Daniel F Carr

University of Liverpool | UoL · Department of Pharmacology and Therapeutics

Background: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Objective: To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the differe...

Background: High-mobility group box 1 (HMGB1) is a damage-associated molecular-pattern protein. Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are serious, immune-mediated skin-blistering conditions. Objectives: To determine serum and/or blister-fluid total HMGB1 levels in SJS/TEN cohorts, and HMGB1 expression in formalin-fixed,...

Background: β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (Type I) reactions mediated by antigen-specific IgE. Objective: To identify genetic predisposing factors for immediate reactions to β-lactam antibiotics. Methods: Patients with a clinical history of immediate hypers...

Stevens Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions (ADRs) characterised by widespread keratinocyte cell-death and epidermal detachment. At present, there is little understanding of how the detachment occurs or how it is abrogated by the TNF-α inhibitor etanercept, an effective SJS/TEN treat...

Purpose of review Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions (SCARs) characterized by widespread epithelial detachment and blistering, which affects the skin and mucocutaneous membranes. To date, therapeutic interventions for SJS/TEN have focused on systematic suppression of the inflamm...

Background Epilepsy is a common neurological disease but around 30% of patients fail to respond to antiepileptic drug (AED) treatment. Genetic variation of the ATP-binding cassette subfamily B, member 1 (ABCB1) gene, a drug efflux transporter may infer treatment resistance by decreasing gastrointestinal absorption and preventing AED entry into the...

Background: Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of life and survivorship in affected patients. Genetic polymorphisms in the CYP3A family have been investigated but the findings have been inconsistent and contradictory. Metho...

Decreased epidermal high-mobility group box 1 (HMGB1) expression is an early marker of epidermal injury in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Etanercept, an anti-tumor necrosis factor therapeutic, is effective in the treatment of SJS/TEN. The objective was to characterize antitumor necrosis factor-alpha (TNF-α)-mediated...

Background & aims: Cellular uptake of the essential nutrient vitamin B12 (cobalamin) occurs via the transcobalamin receptor (TCblR/CD320), a ubiquitous membrane receptor. Polymorphisms in the receptor exist, though the effect of such variants across patient populations is unknown. Methods: We determined CD320 genotype in 377 randomly selected el...

Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pha...

Background Adrenal suppression is a clinically concerning side effect of inhaled corticosteroid (ICS) treatment in patients with asthma. Increased susceptibility to ICS-induced adrenal suppression has previously been identified in those with the rs591118 polymorphism in platelet-derived growth factor D ( PDGFD ). The mechanism underpinning this rel...

Background Adrenal suppression is a clinically concerning side effect of inhaled corticosteroid (ICS) treatment in patients with asthma. Increased susceptibility to ICS-induced adrenal suppression has previously been identified in those with the rs591118 polymorphism in Platelet Derived Growth Factor D (PDGFD). The mechanism underpinning this relat...

Background Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD. Methods Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) w...

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs which are widely used globally for the treatment of pain and inflammation, and in the case of aspirin, for secondary prevention of cardiovascular disease. Chronic non-steroidal anti-inflammatory drug use is associated with potentially serious upper gastrointestinal adverse drug rea...

Many adverse reactions associated with immune checkpoint inhibitor (ICI) treatments are immunologically driven and may necessitate discontinuation of the ICI. Herein, we present a patient who had been administered the radio contrast media amidotrizoate multiple times without issue but who then developed a Stevens-Johnson syndrome reaction after coa...

Oncology has been at the vanguard of pharmacogenomics for a number of years. Indeed, a significant number of clinically utilized genetic tests for predicting safety or efficacy are for ant-cancer drugs. This chapter describes some key examples of clinically utilized pre-emptive tests for pharmacogenomic variants, which can predict patient oncology...

Aims Carbamazepine can cause hypersensitivity reactions in ~10% of patients. An immunogenic effect can be produced by the electrophilic 10,11‐epoxide metabolite but not by carbamazepine. Hypothetically, certain single nucleotide polymorphisms might increase the formation of immunogenic metabolites, leading ultimately to hypersensitivity reactions....

Over the past two decades, our understanding of genetic heritability has been derived from candidate gene and genome-wide studies looking at common allelic variant associations. As our access to advanced genomics technologies increases, so too does the availability of pharmacogenomic data for predicting the risk of ADRs. We now have the ability to...

The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre‐emptive genetic tests are now routinely undertaken prior to anticancer drug administration. Many of these gene–drug interactions are the fruits of candidate gene and genome‐wide association studies, which have largely focus...

