met SNP in relation to stroke recovery and try to identify potential pathophysiologic mechanisms involved. The effects of age on val66met associated alterations in plasticity and potential consequences in terms of stroke are also discussed.

Morphogenetic Variability and Hypertension in Ischemic Stroke Patients—Preliminary Study

Article

Full-text available

Jun 2018

In this study, we evaluated and compared the morphogenetic variability and the degree of recessive homozygosity in patients with manifested ischemic stroke compared to healthy controls. We have evaluated 120 patients with manifested ischemic stroke, of which 64 did not have hypertension and 56 have hypertension. For comparison, we additionally tested 194 healthy individuals without manifested ischemic stroke (controls). For the estimation of the degree of recessive homozygosity, we have performed the homozygously recessive characteristics (HRC) test and tested 19 HRCs. There was a significant difference in the individual variations of 19 HRCs between the controls and patients with manifested ischemic stroke (∑χ2 = 60.162, p < 0.01). The mean values of the tested HRCs significantly differed between the controls and group with manifested ischemic stroke (Controls − 5.71 ± 1.61, Ischemic stroke group − 6.25 ± 1.54, p = 0.012). For the tested individuals with hypertension, the mean values of HRCs did not significantly differ between the controls and those that had manifested ischemic stroke (Controls − 5.28 ± 1.75, Ischemic stroke group − 5.64 ± 1.48, p = 0.435). We found a significant difference in the frequencies of HRCs between those with and without hypertension for controls (p < 0.003) and for those with manifested ischemic stroke (p < 0.001). There are increased degrees of recessive homozygosity along with decreased variability in patients with manifested ischemic stroke compared to controls.

Identification of nine genes as novel susceptibility loci for early‑onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage

Article

Full-text available

May 2018

Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies (GWASs) have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders remain to be identified definitively. We performed exome-wide association studies (EWASs) to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in early-onset subjects with these conditions. A total of 6,649 individuals aged ≤ 65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6,224 individuals (450 subjects with ischemic stroke, 5,774 controls) or 6,179 individuals (261 subjects with ICH, 176 subjects with SAH, 5,742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. The association of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher’s exact test, and 31 SNPs were significantly (FDR < 0.05) associated with ischemic stroke. The association of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher’s exact test, and six or two SNPs were significantly associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P< 0.0004 (0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P< 0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous GWASs, we identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Therefore, to the best of our knowledge, we have newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.

Роль генетических факторов в формировании индивидуальной предрасположенности к ишемическому инсульту

Article

Full-text available

Feb 2016

Интенсивное развитие технологий анализа ДНК и масштабные исследования полногеномных ассоциаций привели к накоплению большого массива данных о связи генетических факторов с различными фенотипическими проявлениями, в т.ч. с моногенными и полигенными наследственными заболеваниями. Благодаря этому значительно расширились возможности клинической диагностики и предиктивной медицины в области социально значимых заболеваний. Так, в настоящее время активно развиваются исследования генетического компонента в формировании риска развития такого многофакторного и полиэтиологического заболевания, как инсульт. В крупномасштабных исследованиях выявлены как общие, так и специфические генетические маркеры, ассоциированные только с инсультом определенного типа и подтипа. В настоящем обзоре проведен анализ современного состояния проблемы использования генетических маркеров для диагностики предрасположенности к инсульту, сложных вопросов, связанных с множественностью факторов риска инсульта, а также возможных путей развития данного направления.

The association of IL-17A polymorphisms with IL-17A serum levels and risk of ischemic stroke

Article

Full-text available

Oct 2017

The aim of our study was to investigate the association of interleukin-17A (IL-17A) polymorphisms with IL-17A serum levels and risk of ischemic stroke (IS) in a Chinese population. 392 IS patients and 443 controls were included in this study. The polymorphisms of IL-17A gene were determined by Snapshot SNP genotyping assay and DNA sequencing. Serum IL-17A levels were measured by enzyme-linked immunosorbent assay (ELISA). We found that the G allele, GA and GG genotypes, and GA/GG vs. AA model of rs2275913 polymorphism were associated with increased risk of IS even after adjusted by clinical characters such as age, gender and diabetes (G vs. A: OR=1.27, 95% CI, 1.05∼1.54, P=0.014; GA vs. AA: OR=1.72, 95% CI, 1.05∼2.81, P=0.032; GG vs. AA: OR=1.99, 95% CI, 1.08∼3.67, P=0.028; GA/GG vs. AA: OR=1.78, 95% CI, 1.11∼2.86, P=0.017). Serum IL-17A levels were increased in IS patients compared with controls (P<0.01). Individuals carrying rs2275913 GA or GG genotype present higher serum IL-17A levels compared with the rs2275913AA genotype in the IS group (P<0.01). In conclusion, this is the first study reporting the rs2275913 polymorphism as a risk factor for IS, which may be partly explained by influencing the levels of IL-17A cytokine.

HIV infection, hypercoagulability and ischaemic stroke in adults at the University Teaching Hospital in Zambia: A case control study

Article

Full-text available

May 2017
BMC INFECT DIS

Background In Zambia, 14.2% of adults have HIV/AIDS. There has been a substantial and significant increase in patients hospitalized for ischaemic stroke with co-existing HIV infection. However, little is known about the mechanism of stroke in these HIV + ve patients let alone studied in our region. The aim of this pilot study was to explore the association of hypercoagulability state in HIV + ve patients with ischaemic stroke. This was achieved by comparing hypercoagulability state markers between HIV + ve ischaemic stroke patients with HIV-ve and HIV + ve patients with and without ischaemic stroke respectively. Methods A matched case control study in which a total of 52 HIV + ve patients with ischaemic stroke were prospectively compared with control groups for the presence of protein S, protein C deficiencies and hyperhomocysteinaemia. The control groups comprised an equal number of consecutively matched for age and sex HIV-ve and HIV + ve patients with and without ischaemic stroke respectively. Data was analysed in contingency tables using Paired t- test, Chi square and conditional logistic regression. Results Ischaemic stroke of undetermined aetiology occurred more frequently in HIV + ve compared to HIV-ve patients (p < 0.001). In addition, protein S deficiency and Hyperhomocysteinaemia were more prominent in HIV + ve than HIV-ve ischaemic stroke patients (P = 0.011). There was no difference in the presence of hyperhomocysteinaemia or protein S deficiency in HIV + ve patients with or without ischaemic stroke. Protein C deficiency was not noted to be significantly different between the cases and the two control arms. Conclusion Protein S deficiency and hyperhomocysteinaemia were associated with HIV infection, but not stroke in our study population. However, this is an area that requires extensive research and one that we cannot afford to ignore as it is an important bridge to all cardiovascular and cerebrovascular diseases.

Association between the 20210G>A prothrombin gene polymorphism and arterial ischemic stroke in children and young adults – two meta-analyses of 3586 cases and 6440 controls in total

Article

Jan 2017

Background: Previous data have shown that the 20210G>A polymorphism of the Factor II gene is related to an increased prothrombin level, which may in turn lead to a procoagulant state. The heterogeneous and multifactorial character of arterial ischemic stroke often results in contradictory reports describing the association between the 20210G>A polymorphism and arterial ischemic stroke in different populations. We performed a meta-analysis of available data addressing the relation between the FII 20210G>A polymorphism and arterial ischemic stroke, both in young adults and children. Methods: We searched PubMed using appropriate keywords. The inclusion criteria for the study were as follows: case-control study, study population consisting of children, study population consisting of young adults, arterial ischemic stroke confirmed by magnetic resonance imaging or computed tomography, and English language. The exclusion criteria included lack of genotype or allele frequencies, study design other than a case-control study, outcome definition other than arterial ischemic stroke, and previously overlapped patient groups. Finally, 30 case-control studies (14 in children and 16 in young adults) were included. Statistical analyses were conducted using R software. Heterogeneity between the studies was evaluated using the Dersimonian and Laird's Q test. In the case of significant between-studies heterogeneity, the pooled odds ratio was estimated with a random-effects model, otherwise a fixed-effects model was used. Results: The pooled analysis showed that carriers of 20210A allele (GA+AA genotypes) of the prothrombin gene are more common in arterial ischemic stroke patients, both in children and young adults, than in control subjects (P = 0.006; odds ratio, 1.83; 95% confidence interval, 1.19 to 2.80 and P = 0.001; odds ratio, 1.69; 95% confidence interval, 1.25 to 2.28, respectively). Conclusions: The results of the present meta-analysis have proven that the FII 20210G>A polymorphism is associated with arterial ischemic stroke in both pediatric and young adult patients.

