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Manhattan plot of the association between genetic variants and percent liver fat, adjusted for age, sex, and genetic ancestry proportions. The red line indicates the statistical significance threshold P = 5 × 10 −8 . Green dots represent known liver fat risk loci on chromosomes 2, 19, and 22.
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The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population‐specific genetic variants associated with liver fat. We conducted a genome‐wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 partic...
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... and self-administered questionnaire. Ninety-one participants were excluded after quality control (QC) filtering of the genotype data (see below), and 61 were excluded for invalid MRI scans (due to motion artifacts or presence of intravisceral masses). Thus, the final study population for analysis was comprised of 1,709 participants (Supporting Fig. S1). (16) peRCentage liVeR Fat, naFlD, total Fat mass The MRI scanners Siemens TIM Trio at UH and General Electric HDx at USC, both with a 3-tesla magnetic field strength, were used to quantify liver fat. The MRI protocol assessed four abdominal intervertebral segments of the intra-abdominal cavity (L1-L2, L2-L3, L3-L4, L4-L5) and did not ...
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... the association analysis with percent liver fat, we identified 10 SNPs that reached a genome-wide significance threshold of P < 5 × 10 −8 , with seven SNPs located in chromosome 22q13 and three SNPs located in chromosome 6q13 ( Fig. 1; Table 2). All variants associated with percent liver fat with P < 10 −6 without adjustment for total fat mass are presented in Supporting Table S3. None of the variants deviated from Hardy-Weinberg equilibrium (threshold for deviation P < 1.0 × 10 −6 ). For 22q13, the seven SNPs associated with percentage liver fat are located in the ...
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... (beta = 0.07; P = 0.017), Latinos (beta = 0.06; P = 0.002), and Native Hawaiians (beta = 0.05; P = 0.101) ( Table 3). Heterogeneity by race/ethnicity was not detected (P heterogeneity = 0.46; Table 3; Supporting Table S5). For 6q13, three genome-wide associations were observed for rs77249491, rs146418612, and rs78276535 with percent liver fat ( Fig. 1; Supporting Table S3) that remained statistically significant with adjustment for total fat mass (Table 2). These three variants were imputed with an imputation score of >0.98 (Table 2) and are in high linkage disequilibrium (LD) (r 2 > 0.95). Thus, we could not distinguish the primary signal and only considered the strongest ...
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Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area ou...
Citations
... We evaluated the effects of previously reported NAFLD/steatosis variants in GOLDPlus (Supplementary Table 19). A literature search was conducted for NAFLD and steatosis GWAS in PubMed, and genome-wide significant variants were identified 8,12,16,27,[92][93][94][95][96][97][98][99][100][101][102] . Variants that were independent of the GOLDPlus genome-wide significant variants (500 kb flanking criteria from the lowest P-value-associated variant) were assessed. ...
Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.
... Genotyping and imputation for the MEC-APS participants have been described previously [23]. Briefly, DNA extraction from buffy coat was performed using the Qiagen QIAMP DNA kit (Qiagen Inc., Valencia, CA). ...
Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10-8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10-9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10-8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females, but not in males, with adjustment for total adiposity (Beta = -0.24; P = 0.028), on the log scale. Rs79837492 and rs2968545 are located in intron 5 of CNTNAP5, and rs79926925, in an intergenic region between GJB6 and CRYL1. These novel findings differing by sex and racial/ethnic group warrant replication in additional diverse studies with direct visceral fat measurements.
... Based on the findings of the current study, we postulate the prominent role of PNPLA3 rs738409 in the progression of the liver disease caused by NAFLD; however, the tentative role of PNPLA3 rs738409 in the initial development of NAFLD was not observed in the current study. A recently published GWAS with multiethnic population-based recruitment found PNPLA3 rs738409 to be strongly associated (P < 1 × 10 5 ) with Percent Liver Fat only in Japanese-Americans and European-Americans while Latinos and African-Americans reached a P < 0.05 and Native Hawaiians showed no statistically significant association (P = 0.101) (21). The latter variation in the ethnicity-specific observation can be caused by the population-based sampling and the lower magnitude of rs738409 in the development of steatosis than that for the progression of liver diseases, globally observed in the clinical studies. ...
Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide. Genetic predisposition increases susceptibility to NAFLD. The PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms are genetic risk factors for NAFLD. Objectives: This study aimed to investigate the association of rs738409 and rs58542926 polymorphisms with NAFLD among the Iranian population in two groups: (1) Population-based NAFLD (PB-NAFLD), and (2) clinic-based NAFLD (CB-NAFLD). Methods: This case-control study included a group of healthy individuals without NAFLD as the control group and two case groups, PB-NAFLD and CB-NAFLD. All individuals underwent clinical and laboratory assessments and were also diagnosed using ultrasonography. Genotyping for rs738409 and rs58542926 polymorphisms was carried out by the PCR-RFLP method. Results: A total of 110 control, 108 PB-NAFLD, and 73 CB-NAFLD individuals were included in the study. The distribution of rs738409 GG+CG in the PB-NAFLD was 39.8% while it was 52.7% in the control group (P = 0.06, OR = 0.59). The distribution of rs738409 GG in the CB-NAFLD was 19.2%, while it was 8.2% in the control group (P = 0.04, OR = 2.66). The distribution of rs58542926 genotypes was not significantly different between the NAFLD and control groups. In multivariate analysis, metabolic syndrome (OR = 2.85) and BMI > 25 (OR = 3.32) were independent determinants of NAFLD in the PB-NAFLD group, and BMI > 25 (OR = 7.15) was an independent determinant of NAFLD in the CB-NAFLD group. Conclusions: In this study, the PNPLA3 rs738409 polymorphism was associated with NAFLD in the CB-NAFLD cohort; however, the same was not observed for the PB-NAFLD cohort. The TM6SF2 rs58542926 polymorphism was not associated with NAFLD in the Iranian population.
... 5 Systematic quantification of hepatic fat in population-based epidemiological studies has led to discovery of common genetic variants associated with NAFLD. [6][7][8][9][10][11][12] Medical centers collect enormous quantities of advanced abdominal imaging data in the course of clinical care, but imaging-derived quantitative traits such as hepatic fat are not systematically generated for research or clinical use. To address the challenges of conventional analysis of large numbers of images obtained in clinical care, machine learning can be brought to bear to provide quantitative image analysis using automation. ...
Nonalcoholic fatty liver disease is common and highly heritable. Genetic studies of hepatic fat have not sufficiently addressed non-European and rare variants. In a medical biobank, we quantitate hepatic fat from clinical computed tomography (CT) scans via deep learning in 10,283 participants with whole-exome sequences available. We conduct exome-wide associations of single variants and rare predicted loss-of-function (pLOF) variants with CT-based hepatic fat and perform cross-modality replication in the UK Biobank (UKB) by linking whole-exome sequences to MRI-based hepatic fat. We confirm single variants previously associated with hepatic fat and identify several additional variants, including two (FGD5 H600Y and CITED2 S198_G199del) that replicated in UKB. A burden of rare pLOF variants in LMF2 is associated with increased hepatic fat and replicates in UKB. Quantitative phenotypes generated from clinical imaging studies and intersected with genomic data in medical biobanks have the potential to identify molecular pathways associated with human traits and disease.
... 6 The heritability of MAFLD has been confirmed with evidence from data from epidemiological, familial aggregation, and twin studies, with heritability estimates ranging from 20% to 70%. [7][8][9][10] With the increasing number of studies on MAFLD susceptibility, progression based on genome-wide association studies and large candidate gene studies, [11][12][13] several single nucleotide polymorphisms (SNPs) have significantly contributed to the development of MAFLD, such as patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, 11,12 transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, 14,15 membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, 16 glucokinase regulator (GCKR) rs1260326 and rs780094, 17 and GATA zinc finger domain containing 2A (GATAD2A) rs4808199. 18 PNPLA3 rs738409 encodes PNPLA3 I148 M, which is a robust variant associated with MAFLD in multiple ethnicities. ...
Introduction
We aimed to confirm the association between some single nucleotide polymorphisms (SNPs) and metabolic dysfunction‐associated fatty liver disease (MAFLD) in western China.