Atorvastatin (ATV) is frequently prescribed and generally well tolerated, but can lead to myotoxicity, especially at higher doses. A genome‐wide association study of circulating levels of ATV, 2‐hydroxy (2‐OH) ATV, ATV lactone (ATV L) and 2‐OH ATV L was performed in 590 patients that had been hospitalised with a non‐ST elevation acute coronary synd...

Introduction Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins play an essential role in the adaptive immune response for the presentation of self and non-self peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug induced agranulocytosis (severe lower white blood...

Objectives: Dolutegravir has replaced efavirenz as first-line treatment in universal HIV guidelines. We sought to ascertain the contributory effect of SNPs in four key genes linked to dolutegravir disposition (UGT1A1, ABCG2, CYP3A and NR1I2) on plasma dolutegravir pharmacokinetics. Methods: Paired pharmacogenetic/pharmacokinetic data from 93 sub...

Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins play an essential role in the adaptive immune response for the presentation of self and non-self peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug induced agranulocytosis (severe lower white blood cell count)...

Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, severe, skin blistering conditions in which areas of skin die and detach. They actually represent a single disease with a spectrum of severity: less than 10% body surface area detachment in SJS and more than 30% in TEN. It affects around 500 people in the UK each year and...

史蒂文斯‐约翰逊综合征 (SJS) 和中毒性表皮坏死松解症 (TEN) 是一种罕见的、严重的、皮肤起泡的疾病,其中皮肤的某些部位会死亡和脱落。它们实际上代表着严重程度不同的同一种疾病:SJS 患者的体表脱皮面积低于 10%,而 TEN 患者超过 30%。 在英国,每年约有 500 人感染此病,最常见的原因是对多种常用处方药产生反应。这项研究汇集了来自英国、西班牙、台湾地区和美国的研究人员和患者,目的是检测 SJS/TEN 患者血清(部分血液)、水泡液和皮肤活检组织中一种名为高迁移率族蛋白B1 (HMGB1) 的水平。HMGB1 是一种蛋白,它被认为是发生在 SJS/TEN 中的 a) 组织/细胞损伤和 b) 免疫反应激活的标志物(生物学标志)。 作者在三个独立的患者群体中检测到 SJS/TE...

Aims: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a mu...

Statins can be associated with myopathy. We have undertaken a Genome‐wide Association Study (GWAS) to discover and validate genetic risk‐factors for statin‐induced myopathy in a “real‐world” setting. 135 statin myopathy patients recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome v1.0 Bead Ch...

Voriconazole is a first-line antifungal agent. Therapeutic drug monitoring is a standard of care. The best way to adjust dosages to achieve desired drug exposure endpoints is unclear due to nonlinear and variable pharmacokinetics. Previously described software was used to prospectively adjust voriconazole dosages. CYP2C19 and CYP3A4 and CYP3A5 geno...

Raltegravir (RAL) is metabolised by UGT1A1 and polymorphisms in the UGT1A1 gene have been associated with plasma concentrations in some but not all previous studies. The current analysis represents the largest study to date for the effect of UGT1A1 polymorphisms on RAL PK/PD. NEAT001/ANRS143 was a randomised study (n=805 participants) that demonst...

Urticarial reactions are characterised by recurrent pruritic edematous lesions (wheals). They are broadly categorised into three subtypes: acute urticaria with reactions lasting <6 weeks; chronic urticaria which is characterised by continuous or persistent symptoms for >6 weeks; and contact urticaria, an immediate reaction to topical application of...

Adverse drug reactions have been linked with genetic polymorphisms in HLA genes in numerous different studies. HLA proteins have an essential role in the presentation of self and non-self peptides, as part of the adaptive immune response. Amongst the associated drugs-allele combinations, anti-HIV drug Abacavir has been shown to be associated with t...

Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) study, we evaluated a comprehensive array of omics platforms across three time-points and multiple tissues in a pilot investigation of t...

Adverse drug reactions have been linked with genetic polymorphisms in HLA genes in numerous different studies. HLA proteins have an essential role in the presentation of self and non-self peptides, as part of the adaptive immune response. Amongst the associated drugs-allele combinations, anti-HIV drug Abacavir has been shown to be associated with t...

Background A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression. Methods We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), a...

Adverse drug reactions can be caused by a wide range of therapeutics. Adverse drug reactions affect many bodily organ systems and vary widely in severity. Milder adverse drug reactions often resolve quickly following withdrawal of the casual drug or sometimes after dose reduction. Some adverse drug reactions are severe and lead to significant organ...

Aims A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility t...

