Harry L. Hebert

Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case–control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8+ memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.

Genetic susceptibility to psoriasis and psoriatic arthritis: implications for therapy

The era of genome‐wide association studies has revolutionized the search for genetic susceptibility loci in complex genetic conditions such as psoriasis. There are currently 16 loci with confirmed evidence for association with psoriasis susceptibility but there is the potential for more to be discovered as the genetic heritability of the disease has not yet been fully explained. Many of the associated loci overlap with those for psoriatic arthritis. In contrast to psoriasis susceptibility, few studies have been performed to identify predictors of drug response in psoriasis. As large‐scale collaborations and registries for psoriasis and psoriatic arthritis are established, it is likely that a genome‐wide approach may be used as a more effective method of searching for genetic predictors of treatment response. However, candidate gene studies will still have a role; for example, it is likely that some disease susceptibility genes will also be markers of treatment response, based on evidence from other diseases. This review summarizes recent advances in investigating the role genetics plays in psoriasis susceptibility and contrasts these to advances made in psoriatic arthritis. Further, it describes the genetics of treatment response in the two diseases and indicates how susceptibility loci could be used to identify drug response in the future.

Polymorphisms in IL-1B distinguish between psoriasis of early and late onset

TO THE EDITOR Chronic plaque psoriasis is a common, genetic, immune-mediated skin disorder that can be dichotomized according to age of onset: early-onset psoriasis (EOP; type 1, onset before 40 years of age, B75% of subjects) and late-onset psoriasis (LOP; type 2, onset over 40 years of age, B25% of subjects; Henseler and Christophers, 1985). Recently, genome-wide association studies (GWAS) have made significant strides in elucidating the genetic basis of EOP with a total of 36 loci now identified (Hébert et al., 2012; Tsoi et al., 2012). In comparison, there are only two genetic studies specifically in LOP: one found no association with HLA-Cw6, the major genetic locus associated with EOP (Allen et al., 2004; Gudjonsson et al., 2006) while a second separate study found a nominal association with a variant (rs16944) mapping to the IL1B promoter region (Reich et al., 2002). Inflammatory cytokines, such as IL-1beta (IL1b) and tumor necrosis factoralpha (TNF-a), have a well-documented role in the pathogenesis of psoriasis (Griffiths and Barker, 2007; Nestle et al., 2009). They are important stimuli of the migration of epidermal Langerhans cells (LC) and plasmacytoid dendritic cells from the skin to draining lymph nodes where they engage with T cells. It has been shown that LC migration in response to these cytokines differs between EOP and LOP (Cumberbatch et al., 2006; Shaw et al., 2010). This combination of genetic and immunological observations implicating a role for IL1b in mechanisms underlying LOP led us to investigate whether genetic variation at the IL1B gene is associated with psoriasis. We compared association of polymorphisms from IL1B between cohorts of EOP and LOP patients. Patients of Caucasian descent with chronic plaque psoriasis were recruited from UK Dermatology Centres at Salford Royal NHS Foundation Trust, Manchester, UK; Guy’s Hospital, London and the National Hospital for Rheumatic Diseases, Bath, UK. The study adheres to the Declaration of Helsinki Principles, was approved by the relevant local research ethics committees, and all subjects provided written informed consent. Patients were divided into two subtypes for analysis: EOP (onset o40 years of age) and LOP (onset X40 years). A secondary analysis was conducted, omitting samples with onset between 30 and 50 years of age. Psoriasis samples were genotyped using the Sequenom MassArray platform with iPLEX Gold chemistry (Sequenom, San Diego, CA) and Taqman (Applied Biosystems, Foster City CA) (rs16944) according to the manufacturer’s instructions. Genotypes for control samples were imputed from GWAS data obtained from the Wellcome Trust Case Control Consortium (www.wtccc.org. uk; Wellcome Trust Case Control Consortium, 2007) using IMPUTE v2 (Howie et al., 2009). Samples and markers were subjected to quality control and association analysis (Cochran–Armitage test for trend with Fisher’s exact test) using PLINK (v1.07) (Purcell et al., 2007). Any sample or marker with a call rate o90%, a minor allele frequency o5%, or Hardy–Weinberg P-value o1 10 4 were removed. Finally, a Bonferroni correction for multiple testing was applied giving a significance threshold of Po3.12 10 , except for rs16944, which was considered significant at Po0.05 because of prior evidence for association. A total of 1,906 psoriasis patients were recruited to the study; 1,263 were EOP patients (mean age of onset 20.3 years, SD 9.7 years) and 643 were LOP patients (mean age of onset 50.7 years, SD 9.2 years). Following quality control, data for 16 tagging single-nucleotide polymorphisms (SNPs) were available within the IL1B gene region. The previously published association at rs16944 (Reich et al., 2002) was replicated in this study (P1⁄4 0.03, odds ratio (OR)1⁄41.15, 95% confidence interval (CI)1⁄41.02–1.31). Furthermore, rs11687624 (P1⁄41.53 10 , OR1⁄4 1.22, 95% CI1⁄4 1.08–1.37), was found to be associated with LOP at Bonferroni significance (Table 1). SNP rs11687624 is located in the intergenic region between IL1B and IL1A. Another two SNPs, rs1143643 and rs2853550, showed nominal association. When the analysis was performed on those with age of psoriasis onset over 50 years rs2853550 (PX501⁄42.91 10 , OR1⁄41.53, 95% CI1⁄4 1.17–2.01) became significantly associated with LOP. Marker rs11687624, although losing Bonferroni significance, retained a nominal association that was very close to the threshold. SNP rs16944 (PX501⁄43.85 10 , OR1⁄41.30, 95% CI1⁄41.09–1.54) remained significant at Po0.05. None of the SNPs analyzed in the study were significantly associated with EOP (Table 2). One SNP, rs12469600 (P1⁄4 0.03, OR1⁄40.89, 95% CI1⁄40.80– 0.99) showed nominal association, however, this was eliminated when samples with psoriasis onset over 30 years were removed. LETTER TO THE EDITOR