Association of GWAS-Supported Variants rs556621 on Chromosome 6p21.1 with Large Artery Atherosclerotic Stroke in a Southern Chinese Han Population

Article

Full-text available

Mar 2017

Recent genome-wide association study associated rs556621 on chromosome 6p21.1 with the risk of large artery atherosclerotic (LAA) stroke in Caucasians. However, subsequent replicate studies showed conflict results in different ethnicities. This study aimed to evaluate whether rs556621 was associated with LAA stroke in Chinese Han population. In this case–control study, 659 patients with LAA stroke and 650 healthy controls were enrolled. Associations between rs556621 genotypes and LAA stroke were analyzed with logistic regression model. Rs556621 variants were associated with increased risks of LAA stroke (codominant model: OR 1.42; 95 % CI 1.01–1.99; P = 0.010; recessive model: OR 1.40; 95 % CI 1.05–1.86; P = 0.003). When subjects were stratified by sex, TT genotype of SNP rs556621 was associated with an increased risk of LAA stroke in female when tested with recessive model (OR 2.36; 95 % CI 1.28–4.36, P = 0.006). In male subjects, however, no significant association was detected. Smoking status, sex did not significantly influence the relationship between genotypes of rs556621 and risk of LAA stroke (Pinteraction = 0.140, Pinteraction = 0.076). Rs556621 may play an important role in the development of LAA stroke in female Chinese of Han ethnicity. Larger studies with subjects of different ethnicities are warranted to confirm these findings.

A Novel Association of the Suppressor of Cytokine Signaling 1 (SOCS1) Gene Polymorphisms in Ischemic Stroke Patients

Article

Full-text available

Dec 2016

Ischemic stroke is a common neurological disease and a leading cause of permanent disability in many countries. Recent studies provide evidence on the role of the suppressor of the cytokine signaling 1 (SOCS1) gene in the development and progression of atherosclerotic lesions. However, few studies have assessed the association between single nucleotide polymorphisms (SNPs) on SOCS1 gene and ischemic stroke. Therefore, the present study aimed to investigate the role of SOCS1 polymorphism in ischemic stroke risk in a northern Chinese Han population. We examined 475 patients with ischemic stroke and 486 normal controls. Three SNPs (rs243327, rs243330, and rs33932899) of SOCS1 gene were determined for TaqMan genotyping assays. We also classified these case samples in depth by complications with hypertension or diabetes and by ischemic stroke subtypes. When adjusting models by multiple factor analysis by logistic regression, then calculated 10,000 permutations were performed for each model to correct the multiple test. Under additive model, the rs243327 was associated with ischemic stroke with hypertension (p = 0.047). Under heterozygous model, the rs33932899 and rs243330 were significantly associated with ischemic stroke subtypes by atherosclerosis (p = 0.038, p = 0.048, respectively). In summary, our data demonstrated for the first time that the polymorphisms of the SOCS1 gene are associated with the risk of ischemic stroke in a northern Chinese Han population, suggesting that SOCS1 gene polymorphisms may play an important role in the pathogenesis of ischemic stroke.

Familial Occurrence and Heritability of Stroke

Chapter

Apr 2024

Clustering of clinical strokes among related family members is an indication of the aggregate genetic, environmental, and lifestyle factors shared by these family members, all of which could increase susceptibility to stroke. A family history of stroke or other atherosclerotic events, such as a myocardial infarction, is a moderate risk factor for stroke, as observed in twin, cohort, and case-control studies (Flossmann et al., Stroke 35(1):212–227, 2004). With the exception of some rare Mendelian disorders, most stroke occurring in a clinical or population sample has a complex inheritance pattern, but the relative importance of genetic factors can be estimated by studying the familial occurrence of stroke. Patterns of familial aggregation can also help prioritize which subgroups to investigate further as more likely to share common underlying genetic variation; thus we could define subgroups by age, sex, ethnicity, presence of vascular risk factors, or stroke subtype (Yates, Lancet 1(7324):65–69, 1964; Marshall, J Med Genet 8(1):84–89, 1971). Focused investigations within these subgroups using modern genotyping techniques (phenotyping ‘splitting’) can increase the yield in identifying gene variants associated with stroke (NINDS Stroke Genetics Network and International Stroke Genetics Consortium, Lancet Neurol 15:174–184, 2016; Lancet Neurol 15(7):695–707, 2016). As a predisposing risk factor, family history can be used clinically for risk prediction and to encourage primary disease prevention (Banerjee, Int J Clin Pract 66(6):536–543, 2012). Polygenic risk scores are being developed to complement family history, but need further study to clinically implement for stroke risk prediction.

Genetic and Nongenetic Components of Stroke Family History: A Population Study of Adopted and Nonadopted Individuals

Article

Full-text available

Oct 2023

Background Genetic and nongenetic factors account for the association of family history with disease risk. Comparing adopted and nonadopted individuals provides an opportunity to disentangle those factors. Methods and Results We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495 640 UK Biobank participants (mean age, 56.5 years; 55% women) stratified by childhood adoption status (5747 adoptees). We estimated hazard ratios (HRs) per affected family member, and for polygenic risk scores in Cox models adjusted for baseline age and sex. A total of 12 518 strokes and 23 923 MIs occurred over a 13‐year follow‐up. In nonadoptees, family history of stroke and heart disease was associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR, 1.16 [95% CI, 1.12–1.19]) and family history of heart disease for incident MI (HR, 1.48 [95% CI, 1.45–1.50]). In adoptees, family history of stroke associated with incident stroke (HR, 1.41 [95% CI, 1.06–1.86]), but family history of heart disease was not associated with incident MI ( P >0.5). Polygenic risk scores showed strong disease‐specific associations in both groups. In nonadoptees, the stroke polygenic risk score mediated 6% risk between family history of stroke and incident stroke, and the MI polygenic risk score mediated 13% risk between family history of heart disease and incident MI. Conclusions Family history of stroke and heart disease increases risk for their respective conditions. Family history of stroke contains substantial potentially modifiable nongenetic risk, indicating a need for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.

Genetic and non-genetic components of family history of stroke and heart disease: a population-based study among adopted and non-adopted individuals

Preprint

Jun 2023

Background: It is increasingly clear that genetic and non-genetic factors account for the association of family history with disease risk in offspring. We sought to distinguish the genetic and non-genetic contributions of family history of stroke and heart disease on incident events by examining adopted and non-adopted individuals. Methods: We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495,640 participants of the UK Biobank (mean age 56.5 years, 55% female) stratified by early childhood adoption status into adoptees (n=5,747) and non-adoptees (n=489,893). We estimated hazard ratios (HRs) per affected nuclear family member, and for polygenic risk scores (PRS) for stroke and MI in Cox models adjusted for baseline age and sex. Results: 12,518 strokes and 23,923 MIs occurred over a 13-year follow-up. In non-adoptees, family history of stroke and heart disease were associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR 1.16 [1.12, 1.19]) and family history of heart disease for incident MI (HR 1.48 [1.45, 1.50]). In adoptees, family history of stroke associated with incident stroke (HR 1.41 [1.06, 1.86]), but family history of heart disease did not associate with incident MI (p>0.5). PRS showed strong disease-specific associations in adoptees and non-adoptees. In non-adoptees, the stroke PRS mediated 6% risk between family history of stroke and incident stroke, and the MI PRS mediated 13% risk between family history of heart disease and MI. Conclusions: Family history of stroke and heart disease increase risk for their respective conditions. Family history of stroke contains a substantial proportion of potentially modifiable non-genetic risk, indicating a need for further research to elucidate these elements for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.