Adverse drug reactions affecting the gastrointestinal (GI) tract are a serious burden on patients, healthcare providers and the pharmaceutical industry. GI toxicity encompasses a range of pathologies in different parts of the GI tract. However, to date no specific mechanistic diagnostic / prognostic biomarkers or translatable pre-clinical models of...

Table of contents Oral Abstracts O1 Functionally distinct HMGB1 isoforms correlate with physiological processes in drug-induced SJS/TEN Daniel F. Carr, Wen-Hung Chung, Rosalind E. Jenkiins, Mas Chaponda, Gospel Nwikue, Elena M. Cornejo Castro, Daniel J. Antoine, Munir Pirmohamed O2 Hypersensitivity reactions to beta-lactams, does the t cell recogni...

Objective: Efavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently the 8-hydroxy (8OH)-EFZ metabolite has been shown to be a potent neurotoxin in vitro, inducing neuronal damage at concentrations of 3.3ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6ng/ml. We investigated the effect of genotype and bloo...

Objective: Many different gene families are currently being investigated for their potential role in epilepsy and in the response to antiepileptic drugs. A common research challenge is identifying the members of a gene family that are most significantly dysregulated within the human epileptic focus, before taking them forward for resource-intensiv...

Rapid developments in pharmacogenomics have been noticeable in recent years, and much of this knowledge has improved understanding of adverse drug reactions. This improved knowledge has largely been the result of improved sequencing technologies and falling costs in this area, as well as improved statistical techniques to analyse the data derived f...

Numerous diverse biological pathways are dysregulated in the epileptic focus. Which of these pathways are most critical in producing the biological abnormalities that lead to epilepsy? Answering this question is key to identifying the primary causes of epilepsy and for discovering new therapeutic strategies with greater efficacy than currently avai...

Various studies have investigated associations between immunogenetic (HLA-allelotypes) factors and the risk of nevirapine-induced hypersensitivity reactions. However, results from individual studies have been inconsistent. To evaluate the association between HLA alleles and nevirapine hypersensitivity, a systematic review and meta-analysis was carr...

Background Nevirapine, an NNRTI used in HIV treatment, can cause hypersensitivity reactions in 6%–10% of patients. In the most serious cases (1.3%) this can manifest as Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Methods DNA samples were obtained and analysed from a total of 209 adult patients with nevirapine hypersensitivi...

Mangravite et al. identified six expression quantitative loci (eQTLs) that interacted with simvastatin exposure by using 480 lymphoblastoid cell lines exposed to β-hydroxy simvastatin acid in vitro. One of these SNPs (rs9806699) within the glycine amidinotransferase (GATM) gene was shown to have an association with statin-induced myopathy in two in...

The non-nucleoside reverse transcriptase inhibitor nevirapine is used in the treatment of HIV in many developing countries. Its use is associated with occurrence of hypersensitivity in 6-10% of patients. This hypersensitivity can manifest as a number of phenotypes which include the severe skin blistering reactions Stevens Johnson syndrome (SJS) and...

Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in human immunodeficiency virus (HIV) treatment can cause hypersensitivity reactions in 6-10% of patients, which in the most serious cases (1.3%) can manifest as Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). A total of 209 patients with NVP hyperse...

Background: Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak. Objectives: (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether b...

Statins are widely used lipid lowering drugs effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardised nomenclature and phenotypic definitions. We have used...

The completion of the human genome project 10 years ago was met with great optimism for improving drug therapy through personalized medicine approaches, with the anticipation that an era of genotype-guided patient prescribing was imminent. To some extent this has come to pass and a number of key pharmacogenomics markers of inter-individual drug res...

To evaluate clinical risk factors associated with myotoxicity in statin users. Cohort study of patients prescribed a statin in UK primary care practices contributing to the Clinical Practice Research Datalink. Outcomes of interest were creatine phosphokinase (CPK) levels and clinical records of rhabdomyolysis. The cohort comprised 641703 statin use...

We modelled nevirapine (NVP) pharmacokinetics in HIV-infected Malawian patients to assess the relationship between drug exposure and patient characteristics, genetic polymorphisms and development of hypersensitivity reaction (HSR). 1117 patients were prospectively recruited and followed for 26 weeks with multiple or single serum samples obtained in...

Electronic health care records (EHRs) are increasingly utilized to store clinical information. A secondary benefit of EHRs is their use, in an anonymised form, for observational research. The Clinical Practice Research Datalink (CPRD) contains EHRs from primary care in the UK and, despite 1083 peer-reviewed research publications, has never been uti...