Methods
A total of 286 cases and 250 healthy controls were enrolled in our study. All samples were genotyped for patatin‐like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, membrane‐bound O‐acyltransferase domain containing 7 (MBOAT7) rs641738, glucokinase regulator (GCKR) rs1260326 and rs780094, and GATA zinc finger domain containing 2A (GATAD2A) rs4808199. Using logistic regression analysis, we evaluated the association between MAFLD and each SNP under different models. Multiple linear regression was used to find the association between SNPs and laboratory characteristics. Multifactor dimensionality reduction was applied to test SNP–SNP interactions.
Results
The recessive model and additive model of PNPLA3 rs738409 variant were related to MAFLD (odds ratio [OR] = 1.791 and 1.377, respectively, p = 0.038 and 0.027, respectively). However, after Benjamini‐Hochberg adjustment for multiple tests, all associations were no longer statistically significant. PNPLA3 rs738409 correlated with AST levels. GCKR rs780094 and rs1260326 negatively correlated with serum glucose but positively correlated with triglycerides in MAFLD. Based on MDR analysis, the best single‐locus and multilocus models for MAFLD risk were rs738409 and six‐locus models, respectively.
Conclusions
In the Han population in western China, no association was found between these SNPs and the risk of MAFLD. PNPLA3 rs738409 was associated with aspartate aminotransferase levels in MAFLD patients. GCKR variants were associated with increased triglyceride levels and reduced serum fasting glucose in patients with MAFLD.
... Interestingly, studies within Hispanics with steatosis reveal heterogeneity in PNPLA3 frequency, from 52% among Mexican-Americans compared to 23% among Dominican-Americans with fatty liver [34]. Data are limited in Asian-Americans, but a recent study from the multiethnic cohort demonstrated the risk allele was present in 43% of Japanese-Americans and 26% of Native Hawaiians, supporting variable penetrance of the risk allele as a contributing factor for fatty liver [35]. Another variant, the 167Lys allele TM6SF2, regulates hepatic steatosis by decreasing VLDL-mediated lipid secretion, but the variant allele occurs with lower frequency: 7.2% in Whites, 4.7% Hispanics, and 3.4% Blacks [36]. ...
Background and AimsMost population-based studies of risk profiles for liver steatosis have relied upon serum markers (e.g., ALT or FIB-4) or ultrasound steatosis index to define cases. We sought to examine racial/ethnic differences in metabolic risk factors associated with liver steatosis and fibrosis at the population level using elastography-based measures.Methods
In total, 4509 adults completed vibration-controlled transient elastography (VCTE) with controlled attenuated parameter (CAP) examinations in the 2017–2018 National Health and Nutrition Examinations Survey. Race/ethnicity was self-identified; metabolic parameters included waist circumference, obesity, diabetes, hypertension, and hyperlipidemia. Primary outcome was steatosis defined by CAP score ≥ 280 decibels per meter and secondary outcome significant fibrosis by VCTE median stiffness ≥ 8 kilopascals. Race-specific logistic regression models were performed to assess the relationship between metabolic parameters and hepatic steatosis and fibrosis.ResultsPrevalence of elastography-based hepatic steatosis was > 30% for all race/ethnicities. Steatosis was associated with increasing waist circumference for all race/ethnicities (OR ranging 1.7–2.3, p < 0.01). Steatosis was associated with diabetes for Whites (OR 2.4, 95% CI 1.2–4.7), Asians (OR 3.0, 1.4–6.3), and Hispanics (OR 2.2, 1.3–3.6), but not Blacks (OR 1.3, 0.8–2.2); hypertension for Whites (OR 1.7, 1.3–4.7) and Asians (OR 2.1, 1.1–3.8); and hyperlipidemia for Blacks only (OR 2.2, 1.3–3.7). Of metabolic risk factors, higher odds of fibrosis were demonstrated with higher waist circumference per 10 cm increase (OR 2.1, 1.8–2.4) and diabetes (OR 2.5, 1.6–3.7), but the effect of diabetes was present in all racial/ethnic groups except Blacks (p-interaction < 0.05).Conclusion
Blacks have a distinct metabolic phenotype for steatosis, while Asians, Whites, and Hispanics are more similar. Racial/ethnic differences in risk profiles are important to consider in prevention, screening strategies, and interventions for fatty liver disease.