10-International-Trakya-Family-Medicine-Congress-Proceedings-Book(1)

Article

Full-text available

Jul 2021

Gazmend Bojaj

Medical Informatics in Primary care in kosovo

Association of Genetic Variation in a Wnt Signaling Pathway Gene ( β-Catenin ) with Susceptibility to Leukoaraiosis

Article

Nov 2020

Aim: Blood-brain barrier (BBB) disruption is the primary initiating cause of cerebral small-vessel diseases including leukoaraiosis (LA). β-Catenin is a key regulator of the BBB and plays an important role in cell-cell adhesion at adherens junctions by interacting with cadherin molecules. Thus, β-Catenin may be a good candidate gene for LA. We performed a genetic analyses to investigate the association between β-catenin alleles and LA. Materials and Methods: A total of 339 LA cases and 203 controls were enrolled from individuals who underwent brain magnetic resonance imaging with obtainable vascular risk factors. Genotyping of β-catenin single nucleotide polymorphisms (SNPs), including rs1880481 C > A, rs13072632 C > T, and rs4135385 A > G, was performed by real-time polymerase chain reaction using a LightCycler 2.0. Results: Two SNPs, rs1880481 and rs4135385, showed significant differences in their allelic frequencies between the control and LA groups and the combinatorial effects of the risk alleles for these two SNPs also significantly increased the risk of LA. The G-T-A, A-T-A, and A-T-G haplotypes for the three SNPs showed significant differences in both types of LA: LA-periventricular white matter and LA-deep white matter. However, the C-T-G haplotype was only significantly different for LA-PVWM, while the A-C-A was only significantly different for LA-DWM. The combination of diabetes mellitis, hypertension, and these risk alleles increased the likelihood of both types of LA. Conclusion: This study provides evidence that β-catenin polymorphisms and their associated haplotypes are associated with susceptibility to LA.

The Relationship between Serum Vitamin D Level, Ischemic Stroke Severity and Lesion Volume in Ischemic Stroke Patients in Iran, 2019: An Analytic Cross-sectional Study

Article

Full-text available

Aug 2020

Vitamin D deficiency is a major global problem. The relationship between serum vitamin D level, ischemic stroke severity, and the resulted lesion volume is controversial. This study is aimed at investigating the relationship between serum vitamin D level, severity of ischemic stroke, and lesion volume compared to the control group. This analytic cross-sectional study was performed on 93 ischemic stroke patients compared to the control group during 2019. Brain imaging, lesion volume measuring, and record were performed for all patients. Severity of stroke was assessed by MRS score at the time of admission and discharge. Serum 25(OH) D levels were measured by enzyme-linked immunosorbent assay (ELISA). In the end, the data were analyzed by SPSS19 software. The mean ±standard deviation of vitamin D was 28.78±9.5 ng.ml-1 with the range of (10-49) in patients, and 29.11±8.7 with range of (12-51) in control group. Vitamin D level significantly decreased depending on age (P=0.003). The mean vitamin D levels had a significant negative relationship with the first and second MRS scores (P<0.001). Mean vitamin D levels had a significant negative relationship with the severity of stroke and lesion volume (P<0.001). Reduced vitamin D serum level is associated with higher severity of stroke and lesion volume.

The Clinical Effectiveness of Frequently Used Herbal Medicines for Cerebrovascular Disease: A Retrospective Study

Article

Dec 2019

Molecular basis of stroke

Chapter

Jan 2020

Yoshiji Yamada

Association between MTHFR Gene Polymorphism (C677T) and Coronary Artery Disease

Article

Full-text available

Jan 2019

Background and purpose: Coronary artery disease (CAD) is a complex disease that is caused by both environmental and genetic factors. Methylenetetrahydrofolate (MTHFR) enzyme is associated with metabolism of homocysteine and its impaired function is considered as a risk factor for developing CAD. Some variants are involved in decreased activity of MTHFR and its deficiency. The polymorphism of C677T (rs1801133) seems to be a significant variant that is related with CAD. The purpose of this study was to determine the relationship between MTHFR C677T gene polymorphism and susceptibility of CAD. Materials and methods: This case-control study was performed in 71 patients with coronary artery disease and 71 healthy subjects (control group). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to genotype MTHFR polymorphism. Results: The mean ages of subjects in case and control groups were 58.2±8.9 and 46±13.9 years, respectively (P= 0.0000). The case group included 37 (52.1%) males and 34 (47.9%) females. In control group, there were 38 (53.5%) males and 33 (46.5%) females. The frequency of CC, CT, and TT genotypes in C677T polymorphisms was 59.2%, 35.2%, and 5.6%, in CAD patients and 62%, 32.4%, and 5.4%, in controls, respectively, indicating no significant differences between the cases and controls (p= 0.937). The frequency of T allele was 40.8% in cases and 38% in controls which also showed no significant difference between the two groups (P= 0.864). Conclusion: Current study found no relationship between MTHFR C677T gene polymorphism and CAD. However, further studies in larger population are recommended to achieve better understand this relationship.

Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: Cohort study of 306 473 UK Biobank participants

Article

Full-text available

Oct 2018

Objective To evaluate the associations of a polygenic risk score and healthy lifestyle with incident stroke. Design Prospective population based cohort study. Setting UK Biobank Study, UK. Participants 306 473 men and women, aged 40-73 years, recruited between 2006 and 2010. Main outcome measure Hazard ratios for a first stroke, estimated using Cox regression. A polygenic risk score of 90 single nucleotide polymorphisms previously associated with stroke was constructed at P<1×10 ⁻⁵ to test for an association with incident stroke. Adherence to a healthy lifestyle was determined on the basis of four factors: non-smoker, healthy diet, body mass index <30 kg/m ² , and regular physical exercise. Results During a median follow-up of 7.1 years (2 138 443 person years), 2077 incident strokes (1541 ischaemic stroke, 287 intracerebral haemorrhage, and 249 subarachnoid haemorrhage) were ascertained. The risk of incident stroke was 35% higher among those at high genetic risk (top third of polygenic score) compared with those at low genetic risk (bottom third): hazard ratio 1.35 (95% confidence interval 1.21 to 1.50), P=3.9×10 ⁻⁸ . Unfavourable lifestyle (0 or 1 healthy lifestyle factors) was associated with a 66% increased risk of stroke compared with a favourable lifestyle (3 or 4 healthy lifestyle factors): 1.66 (1.45 to 1.89), P=1.19×10 ⁻¹³ . The association with lifestyle was independent of genetic risk stratums. Conclusion In this cohort study, genetic and lifestyle factors were independently associated with incident stroke. These results emphasise the benefit of entire populations adhering to a healthy lifestyle, independent of genetic risk.

Significant association between paraoxonase 1 rs662 polymorphism and coronary heart disease: A meta-analysis in the Chinese population

Article

Aug 2018

Background A growing number of studies have suggested that the single nucleotide polymorphism (SNP) rs662 (G>A) in paraoxonase 1 (PON1) is significantly associated with susceptibility to coronary heart disease (CHD) in the Chinese population. To further evaluate the effects of the PON1 RS662 (G>A) polymorphism on the risk of CHD, we performed a meta-analysis in a Chinese population. Methods PubMed, Embase, Wanfang Data, Chinese National Knowledge Infrastructure (CNKI) were searched to identify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations between RS662 (G>A) and CHD. Result In the meta-analysis, we identified 14 articles, including a total of 4835 CHD patients and 5111 controls in the Chinese population. Our result showed that overall rs662 (G>A) was significantly associated with susceptibility to CHD in the Chinese population when compared with healthy controls. Furthermore, a G allele suggested an elevated risk of CHD. In the subgroup analyses stratified by ethnicity and geographic areas, significant associations were found in Chinese Han and South China, but not in North China. Conclusion The present meta-analysis suggests that rs662 (G>A) SNP in PON1 is associated with CHD risk; the G allele might be the risk allele for CHD susceptibility in the Chinese population. However, more research is required to make a definite conclusion.

Association of ABCG 2 polymorphisms with ischemic stroke in a Chinese population

Article

Jun 2018

ATP‐binding cassette, superfamily G, member 2 (ABCG2) has been shown to play an important role in the development of ischemic stroke in European and African American populations. The aim of the present study is to test the hypothesis that there are associations between ABCG2 polymorphisms and ischemic stroke risk in a Chinese population. We conducted a case–control study including 967 participants with ischemic stroke and 939 stroke‐free controls. The rs2231137C > T and rs2231142G > T were genotyped using a TaqMan real‐time polymerase chain reaction assay. We found the rs2231137C > T and rs2231142G > T in ABCG2 were significantly associated with ischemic stroke (sex‐, age‐, BMI‐, SBP‐, DBP‐adjusted OR = 1.252; 95% CI, 1.035–1.515; P‐value = 0.021 and OR = 1.526; 95% CI, 1.085–2.146; P‐value = 0.015, respectively). By haplotype analyses, the haplotype T‐G still had a strongly significant association with ischemic stroke (OR = 0.806; 95% CI, 0.692–0.939; P‐value = 0.00568). Our findings identified the rs2231137C > T and rs2231142G > T polymorphisms of the ABCG2 as risk factors for ischemic stroke in a Chinese population.