Identification of loci associated with late-onset psoriasis using dense genotyping of immune-related regions.

Chronic plaque psoriasis can be subdivided into two groups according to the age of onset: type 1 (early onset, before 40 years) and type 2 (late onset, at or beyond 40 years). So far, 36 genetic loci have been associated with early‐onset psoriasis in genome‐wide association studies of white populations, while few studies have investigated genetic susceptibility to late‐onset psoriasis.

Cohort Profile: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS)

Cohort Profile: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) Harry L Hébert, Bridget Shepherd, Keith Milburn, Abirami Veluchamy, Weihua Meng, Fiona Carr, Louise A Donnelly, Roger Tavendale, Graham Leese, Helen M Colhoun, Ellie Dow, Andrew D Morris, Alexander S Doney, Chim C Lang, Ewan R Pearson, Blair H Smith and Colin NA Palmer* Division of Population Health Sciences, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Health Informatics Centre Services, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK, Institute of Genetics & Molecular Medicine and Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

Risk factors for neuropathic pain in diabetes mellitus

According to the International Diabetes Federation, diabetes mellitus (DM) is estimated to affect around 415 million adults worldwide, roughly 8.8% of the adult population, with the figure projected to rise to over 600 million by 2040. Regional prevalence varies from 3.2% in Africa to 12.9% in North America. Diabetesmellitus is associatedwith a number of chronic sequelae and around 50% of people with DM go on to develop polyneuropathy. This condition has a variety of clinical manifestations, which are grouped into positive symptoms including dysesthesia (abnormal sense of touch), tingling and itching, and negative symptoms including numbness, muscle weakness, and trouble with balance. Up to 25% of people with diabetic neuropathy (DN) also develop neuropathic pain (NP). Neuropathic pain is defined by the International Association for The Study of Pain as “pain directly caused by a lesion or disease affecting the somatosensory system.” Symptoms of painful diabetic neuropathy (PDN) include those described above for nonpainful DN with additional “burning,” “electric shocks,” “stabbing,” and “pins and needles” symptoms all being described. Painful diabetic neuropathy is associated with increased distress and poor quality of life compared with nonpainful DN, DM, and the general population including depression, anxiety, and sleep disturbance. In addition, an association has been described with reduced productivity and employability at work compared with nonpainful DN. The combination of these factors places a large economic burden on patients and health care services, a situation likely to grow steadily worse with the aforementioned projected rise in DM prevalence. This situation is further exacerbated by the fact that 13% of patients with PDN do not report their symptoms to primary care, and 39% of patients with PDN have never received treatment. Even for those patients whodo attend primary and secondary care for their diabetes, pain is not a symptom that is always included in clinical assessments. Furthermore, not all patients with DN develop PDN, and the reasons for this are unclear. Understanding the risk factors for PDN will go some way to resolving this and will also help to inform management and prevention of this painful condition by health care services. Any factor that increases the risk of DM or DN is likely to be a risk factor for PDN. However, it is the specific nature and magnitude of the risk that remains unclear and is the focus of this topical review.