... Furthermore, the two genes are totally different in DNA sequences when using NCBI BLAST to compare. Several studies reported that ZNF582 expression was low in cancer, and low expression was associated with promoter hypermethylation and disease outcomes [29][30][31][32][33][34]. To assess if the two genes have any relationship in expression, we analyzed their correlation in breast cancer. ...
Simple Summary
ZNF582-AS1 expression is lower in breast cancer compared to adjacent normal tissues, and low expression is associated with poor disease-free and overall survival. Bioinformatic interrogation of ZNF582-AS1 expression and methylation signatures suggests the lncRNA’s involvement in cell cycle and cell death regulation. The lncRNA may act as a miR-940 sponge, and miR-940 is known to be an onco-miRNA suppressing PTEN. Elevation of transcription factor HIF-1 in cancer cells may repress the expression of ZNF582-AS1.
Abstract
Background: Long non-coding RNAs (lncRNAs) play an important role in cellular activities and functions, but our understanding of their involvement in cancer is limited. Methods: TCGA data on RNA expression and DNA methylation were analyzed for lncRNAs’ association with breast cancer survival, using the Cox proportional hazard regression model. Fresh tumor samples and clinical information from 361 breast cancer patients in our study were used to confirm the TCGA finding on ZNF582-AS1. A RT-qPCR method was developed to measure ZNF582-AS1 expression. Survival associations with ZNF582-AS1 were verified with a meta-analysis. In silico predictions of molecular targets and cellular functions of ZNF582-AS1 were performed based on its molecular signatures and nucleotide sequences. Results: ZNF582-AS1 expression was lower in breast tumors than adjacent normal tissues. Low ZNF582-AS1 was associated with high-grade or ER-negative tumors. Patients with high ZNF582-AS1 had a lower risk of relapse and death. These survival associations were confirmed in a meta-analysis and remained significant after adjustment for tumor grade, disease stage, patient age, and hormone receptor status. Correlation analysis indicated the possible suppression of ZNF582-AS1 expression by promoter methylation. Bioinformatics interrogation of molecular signatures suggested that ZNF582-AS1 could suppress tumor cell proliferation via downregulating the HER2-mediated signaling pathway. Analysis of online data also suggested that HIF-1-related transcription factors could suppress ZNF582-AS1 expression, and the lncRNA might bind to hsa-miR-940, a known oncogenic miRNA in breast cancer. Conclusions: ZNF582-AS1 may play a role in suppressing breast cancer progression. Elucidating the lncRNA’s function and regulation may improve our understanding of the disease.
... The MEC is a population-based cohort of >215,000 men and women of five race/ethnic groups (African American, Japanese American, Latino, Native Hawaiian, and White) who were aged between 45 and 75 years and residing in Hawaii or Los Angeles County, California, at the baseline (1993)(1994)(1995)(1996) [21]. Self-reported race/ethnicity was used for the cohort design and current analysis since self-identified race/ethnicity as a social construct is thought to capture different lived experiences and related individual behaviors and contextual factors [22]: in the MEC, self-reported race/ethnicity has been observed to be largely concordant with genetic ancestry [23,24]. ...
Background:
The human gut microbiome (GM) has been observed to vary by race/ethnicity.
Objective:
Assess whether racial/ethnic GM variation is mediated by differences in diet.
Design:
Stool samples collected from 2013 to 2016 from 5267 healthy Multiethnic Cohort participants (age 59-98) were analyzed using 16S rRNA gene sequencing to estimate the relative abundance of 152 bacterial genera. For 63 prevalent genera (>50% in each ethnic group), we analyzed the mediation of GM differences among African Americans, Japanese Americans, Latinos, Native Hawaiians, and Whites by overall diet quality (Healthy Eating Index score (HEI-2015)) and intake amounts of 14 component foods/nutrients assessed from 2003 to 2008. For each significant mediation (p < 1.3 × 10-5), we determined the percent of the total ethnicity effect on genus abundance mediated by the dietary factor.