Genetics and Genomics of Stroke

Chapter

Jan 2018

Stroke is defined as the acute onset of focal neurological disturbance arising due to a cerebrovascular cause, confirmed histopathologically or on imaging, where other causes have been excluded. Strokes may either be ischaemic (approximately 80% of cases) or haemorrhagic (20%). Although often thought of as a single disease, stroke represents the end stage of many different pathologies, each of which can result in cerebral ischaemia and/or haemorrhage. Therefore when investigating a stroke patient, investigations are performed to identify the underlying cause. Most cases of ischaemic stroke are caused by one of three pathologies: large vessel atherosclerotic disease (LVD), cerebral small vessel disease (SVD) or cardioembolism, although there are multiple rarer causes including cervical artery dissection. However, even with detailed investigation an underlying cause cannot be found in approximately a quarter of all ischaemic strokes. Haemorrhagic strokes are categorized according to the brain region they arise from; lobar or cortical haemorrhages are commonly caused by cerebral amyloid angiopathy, or an underlying structural lesion for example an arteriovenous malformation. Subcortical haemorrhages are usually associated with hypertension and believed to be often a manifestation of SVD.

Familial Occurrence and Heritability of Stroke

Chapter

Jul 2017

Clustering of clinical strokes among related family members is an indication of the aggregate genetic, environmental, and lifestyle factors shared by these family members, all of which could increase susceptibility to stroke. A family history of stroke or of other atherosclerotic events, such as a myocardial infarction, is a moderate risk factor for stroke, as observed in twin, cohort, and case-control studies [1]. With the exception of some rare Mendelian disorders, most stroke occurring in a clinic or population sample has a complex inheritance pattern, but the relative importance of genetic factors can be estimated by studying the familial occurrence of stroke. Patterns of familial aggregation can also direct which subgroups to investigate further as more likely to share common underlying genetic variation; thus we could define subgroups by age, gender, ethnicity, presence of vascular risk factors, or stroke subtype [2, 3]. Focused investigations within these subgroups using modern genotyping techniques (phenotyping ‘splitting’) can increase the yield in identifying gene variants associated with stroke [4, 5]. As a predisposing risk factor, family history can be used clinically for risk prediction and to encourage primary disease prevention [6].

Association of GWAS-Reported Variant rs11196288 near HABP2 with Ischemic Stroke in Chinese Han Population

Article

Full-text available

Jun 2017
J MOL NEUROSCI

A recent genome-wide association analysis identified a novel single nucleotide polymorphism locus on chromosome 10q25.3 (rs11196288, near HABP2) associated with the risk of early-onset ischemic stroke (IS) in European population, but not with late-onset IS. However, the role of this genome-wide association study (GWAS)-reported variant in ischemic stroke in Chinese Han population remained unknown. In our study, 389 adult ischemic stroke patients with an age of onset <60 years and 389 matched healthy controls were enrolled to investigate association of rs11196288 genotypes with early-onset ischemic stroke and its subtypes; the association was further examined in another independent population consisting of 349 ischemic stroke patients with an age of onset ≧60 years and 349 matched healthy individuals. Logistic regression analysis showed no significant association between rs11196288 and early-onset ischemic stroke (IS), large artery atherosclerotic (LAA) stroke, or small vessel disease (SVD) stroke (all P > 0.050). Nevertheless, in subgroup analysis of the older population, rs11196288 presented significant effect on late-onset SVD stroke susceptibility in the dominant model (GG/GA vs AA, OR 1.70; 95%CI 1.02 to 2.85; P = 0.042). The results indicated that the role of rs11196288 polymorphism in ischemic stroke susceptibility in Chinese Han population may be different from that in European. Larger studies with diverse populations are warranted to confirm and extend our findings.

Zerebrale Ischämie

Chapter

Jan 1999

Das Gehirn, das etwa 2% des gesamten Körpergewichts wiegt, wird von knapp 20% des Herzminutenvolumens durchströmt, es verbraucht dabei etwa 20% des Sauerstoffs des Körpers. Bei einem respiratorischen Quotienten von nahezu 1 wird der Energiebedarf des Gehirns unter Ruhebedingungen praktisch ausschließlich durch oxidative Phosphorylierung gewonnen, wobei das Gehirn pro Tag etwa 75 1 molekularen Sauerstoff und 120 g Glukose verbraucht. Das Gehirn hat damit einen außerordentlich hohen Bedarf an Sauerstoff und Glukose. Unterbrechungen der Substratzufuhr durch Mangeldurchblutung („zerebrale Ischämie“) führen deshalb innerhalb sehr kurzer Zeit zu Symptomen und zu reversiblen („funktionellen“) bzw. irreversiblen („strukturellen“) Schäden. Abhängig vom Grad der Einschränkung der zerebralen Perfusion kommt es zum Zusammenbruch wichtiger metabolischer Funktionen, wobei die Proteinsynthese am empfindlichsten ist (Abb. 3.7.1).

Dépression post Accident Vasculaire Cérébral au CHU de Brazzaville

Article

Mar 2017
REV NEUROL-FRANCE

Introduction La depression est l’une des complications des AVC les moins documentees en Afrique. Objectifs Le but de cette etude etait de decrire les aspects epidemiologiques, cliniques et therapeutiques de la depression post-AVC. Patients et methodes Nous avons realise une etude de cohorte de 77 patients atteints d’hemiplegie vasculaire, sur 6 mois, dans les services de neurologie et reeducation fonctionnelle de Brazzaville. La depression a ete evaluee par le questionnaire de Beck, l’autonomie fonctionnelle et la qualite de vie, respectivement par l’index de Barthel et le Stroke Impact Scale. Un cahier d’observation a ete utilise pour obtenir des donnees socio-demographiques, cliniques et therapeutiques. Resultats Nous avons enregistre 3 deces au cours du 1er mois. Sur les 74 patients evalues, 73 (98,64 %) etaient deprimes. L’âge moyen etait de 56,50 ± 11,81 ans, le sex-ratio de 1,08. L’hemisphere gauche etait le plus atteint (52,78 %). L’evolution a 6 mois etait defavorable dans 56,51 % des cas. L’âge et la reprise de l’activite professionnelle, respectivement avec p = 0,01 et p = 0,007. Plus les patients etaient autonomes moins ils etaient deprimes (p < 0,001) et avaient une meilleure qualite de vie (p < 0,001). Discussion La depression survient precocement. Elle s’explique par le stress lie au sejour hospitalier, le caractere soudain et imprevu de l’installation du deficit, le desarroi et la grande inquietude qui entourent le patient et ses proches durant la phase aigue. La frequence de la depression post-AVC dans notre cohorte est elevee en raison de l’utilisation de l’echelle de Beck. Conclusion La prise en charge de la depression post-AVC permet d’ameliorer la qualite de vie des patients, elle requiert une prise en charge precoce.

Introduction to Stroke Genomics

Chapter

Oct 2004

Translation of the explosion in knowledge of acute ischemic stroke into satisfactory treatment regimens has yet to happen. At present tPA, intra-arterial prourokinase and low-molecular-weight heparin form the vanguard for therapeutic intervention, yet these treatments have a limited therapeutic window. Part of this expansion in understanding has been driven by the contribution of stroke genetics and genomics. However, despite the enormous preclinical and clinical information of receptors, enzymes, second messenger systems, and so forth, that are implicated in stroke pathophysiology, delivery of novel drug treatment has been slow. This introductory chapter discusses the multiple sources of clinical and preclinical genetic information. It will describe the importance of integrating expression information into multiple preclinical models with temporal and spatial roles in lesion pathology and, furthermore developing an understanding of function in the clinic before claiming a role in ischemic stroke. The goal of such a holistic integration of information is to increase the yield from current datasets of gene expression and ultimately to help expand the choice of treatment available to the physician and patient.

Practicalities of Genetic Studies in Human Stroke

Chapter

Jan 2004

Considerable evidence suggests genetic factors are important in the pathogenesis of multifactorial stroke. However, studies identifying the underlying genes have been largely disappointing. This chapter reviews the different approaches and their relative merits. It is likely stroke is a polygenic disorder and that underlying genes may interact within environmental risk factors. Stroke itself is a syndrome caused by a number of different pathologies, which may result from different genetic predispositions. Therefore accurate stroke subtyping is likely to be important in identifying genetic associations. Previous studies have suffered from small sample size, lack of adequate phenotyping, and poor case-control matching. The most popular approach to identifying genes in human polygenic ischemic stroke has been the candidate gene approach. The relative merits of this approach are discussed. More recently this has been extended to famly-based association studies. Linkage-based approaches have been used less although current studies are implementing the affected-sibling-pair method. In the future genome-wide association studies are likely to become more widely used.