A Genome-Wide Association Study Finds Genetic Associations with Broadly-Defined Headache in UK Biobank (N = 223,773)

Background Headache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. Methods We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. Results We identified 3343 SNPs which reached the genome-wide significance level of P < 5 × 10− 8. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92 × 10− 47. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87 × 10− 15 in the LINC02210-CRHR1 gene was the top SNP. Significant relationships between multiple brain tissues and genetic associations were identified through tissue expression analysis. We also identified significant positive genetic correlations between headache and many psychological traits. Conclusions Our results suggest that brain function is closely related to broadly-defined headache. In addition, we found that many psychological traits have genetic correlations with headache.

A systematic review and meta-analysis of genetic risk factors for neuropathic pain

Abstract Neuropathic pain (NP) is an increasingly common chronic pain state and a major health burden, affecting approximately 7% to 10% of the general population. Emerging evidence suggests that genetic factors could partially explain individual susceptibility to NP and the estimated heritability in twins is 37%. The aim of this study was to systematically review and summarize the studies in humans that have investigated the influence of genetic factors associated with NP. We conducted a comprehensive literature search and performed meta-analyses of all the potential genetic variants associated with NP. We reviewed 29 full-text articles and identified 28 genes that were significantly associated with NP, mainly involved in neurotransmission, immune response, and metabolism. Genetic variants in HLA genes, COMT, OPRM1, TNFA, IL6, and GCH1, were found to have an association with NP in more than one study. In the meta-analysis, polymorphisms in HLA-DRB1*13 (odds ratio [OR], 2.96; confidence interval [CI], 1.93-4.56), HLA-DRB1*04 (OR, 1.40; CI, 1.02-1.93), HLA-DQB1*03 (OR, 2.86; CI, 1.57-5.21), HLA-A*33 (OR, 2.32; CI, 1.42-3.80), and HLA-B*44 (OR, 3.17; CI, 2.22-4.55) were associated with significantly increased risk of developing NP, whereas HLA-A*02 (OR, 0.64; CI, 0.47-0.87) conferred reduced risk and neither rs1799971 in OPRM1 (OR, 0.55; CI, 0.27-1.11) nor rs4680 in COMT (OR, 0.95; CI, 0.81-1.13) were significantly associated with NP. These findings demonstrate an important and specific contribution of genetic factors to the risk of developing NP. However, large-scale replication studies are required to validate these candidate genes. Our review also highlights the need for genome-wide association studies with consistent case definition to elucidate the genetic architecture underpinning NP.

A genome-wide association study suggested that the mitogen-activated protein kinase 14 gene (MAPK14) is associated with diabetic foot ulcer

Diabetic foot ulcers (DFUs) are a devastating complication of diabetes.

A Genome-Wide Association Study Provides New Evidence That CACNA1C Gene is Associated With Diabetic Cataract.

Purpose Diabetic cataract is one of the major eye complications of diabetes. It was reported that cataract occurs two to five times more frequently in patients with diabetes compared with those with no diabetes. The purpose of this study was to identify genetic contributors of diabetic cataract based on a genome-wide association approach using a well-defined Scottish diabetic cohort. Methods We adapted linked e-health records to define diabetic cataract. A diabetic cataract case in this study was defined as a type 2 diabetic patient who has ever been recorded in the linked e-health records to have cataracts in both eyes or who had previous cataract extraction surgeries in at least one eye. A control in this study was defined as a type 2 diabetic individual who has never been diagnosed as cataract in the linked e-health records and had no history of cataract surgeries. A standard genome-wide association approach was applied. Results Overall, we have 2341 diabetic cataract cases and 2878 controls in the genetics of diabetes audit and research in Tayside Scotland (GoDARTS) dataset. We found that the P value of rs2283290 in the CACNA1C gene was 8.81 × 10−10, which has reached genome-wide significance. We also identified that the blood calcium level was statistically different between diabetic cataract cases and controls. Conclusions We identified supporting evidence that CACNA1C gene is associated with diabetic cataract. The role of calcium in the cataractogenesis needs to be reevaluated in future studies.