Fludarabine plus cyclophosphamide (FC) is the chemotherapy backbone of modern chronic lymphocytic leukemia (CLL) treatment. CYP2B6 is a polymorphic cytochrome P450 isoform that converts cyclophosphamide to its active form. This study investigated the possible impact of genetic variation in CYP2B6 on response to FC chemotherapy in CLL. Available DNA...

The study aimed to determine whether patients with statin-induced myopathy could be identified using the United Kingdom Clinical Practice Research Datalink (CPRD), DNA obtained, and thereby replicate previously reported associations of statin myopathy with the SLCO1B1 c.521T>C and COQ2 rs4693075 polymorphisms.Seventy seven statin-myopathy patients...

Purpose: The response of colorectal liver metastases to the cytotoxic agent irinotecan varies widely. Attempts to correlate tumour metabolism with response have been mixed. This study investigated the hepatic metabolism of irinotecan as a potential predictor of tumour response to irinotecan-eluting beads (DEBIRI). Methods: Ten patients with colo...

The Wolfson Centre for Personalised Medicine is part of the Institute of Translational Medicine at the University of Liverpool (Liverpool, UK). It houses a multidisciplinary team of personalized medicine researchers engaged in collaborative research with partners across the globe. The primary focus of the centre is the identification of predictive...

Background. The nonnucleoside reverse transcriptase inhibitor nevirapine is the cornerstone of treatment for human immunodeficiency virus (HIV) in many sub-Saharan African countries. However, nevirapine is associated with a 6%–10% risk of developing a hypersensitivity reaction, with different phenotypes, including the blistering conditions Stevens-...

Introduction Corticosteroids are the main stay of preventative therapy for asthma-related symptoms. There is a wide range of inter-patient variability both in terms of response to therapy, and suppression of the HPA axis leading to potentially fatal adrenal suppression. A recently undertaken GWAS identified the GLCCI1 variant rs37973 as a biomarker...

Single-nucleotide polymorphisms (SNPs) in the CYP2C gene cluster have been extensively investigated as predisposing factors for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer disease (PUD) or upper gastrointestinal bleeding (UGIB). However, results have been inconclusive owing to different study designs, limited genotyping strateg...

The joint Cold Spring Harbor/Wellcome Trust Conference on pharmacogenomics, held in the USA and the UK in alternate years, focuses on the growing contribution of genomic technologies to the study of variable human responses to therapeutic agents. The meeting brings together researchers from academic, medical, regulatory and industrial sectors who d...

IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucle...

IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucle...

Purpose of the study: Despite risk of hypersensitivity (HS), nevirapine (NVP) underpins first-line HIV therapy in Africa. The relationship between NVP exposure and HS is unknown but could be influenced by polymorphisms in CYP2B6 and CYP3A4 affecting drug metabolism. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV In...

Efavirenz is extensively metabolized by CYP2B6, and associations between CYP2B6 polymorphisms and plasma efavirenz exposure have been reported. The objective of this study was to investigate CYP2B6 haplotype structure and functional consequences in a Latin American population. Two hundred and nineteen patients were recruited at Fundación Arriarán,...

Genetic polymorphisms in the one-carbon folate pathway have been widely studied in association with a number of conditions. Most of the research has focused on the 677C>T polymorphism in the coding region of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. However, there are a total of 25 genes in this pathway coding for enzymes, transpor...

Tacrine, the first acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease, is associated with transaminase elevation in up to 50% of patients. The mechanism of tacrine-induced liver damage is not fully understood, but earlier studies have suggested that genetic factors may play a role. Our aim was to investigate whether single-...

Background: Tacrine, an anticholinesterase used to treat Alzheimer's disease (AD), leads to an increase in serum alanine aminotransferase (ALT) levels. The factors determining individual susceptibility are largely unknown. The purpose of this study was to investigate genetic predisposition. Methods: Rats were administered single dose tacrine (3-40...

The anticholinesterase inhibitor tacrine hydrochloride was the first drug used in the treatment of Alzheimer's Disease (AD). Despite some efficacy in treating patients with AD, there were safety concerns regarding liver injury, manifested as an increase in serum aminotransferase (ALT) levels. The rise in ALT typically occurred after 4-12 weeks. The...

Tacrine, the first acetylcolinesterase inhibitor for treatment of Alzheimer's disease, is known to cause transaminitis in up to 50% of patients. We have recently investigated whether polymorphisms in 20 candidate genes were associated with tacrine-induced liver damage. The strongest association was found with a number of SNPs in the ABCB4 gene, whi...