Genetic Polymorphisms and Arterial Thrombosis

Chapter

Jan 1998

In Western countries, acute myocardial infarction and stroke, are major causes of morbidity and mortality (1). An occlusive coronary thrombus on an ulcerated atherosclerotic plaque in the coronary arteries is the central event in more than 90% of patients with Q-wave myocardial infarction (2). The underlying abnormality in non-Q-wave infarctions is a ruptured atherosclerotic plaque, which acts as a nidus for the deposition and activation of platelets. Atherosclerotic changes in the carotid and vertebrobasilar arteries resemble those of coronary arteries (3). These lesions may progress to local occlusions, but most often do not become symptomatic until embolization to more distal arteries takes place (ischemic stroke). In the cerebral arteries, vessel wall and lumen may be normal until the artery is occluded by an embolus from a more proximal arterial lesion or from the heart (4). Rather than to emboli, occlusion of the small penetrating arteries is often due to degenerative changes of the vessels or to extracranial large-artery disease (5).

Molecular Genetics of Stroke

Article

Mar 2012

Yoshiji Yamada

Stroke is an important clinical problem because of its large contribution to mortality. The main causal and treatable risk factors for stroke include hypertension, diabetes mellitus, dyslipidemia, and smoking. In addition to these risk factors, recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Genetic linkage analyses of families and sib-pairs as well as candidate gene association studies have implicated several loci and many candidate genes in predisposition to ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Recent genome-wide association studies identified various loci and genes that confer susceptibility to ischemic stroke or intracranial aneurysm. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Table of Contents: Introduction / Genetics of Stroke / Single-Gene Disorders Associated with Stroke / Genetics of Common Forms of Stroke / Clinical Implications / Conclusion / References / Titles of Related Interest

An rs4705342 T>C polymorphism in the promoter of miR-143/145 is associated with a decreased risk of ischemic stroke

Article

Full-text available

Oct 2016

The expression of miR-143/miR-145 was up-regulated in ischemic stroke (IS), which may be used as biomarkers and/or therapeutic targets for IS. We aimed to investigate the association of rs4705342 and rs4705343 polymorphisms in the promoter of miR-143/145 with risk of IS. The study population comprised 445 patients with IS and 518 controls. The rs4705342 genotype was analyzed by using a TaqMan Assay and the rs4705343 genotype was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Relative expression of miR-143/miR-145 was measured by quantitative real-time PCR. We found that the rs4705342 was associated with a decreased risk of IS (TC vs. TT: adjusted OR = 0.74, 95% CI, 0.57–0.97; CC vs. TT: adjusted OR = 0.53, 95% CI, 0.34–0.83). Haplotype analysis showed that the TC haplotype was associated with an increased risk of IS risk (OR = 1.33, 95% CI, 1.01–1.75), whereas the CT haplotype was associated with a decreased risk of IS risk (OR = 0.68, 95% CI, 0.50–0.92). Importantly, patients carrying the rs4705342TC/CC genotypes had a lower level of miR-145 (P = 0.03). We found for the first time that the rs4705342 CC was a protective factor for IS, probably by reducing the level of miR-145.

Epidemiology of Ischemic Stroke

Article

Nov 2016

Ischemic stroke is a heterogeneous multifactorial disorder recognized by the sudden onset of neurologic signs related directly to the sites of injury in the brain where the morbid process occurs. The evaluation of complex neurologic disorders, such as stroke, in which multiple genetic and epigenetic factors interact with environmental risk factors to increase the risk has been revolutionized by the genome-wide association studies (GWAS) approach. This article reviews salient aspects of ischemic stroke emphasizing the impact of neuroepidemiology and GWAS.

RhoA/Rho-Associated Kinase as Marker of Cardiovascular Health

Chapter

Sep 2016

Rho-associated coiled-coil kinase (ROCK) is a widely expressed intracellular signaling molecule. ROCK is the best-described downstream regulator of Rho and regulates numerous cellular functions such as division, migration, growth, and death. ROCK activity has been implicated in the development of various forms of cardiovascular disease including stroke, coronary artery disease, hypertension, and several others. While much effort has been devoted to the study of ROCK inhibitors and their potential role in the treatment of cardiovascular disease, a growing body of evidence suggests that HMG-CoA reductase inhibitors (statins) indirectly inhibit ROCK by preventing the necessary preceding step of Rho tethering to the plasma membrane. In this way, statins are believed to exert beneficial cholesterol-independent or “pleiotropic” effects. In the following chapter, we will discuss the molecular structure of ROCK, the regulation of the Rho/ROCK pathway, the role of Rho/ROCK in numerous forms of cardiovascular disease, and the available evidence implicating ROCK as a pharmaceutical target.

RhoA/Rho-Associated Kinase as Marker of Cardiovascular Health

Chapter

Jan 2015

Heritability of Cognitive Performance in Aging Twins The National Heart, Lung, and Blood Institute Twin Study

Article

Full-text available

Apr 1990
ARCH NEUROL-CHICAGO

The genetic contribution to performance on scales designed to measure mild to moderate decrements in cognitive functioning in a population at risk is unknown. In the present analysis, 134 monozygotic and 133 dizygotic male twin pairs (mean age, 63 years) were given three cognitive tests: the Mini-Mental State examination, the Iowa Screening Battery for Mental Decline, and, for comparison, the Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale. The primary objective of the analysis was to test for a significant heritable component to performance on these measures. A secondary objective was to determine the extent to which shared variance with significant confounders such as education, age, and depression affects the outcome of the heritability analysis. Results indicate that performance on tests intended to measure cognitive decline in the elderly does have a significant genetic component and that these estimates tend to increase after adjustment for covariates. Heritability estimates adjusted for covariates were 30% for the Iowa Screening score, 60% for the Mini-Mental State score, and 67% for the Digit Symbol Substitution score.

Twin studies: their use and limitations

Article

Jan 1976

A. Emery

Behavioral Genetics: A Primer

Book

Jan 1990

Behavior Genetics: A Primer

Book

Jan 1980

Heritability of cognitive performance in aging twins

Article

G. E. Swan

Human Behavioral Genetics of Aging

Article

Dec 1990

begins with a description of the recent history of research on the genetics of human behavioral aging, emphasizing the need for serious consideration of both genetic and environmental sources of individual differences among the elderly the second section illustrates the evolution of this research beyond simple nature-nurture comparisons, using as an example the newly emerging subdiscipline of developmental behavioral genetics the third section describes what is known about the genetics of psychological aging, emphasizing early results from the first large-scale behavioral genetic study of aging Swedish Adoption/Twin Study on Aging (SATSA) (PsycINFO Database Record (c) 2012 APA, all rights reserved)

Possibilities of a preventive approach to coronary heart disease starting in childhood

Article

Apr 1985
ACTA PAEDIATR

Pekka Puska

Promotion in youth of lifestyles that are likely to result in optimum levels of cardiovascular risk factors is the basis for early prevention of cardiovascular diseases and promotion of health. Health behaviour is closely linked to the general lifestyle of any community. Thus for any long-term major change, a community-based approach is essential. Experience from the North Karelia project indicates that through a comprehensive community-based programme, health behaviour and risk factor levels of a whole country could be changed, and that resulted in reduction of coronary heart disease (CHD) in the area. Studies among children carried out as part of the North Karelia project have shown that children's smoking rates and nutrition habits can be influenced and their serum cholesterol levels can be modified. At least in Finland, family-based practical counselling and provision of Social support seems to be an effective strategy in changing the nutrition habits of both adults and children. No evidence has been observed to indicate that this type of intervention would have any harmful emotional consequences among children. A study to show the impact of risk factor modification on coronary heart disease risk in adulthood is hardly feasible and, instead, studies to test the feasibility and effects of different intervention approaches for influencing health related behaviour and risk factors in children and adolescents should be emphasized.

Heritability Estimates from Twin Studies. I. Formulae of Heritability Estimates

Article

Feb 1978

Over the past 50 years a large number of methods have been proposed for estimating heritability from twin studies. The present paper describes the most commonly cited of these estimates as a first step in evaluating their usefulness. A critical review will then follow.