Results:
Ethnic differences in the abundance of 12 genera were significantly mediated by one or more of eight dietary factors, most frequently by overall diet quality and intakes of vegetables and red meat. Lower vegetable intake mediated differences in Lachnospira (36% in African Americans, 39% in Latinos) and Ruminococcus-1 (-35% in African Americans, -43% in Latinos) compared to Native Hawaiians who consumed the highest amount. Higher red meat intake mediated differences in Lachnospira (-41%) and Ruminococcus-1 (36%) in Native Hawaiians over African Americans, who consumed the least. Dairy and alcohol intakes appeared to mediate and counterbalance the difference in Bifidobacterium between Whites and Japanese Americans.
Conclusions:
Overall diet quality and component food intakes may contribute to ethnic differences in GM composition and to GM-related racial/ethnic health disparities.
... It also implies that MAFLD may coexist with other liver diseases, for instance, hepatitis B and C[15,35-37], HIV infection[38], Gaucher [39], and coeliac disease [40], hence making it more plausible than NAFLD. Table 1 shows all the studies comparing the two terms [41][42][43][44]. ...
Recently, a single letter change has taken the world by storm. A group of experts have developed a consensus to upgrade the term non-alcoholic fatty liver disease (NAFLD) to metabolic associated fatty liver disease (MAFLD), suggesting that MAFLD would more accurately reflect not only the disease pathogenesis but would also help in patient stratification for management with NAFLD. However, the difference of opinion exists, which has made the NAFLD vs MAFLD debate the current talk of the town. This review will focus on the plausibility and implications of redefining NAFLD as MAFLD.
... Some of these disparities have been attributed to genetic differences, such as the PNPLA3 risk variant for NAFLD (rs738409), which is more common in Asians and Latinos [10]. Still, underlying biological mechanisms on racial/ethnic disparities in health are poorly understood [11]. ...
... Considering the potentially important role of DNA methylation in mediating the racial/ethnic health disparities as reviewed above, and based on our previous findings of distinct metabolic disparities among Asian Americans for NAFLD and related liver disease in the MEC [5][6][7][8]11], we examined the blood DNA methylome between heathy Japanese American and European American women in the current study. Specifically, we identified differentially methylated CpGs between Japanese Americans and European Americans. ...
... We utilized the Illumina MEGA EX array. After excluding poor quality SNPs, all SNPs had a call rate ≥ 0.95 and a replicate concordance 1.00 based on 39 QC replicate samples [11]. Eight well-studied SNPs in metabolic disease-related genes (Additional file 1: Table 1) were selected a priori to be tested for association with identified differentiated CpGs methylation by race/ethnicity. ...
Background
Racial/ethnic disparities in health reflect a combination of genetic and environmental causes, and DNA methylation may be an important mediator. We compared in an exploratory manner the blood DNA methylome of Japanese Americans (JPA) versus European Americans (EUA).
Methods
Genome-wide buffy coat DNA methylation was profiled among healthy Multiethnic Cohort participant women who were Japanese (JPA; n = 30) or European (EUA; n = 28) Americans aged 60–65. Differentially methylated CpGs by race/ethnicity (DM-CpGs) were identified by linear regression (Bonferroni-corrected P < 0.1) and analyzed in relation to corresponding gene expression, a priori selected single nucleotide polymorphisms (SNPs), and blood biomarkers of inflammation and metabolism using Pearson or Spearman correlations (FDR < 0.1).
Results
We identified 174 DM-CpGs with the majority of hypermethylated in JPA compared to EUA (n = 133), often in promoter regions (n = 48). Half (51%) of the genes corresponding to the DM-CpGs were involved in liver function and liver disease, and the methylation in nine genes was significantly correlated with gene expression for DM-CpGs. A total of 156 DM-CpGs were associated with rs7489665 (SH2B1). Methylation of DM-CpGs was correlated with blood levels of the cytokine MIP1B (n = 146). We confirmed some of the DM-CpGs in the TCGA adjacent non-tumor liver tissue of Asians versus EUA.
Conclusion
We found a number of differentially methylated CpGs in blood DNA between JPA and EUA women with a potential link to liver disease, specific SNPs, and systemic inflammation. These findings may support further research on the role of DNA methylation in mediating some of the higher risk of liver disease among JPA.