The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results

Article

Nov 1977
AM J EPIDEMIOL

Feinleib, M. (National Heart, Lung, and Blood institute, NIH, Federal Bldg., Room 2C08, Bethesda, MD 20014), R. J. Garrison, R. Fabsitz, J. C. Christian, Z. Hrubec, N. O. Borhani, W. B. Kannel, R. Rosenman, J. T. Schwartz and J. O. Wagner. The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results. Am J Epidemiol 106:284–295, 1977. Coronary heart disease (CHD) risk factors were studied in 250 monozygotic (MZ) and 264 dizygotic (DZ) male veteran twin pairs, aged 42–56. All coronary heart disease risk factors studied showed significant correlations in both MZ and DZ twins. Substantial genetic variation was detected for height, blood pressure, glucose intolerance, uric acid, plasma triglyceride, and relative weight but little or no significant genetic variability in low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), total plasma cholesterol or hematocrit was demonstrable. These findings suggest that familial aggregation results from genetic influence on blood pressure, glucose intolerance, uric acid, triglyceride and, possibly, obesity, while largely shared environmental factors contribute to familial similarities in HDL, LDL, total cholesterol and hematocrit.

The National Academy of Sciences--National Research Council Twin Registry: ten years of operation

Article

Feb 1978
Progr Clin Biol Res

Concordance for mortality with special reference to ischaemic heart disease and cerebrovascular disease. A Study on the Swedish Twin Registry

Article

Jan 1976

The Swedish Twin Registry contains about 11 000 same-sexed twin pairs born between 1886 and 1925 with both members alive when the registry was formed in 1961. During the years 1962 to 1973, 2780 deaths occurred. 727 deaths were due to ischaemic heart disease (IHD), 345 due to cerebrovascular disease (CVD), and 727 due to cancer. The rate of concordance for the whole twin population revealed a significantly (p < 0.05) higher concordance rate for IHD among the male monozygotic (MZ) pairs as compared to the dizygotic (DZ) pairs (15.8% versus 8.0%). The corresponding figures for the female pairs were 11.0% (MZ) and 7.5% (DZ), respectively. With regard to death in CVD and cancer, the rates of concordance were about the same for MZ and DZ pairs in both males and females. When subgrouping was made for age groups, the difference in concordance rate for IHD in males was still more pronounced for the younger age group, born 1901–1925, (16.1% versus 5.4%). These data may indicate the existence of a genetic determination on death in IHD, especially in males, whereas a genetic determination on death in CVD and cancer seems more uncertain.

Genetics of cerebrovascular disease

Article

Dec 1990

M J Alberts

Stroke is a complex disease, with both genetic and environmental factors having a role in its pathogenesis. A review of past studies shows some evidence of genetic influences in the development of stroke. This is supported by studies of cardiovascular disease, which indicate major genetic influences at several levels including the development of risk factors. New approaches to phenotypic classifications, patient ascertainment, and genetic analysis will stimulate research into the role of genetics in cerebrovascular disease.

The Response to Long-Term Overfeeding in Identical Twins

Article

Jun 1990

We undertook this study to determine whether there are differences in the responses of different persons to long-term overfeeding and to assess the possibility that genotypes are involved in such differences. After a two-week base-line period, 12 pairs of young adult male monozygotic twins were overfed by 4.2 MJ (1000 kcal) per day, 6 days a week, for a total of 84 days during a 100-day period. The total excess amount each man consumed was 353 MJ (84,000 kcal). During overfeeding, individual changes in body composition and topography of fat deposition varied considerably. The mean weight gain was 8.1 kg, but the range was 4.3 to 13.3 kg. The similarity within each pair in the response to overfeeding was significant (P less than 0.05) with respect to body weight, percentage of fat, fat mass, and estimated subcutaneous fat, with about three times more variance among pairs than within pairs (r approximately 0.5). After adjustment for the gains in fat mass, the within-pair similarity was particularly evident with respect to the changes in regional fat distribution and amount of abdominal visceral fat (P less than 0.01), with about six times as much variance among pairs as within pairs (r approximately 0.7). We conclude that the most likely explanation for the intrapair similarity in the adaptation to long-term overfeeding and for the variations in weight gain and fat distribution among the pairs of twins is that genetic factors are involved. These may govern the tendency to store energy as either fat or lean tissue and the various determinants of the resting expenditure of energy.

Carotid arteriosclerosis in identical twins discordant for cigarette smoking

Article

Aug 1989

From a nationwide twin panel, identical twin pairs with highest discordance in cigarette smoking were selected for a study of arteriosclerosis (49 pairs with a mean age of 52 years). Smoking history was obtained in 1975, 1981, and 1986. The mean life-long smoking dose of the smoking cotwins was 20 package-years. The smoking and nonsmoking cotwins had similar systolic and diastolic blood pressures, total plasma cholesterol level, body mass index, and some psychosocial factors; the only difference was found in use of alcohol, which was greater among smoking cotwins. Duplex sonography of carotid arteries was performed. Carotid artery stenoses (narrowing of area of the lumen with 15-60%) were found in nine pairs: in nine smoking twins and in two of their nonsmoking cotwins (p = 0.036). The total area of carotid plaques was 3.2 times larger in smoking cotwins (p less than 0.001). The thickness of the inner layer of carotid arteries was more marked in smoking cotwins (p less than 0.001). The size of plaques and the degree of inner layer thickening correlated with the dose of smoking (NS). The association of smoking with carotid arteriosclerosis was highly significant even after the adjustment for age, total plasma cholesterol level, diastolic blood pressure, and body mass index in multiple logistic regression analyses.

Cardiovascular risk factors in children and early prevention of heart disease

Article

Feb 1988

Clinical and anatomical observations from the Bogalusa Heart Study over a 15-year span provide data on cardiovascular risk factors and the early natural history of arteriosclerosis. These studies established that: cardiovascular risk can be predicted in early life; interrelationships of risk factors in children are similar to those observed in adults; and concentrations of serum lipoproteins change during sexual maturation. Strategies involving the general population and high-risk groups should be considered to help reduce atherosclerosis and coronary artery disease. Active modification of risk factors in the general populace would include using such methods as screening, education, and mass-media campaigns. Educational promotion ("Heart Smart") has already been implemented in the New Orleans area, focusing on using the total school environment to teach cardiovascular health and to encourage children to adopt desirable lifestyles. Inclusion of cardiovascular health education into general educational studies of children should be a major objective of the future.

Characteristics of Participants and Nonparticipants in the NHLBI Twin Study

Article

Feb 1988

The NHLBI Twin Study is a longitudinal study of cardiovascular disease risk factors in 514 pairs of white, middle aged, male, veteran twins. The initial examination took place between 1969-1973. Ten years later, 81% of the living cohort returned for a second examination. Data collected up to 30 years prior to recruitment for the initial examination were used to characterize participants and nonparticipants; data from the initial examination were used to characterize returnees and nonreturnees to the second examination. Participants had significantly lower diastolic blood pressure and higher socioeconomic status than nonparticipants as measured thirty years earlier. Between the first and second examinations, the mortality of participants was less than 50% of the mortality of nonparticipants. Returnees to the second examination had a better health profile at the initial examination than nonreturnees, with significantly lower levels of cigarette smoking, glucose intolerance, hypertension, and diabetes and higher levels of pulmonary function. However, returnees were more obese than nonreturnees. Thus, this study of cardiovascular disease risk factors in twins appears to be affected by response bias in a way similar to studies of individuals. Additional analyses of biases that may affect the genetic component of the study indicated that factors related to classical twin analyses were relatively unaffected by selection.

Mendelian etiologies of stroke

Article

Aug 1987

There are many genetic disorders associated with an increased risk for stroke that may easily be overlooked in the evaluation of both adult and pediatric acute stroke victims. The recognition of a genetic disorder as the cause of a stroke has important implications not only for the immediate care of the stroke victim, but often also for others in the patient's family who may be at risk for the same disease and for whom preventive measures sometimes can be taken. We present here a comprehensive review of genetic disorders associated with stroke in the nongeriatric age groups for which a causative role in the evolution of stroke has been recognized or is likely. For each disorder, the major clinical and biochemical characteristics as well as the probable pathogenetic mechanisms of stroke are discussed, together with the appropriate testing required to screen for and confirm the diagnosis. The great variety of genetic disorders and mechanisms causing stroke underscores the increasing importance of understanding genetic disease for appropriate diagnosis and treatment of a common clinical problem affecting both children and adults.

Genetic heritability and shared environmental influences of type A measures in the NHLBI Twin Study

Article

Jun 1988
AM J EPIDEMIOL

Data from the NHLBI Twin Study were used to investigate the genetic component in a number of Type A measures given to these twins during a second cardiovascular examination. Specifically, the objective of the current study was to determine the extent to which various Type A measures are influenced by genetic effects and by measurable environmental and cultural factors. Analyses of these data for twins yielded a number of results. First, the Type A behavior pattern as assessed by the structured interview was only weakly associated with self-report inventories developed as alternatives to the structured interview. Second, among the self-report measures of Type A, only the Thurstone Temperament Schedule Active scale showed a clear significant genetic component. Most important, a number of demographic and social characteristics known to be associated with the various Type A scales had a differential effect on twin similarities. Specifically, for the job involvement subscale of the Jenkins Activity Survey, twins of both zygosities became equally similar after adjustments for covariates, while no effect on twin similarity was noted for the Thurstone Temperament Schedule Active scale. It is concluded that a complex constellation of genetic predispositions and acquired behaviors underlies the Type A behavior construct.

Genetic aspects of arteriosclerosis

Article

Jul 1986
Arteriosclerosis

This review discusses the genetic factors in the development of arteriosclerosis and coronary heart disease (CHD). In several studies, multivariate analysis of prospective mortality/morbidity data and angiographic findings have indicated that a family history of CHD contributed to CHD risk independently of the established risk factors. In addition, ethnic groups that differ in the prevalence and incidence of CHD also markedly differ in blood groups and protein-enzymatic markers. These or other genetic differences may affect CHD rates. Data from fraternal and identical twins, the source of some early genetic CHD findings, are reviewed. Genetic disorders of lipoprotein metabolism and transport, such as familial hypercholesterolemia, as well as other monogenic disorders are discussed. The role of apoprotein E polymorphism i other monogenic disorders are discussed. The role of apoprotein E polymorphism in determining plasma LDL variability among individuals is considered. Recombinant DNA technology, molecular cloning, and the identification of restriction fragment length polymorphisms are new tools for investigators who assess DNA polymorphism. Recent advances in that domain include: DNA polymorphisms affecting blood levels of apo A-I and A-II, association of a DNA insertion on chromosome 19 with severe premature atherosclerosis, and information concerning linkage of the genes for various apolipoproteins. In addition, the evidence for a major genetic component in diabetes mellitus and research into the genetic aspects of hypertension are reviewed. The male/female ratio in pathologically and epidemiologically assessed atherosclerosis may provide clues to the role of genetics. Early structural changes in the coronary artery intima are compatible with the ethnic and gender predilection. A key question in understanding underlying mechanisms in atherosclerosis is why coronary arteries are occluded in individuals whose other arterial systems are largely unaffected. The review concludes with a discussion of the directions and implications of future genetic research in arteriosclerosis with an emphasis on uncovering genetically determined differences in arterial wall response to blood flow. Subpopulations with different genetic risks may be identified, in which case universal preventive strategies might be replaced with specific ones.

Family history of heart attack: A modifiable risk factor?

Article

Sep 1986

A family history of heart attack is reported to be an independent predictor of cardiovascular death in men. In a 9 year follow-up of 4014 adults from 40 to 79 years old in the Rancho Bernardo Study, men under 60 years of age with a family history of heart attack were at fivefold increased risk. In this study, we sought to determine whether modifiable risk factors, i.e., blood pressure, plasma cholesterol, obesity, and cigarette smoking, have a differential effect on cardiovascular risk in those with and without a family history of heart attack. For both sexes, cigarette smoking was a stronger predictor of cardiovascular disease in those with a family history of heart attack (relative risk of smokers vs nonsmokers was 2.5 for men and 4.0 for women) than in those with no such family history (relative risk of smokers vs nonsmokers was 1.1 for men and 1.7 for women). Conversely, an increased risk of cardiovascular mortality in men with a family history of heart attack was present predominantly in smokers (relative risk related to positive family history was 1.2 in nonsmokers, and 3.3 in smokers). An estimated 68% of the excess deaths in men with a family history of heart attack were attributable solely to the interaction of family history with smoking habit and were therefore potentially avoidable. The risk of cardiovascular disease associated with an apparently inherited predisposition appears to be profoundly affected by modifiable behavior.

Differential Enrollment in Twin Registries: Its Effect on Prevalence and Concordance Rates and Estimates of Genetic Parameters

Article

Feb 1985

In the NAS-NRC Registry, all major diseases are more common in DZ than in MZ twins. Furthermore, concordance rates for most disorders are lower in the registry than would be expected. In this article we propose a general model which seeks to explain these phenomena. The model explores the impact of traits which increase or decrease the probability of enrollment of individuals given that the registry, like the NAS-NRC, includes only pairs where both members are enrolled. If the trait decreases the probability of selection into the registry, both the prevalence of and concordance for the trait in the registry will be lower than that found in the population. A trait which increases the probability of selection has the opposite effects. However, the magnitude of these effects are a function of the population concordance. If population concordance differs in MZ and DZ twins, the effect of differential enrollment will not be the same for the two zygosity groups. The article examines the impact of differential enrollment on estimates of heritability and common environment and explores ways in which estimates of prevalence and concordance rates can be obtained which are free of the bias introduced by selection.

Possibilities of a preventive approach to coronary heart disease starting in childhood

Article

Feb 1985
Acta Paediatr Scand Suppl

P Puska

Promotion in youth of lifestyles that are likely to result in optimum levels of cardiovascular risk factors is the basis for early prevention of cardiovascular diseases and promotion of health. Health behaviour is closely linked to the general lifestyle of an community. Thus for any long-term major change, a community-based approach is essential. Experience from the North Karelia project indicates that through a comprehensive community-based programme, health behaviour and risk factor levels of a whole country could be changed, and that resulted in reduction of coronary heart disease (CHD) in the area. Studies among children carried out as part of the North Karelia project have shown that children's smoking rates and nutrition habits can be influenced and their serum cholesterol levels can be modified. At least in Finland, family-based practical counselling and provision of social support seems to be an effective strategy in changing the nutrition habits of both adults and children. No evidence has been observed to indicate that this type of intervention would have any harmful emotional consequences among children. A study to show the impact of risk factor modification on coronary heart disease risk in adulthood is hardly feasible and, instead, studies to test the feasibility and effects of different intervention approaches for influencing health related behaviour and risk factors in children and adolescents should be emphasized.

Effects of selection on mortality

Article

Dec 1974
AM J EPIDEMIOL

The effect of the bias of medical selection on subsequent mortality by cause, was examined in a series of 85,491 white male World War II U.S. Army veterans who have been followed for a period of 23 yr, 1947 to 1969. The results indicate that the selection process for military service exerted a profound effect on mortality of Army veterans after separation from service. Generally, the mortality rates are well below those of the general population within the first few years of discharge, but thereafter gradually approach those of the parent population. The effect of the bias of selection on subsequent mortality rates may persist even after 23 yr from Army discharge. The effect of the bias varies considerably according to the nature of the cause of death.

Ischaemic heart disease in death discordant twins. A study on 205 male and female pairs

Article

Feb 1974
Acta Med Scand Suppl

Ulf de Faire

Concordance in twins: Methods and Interpretation

Article

Aug 1974

C. A. B. Smith

Proband concordance rates in twins provide estimates of correlation among twins in liability to a trait or condition. The correlations in turn can be interpreted genetically by the expression 2(r(MZ)-r(DZ)) which eliminates nongenetic familial effects on twins and estimates the coefficient of genetic determination for the trait. The rates of diagnosis and of ascertainment of individuals and their cotwins must also be taken into account, along with other factors such as differences in frequency between sexes, variable age of onset, and variable expressivity or severity. A set of rules for the minimal set of data required and for a standard form of analysis is presented. The genetic interpretation of other measures of concordance is difficult and their value is questionable. The indices of 'heritability' proposed by Holzinger, widely used by human geneticists, are shown to be unsatisfactory and their use should be discontinued.

Ascertainment of mortality in the U. S. Veteran population

Article

Jul 1969
AM J EPIDEMIOL

The veteran population is increasingly recognized as a major resource for medical follow-up and epidemiologic studies. NAS-NRC monitoring of mortality ascertainment through the files of the Veterans Administration, based on deaths in 1956, and most recently in 1962, shows that routine VA flies are quite complete for deaths among all veterans of World War I, World War II, and the Korean War. Most recently, a representative sample of 2,291 deaths in June, 1962, was checked against military flies in St. Louis to identify veterans with war service, whose mortality status was then sought in VA files by routine procedures. For World War I veterans, VA records and procedures were 92% complete, and for World War 11, 98%. For veterans of the Korean War the estimate for World War II veterans seems appropriate.

The estimation of genetic variance from twin data

Article

Mar 1970

Methods are presented for estimating genetic variance simultaneously from monozygotic and dizygotic twin data, care being taken to clarify the necessary underlying assumptions. Testing for the presence of genetic variance is also considered, by both parametric and non-parametric means.

The NAS-NRC Twin Panel: Methods of Construction of the Panel, Zygosity Diagnosis, and Proposed Use

Article

Apr 1967

The Study of Human Twins in Medical Research

Article

Mar 1984

Identical and fraternal human twins are a unique resource for studies of the origin and natural history of various diseases, because their genetic similarities are well defined and easily understood. Most investigations using twins fall into two basic categories. In one, genetic factors that contribute to the cause of disease are assessed directly. In the other category, hereditary factors are excluded so that the etiologic importance of nongenetic factors can be evaluated in comparisons that control genetic variation. Both kinds of studies have helped to confirm or dispel specific hypotheses, have provided insights into disease processes, and have shed new light on the usefulness of this study population for future research. Laboratory and clinical investigators assign subjects randomly to different treatment groups to control and evaluate perturbations in their data that are due to factors not specifically accounted for in the study design. In studies on nonhuman subjects, littermates of inbred strains are often randomly assigned to treatment groups to reduce as much as possible the extraneous effects of genetic and early environmental factors. Research on human beings must accommodate a number of constraints: human beings are genetically heterogeneous; they may not be assigned to potentially harmful treatments; and they cannot be assigned at random in studies of spontaneously occurring outcomes, such as diseases of unknown cause. Human twins, however, provide opportunities for evaluating genetic and environmental factors in pairs of subjects of the same age who are either genetically identical or closely related and who have usually shared a common family background and many childhood environmental exposures and experiences.

Twin Studies of Coronary Heart Disease and Its Risk Factors

Article

Feb 1984

Kare Berg

Traditional twin studies have resulted in higher concordance rates for premature coronary heart disease (CHD) in MZ than in DZ twin pairs. This is in agreement with strong evidence from several other studies, that genetic factors are of importance in the etiology of early onset CHD. Also, in a study of 291 Norwegian twin pairs the concordance rate for hypertension was 0.36 in MZ and 0.08 in DZ pairs. Relationship between diseases and traditional gene markers have been extensively studied and several associations have been uncovered for CHD. Our group has developed a method to examine a possible permissive or restrictive effect of single genes on the degree of variation that environmental and/or life style factors can cause in a given parameter. This method for studying gene-environment interaction is based on the fact that MZ twins are identical with respect to genes, so that any difference between the two members of an MZ pair must necessarily be caused by environmental or life style factors. The possibility that a given gene influences the degree of variability in a parameter such as cholesterol is examined by comparing the within-pair difference in cholesterol level between MZ pairs possessing, and MZ pairs lacking the gene in question, and results of such studies will be presented. New possibilities to study restriction fragment length polymorphisms (RFLPs) at apolipoprotein loci have added a new dimension to research on genetics of CHD and hyperlipidemias. Association between apolipoprotein B, cholesterol and fasting triglyceride levels on one hand and DNA variation at the apolipoprotein B Locus on the other has been found. We have studied RFLPs at apolipoprotein loci in twin families. The results are presented.

Cerebral infarction after middle cerebral artery occlusion in progenies of spontaneously stroke-prone and normal rats

Article

Jul 1984

A differential outcome results from rapid middle cerebral artery (MCA) occlusion in young normotensive Wistar (NW) rats as compared to the spontaneously hypertensive stroke-prone (SHRSP) rat. The SHRSP invariably infarcts; the NW usually does not. To determine if segregation at a single autosomal locus explains the difference between strains, a NW male was crossed with several SHRSP females to produce F1 rats. The segregation of the strain difference was studied in the F2 and backcrosses to the NW and SHRSP parental strains. The relative frequency of infarcting and noninfarcting animals in the segregating progenies supported a single locus recessive model of inheritance for susceptibility to infarction after sudden occlusion of the MCA. Mean infarct size was largest for SHRSP and proportional to the SHRSP gene dosage in the segregating progenies. Variation in the size of the infarct within segregating classes may be attributable to the segregation of polygenes and/or environmental influences during the initial formation of the cerebral anastomoses.

Familial Factors in Mortality with Control of Epidemiological Covariables. Swedish Twins Born 1886-1925

Article

Feb 1984

A Cox proportional hazard regression analysis was carried out that evaluated age-specific death risk among 21,890 twins born in Sweden during 1886 through 1925 and followed during 1962 through 1980. Cotwin's survival was used as the primary covariable, and auxiliary covariables were smoking, marital status and, among men, police registration for alcohol abuse. In each age, sex and zygosity group, except the oldest DZ males, cotwin's mortality had a significant, independent, positive relationship to the mortality risk of the individual. The auxiliary covariables, except marital status among females, had significant, independent, positive relationships to mortality among the youngest twins of both zygosity groups and in the middle age group of MZ twins. In the oldest age group, the death of MZ cotwins was the only variable significantly related to the individual's mortality. Heritability estimates for the age-specific probability or death risk, developed by different methods for different analysis groups, range between 0.4 and 0.6. They have reasonable internal consistency, are not much affected by the covariates, and are in agreement with other studies that did not control covariates.

The 'new genetics' in blood and cardiovascular research: Applications to prevention and treatment

Article

Dec 1984

A G Motulsky

Genetic approaches have become an important component of both fundamental and disease-oriented research. Certain diseases of the blood--the hemoglobinopathies--have been elucidated by the spectacular methods of molecular genetics. Some of these advances have already been incorporated in disease management. Often, common conditions such as coronary heart disease and hypertension show familial aggregation. Genetic analysis of these diseases together with biochemical and molecular methods are likely to be useful for further understanding and ultimate prevention and control.

Plasma lipids in twins. Environmental and genetic influences

Article

Oct 1983
Atherosclerosis

A study on 205 pairs of male and females twins, aged from 18 to 34 years. showed significant heritabilities for total and high density lipoprotein cholesterol and for triglycerides. Significant effects of shared environment were also found for total and HDL cholesterol, possibly to a greater extent in women than in men. Triglycerides showed greater variance in men but a model specifying different sized environmental and genetic parameters in the two sexes gave a good fit and indicated that the factors influencing plasma triglycerides are the same in men and women although the effects they produce are scaled differently.

Diabetes in identical twins. A study of 200 pairs

Article

Mar 1981

A prospective study of 1152 hospital autopsies: I. Inaccuracies in death certification

Article

Apr 1981

Comparison of certified clinical diagnoses with autopsy findings showed that, while the major cause of death was confirmed in 61 per cent. of cases, many diagnoses—both major and contributory—were wrong; many clinical diagnoses were either disproved or relegated to a less important role, and many autopsy findings had not apparently been anticipated. Accuracy was particularly poor in some clinical categories: notably cerebro‐vascular disease and infections. In these, the diagnosis was more often wrong than right. Thus, death certificates are unreliable as a source of diagnostic data. The clinician's confidence in his major diagnosis bore a fairly close relationship to the frequency of its confirmation. Nevertheless, even when certified as “fairly certain”, the major diagnosis was wrong in about one‐quarter of these cases. An attempt was made to assess the significance of incorrect diagnoses; one half of these might be clinically significant. Diagnostic accuracy did not improve with the time spent in hospital, and it bore an inverse relationship to the patient's age.

Cardio-vascular risk factors in children and early prevention of heart disease

115-12

Gs Bereson
Srinivasan
Sr
Ta Nicklas
Webber

Bereson GS, Srinivasan SR, Nicklas TA, Webber LS: Cardio-vascular risk factors in children and early prevention of heart disease. Clin Chem 1988;34:B115-B12

Cardiovascular risk factors in children and early prevention of heart disease

Jan 1988
B115

Bereson GS

Twin studies: Their use and limitations in: Methodology in Medical Genetics

Aeh Emery

Coronary heart disease in male twins: Hereditary and environmental factors in concordant and discordant pairs

Jan 1970
9

Lilijefors I

A study of twins and stroke

Abstract

No full-text available

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