Jane Worthington

The University of Manchester, Manchester, England, United Kingdom

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Publications (300)2553.7 Total impact

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    ABSTRACT: Objectives: A recent study identified 16 genetic variants associated with N-glycosylation of human IgG. Several of the genomic regions where these single nucleotide polymorphisms (SNPs) reside have also been associated with autoimmune disease (AID) susceptibility, suggesting there may be pleiotropy (genetic sharing) between loci controlling both N-glycosylation and AIDs. We investigated this by testing variants associated with levels of IgG N-glycosylation for association with rheumatoid arthritis (RA) susceptibility using a Mendelian randomisation study, and testing a subset of these variants in a less well-powered study of treatment response and severity. Methods: SNPs showing association with IgG N-glycosylation were analysed for association with RA susceptibility in 14 361 RA cases and 43 923 controls. Five SNPs were tested for association with response to anti-tumour necrosis factor (TNF) therapy in 1081 RA patient samples and for association with radiological disease severity in 342 patients. Results: Only one SNP (rs9296009) associated with N-glycosylation showed an association (p=6.92×10(-266)) with RA susceptibility, although this was due to linkage disequilibrium with causal human leukocyte antigen (HLA) variants. Four regions of the genome harboured SNPs associated with both traits (shared loci); although statistical analysis indicated that the associations observed for the two traits are independent. No SNPs showed association with response to anti-TNF therapy. One SNP rs12342831 was modestly associated with Larsen score (p=0.05). Conclusions: In a large, well-powered cohort of RA patients, we show SNPs driving levels of N-glycosylation have no association with RA susceptibility, indicating colocalisation of associated SNPs are not necessarily indicative of a shared genetic background or a role for glycosylation in disease susceptibility.
    Annals of the rheumatic diseases 09/2015; DOI:10.1136/annrheumdis-2014-207210 · 10.38 Impact Factor
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    ABSTRACT: TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc. This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method. Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10(-13), OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10(-3), OR=0.80; p=1.27×10(-3), OR=0.59; p=2.63×10(-5), OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants. We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases 09/2015; DOI:10.1136/annrheumdis-2015-208154 · 10.38 Impact Factor
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    ABSTRACT: Objectives: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. Methods: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. Results: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88 x 10-2, OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89 x 10-2, OR=1.13; p=1.69 x 10-2, OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00 x 10-4, OR=1.16) comparing with healthy controls. Conclusions: Our work confirms the association of CCR6 gene and ATA+ SSc patients.
    Clinical and experimental rheumatology 08/2015; · 2.72 Impact Factor
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    ABSTRACT: A long-standing epidemiological puzzle is the reduced rate of rheumatoid arthritis (RA) in those with schizophrenia (SZ) and vice versa. Traditional epidemiological approaches to determine if this negative association is underpinned by genetic factors would test for reduced rates of one disorder in relatives of the other, but sufficiently powered data sets are difficult to achieve. The genomics era presents an alternative paradigm for investigating the genetic relationship between two uncommon disorders. We use genome-wide common single nucleotide polymorphism (SNP) data from independently collected SZ and RA case-control cohorts to estimate the SNP correlation between the disorders. We test a genotype X environment (GxE) hypothesis for SZ with environment defined as winter- vs summer-born. We estimate a small but significant negative SNP-genetic correlation between SZ and RA (-0.046, s.e. 0.026, P = 0.036). The negative correlation was stronger for the SNP set attributed to coding or regulatory regions (-0.174, s.e. 0.071, P = 0.0075). Our analyses led us to hypothesize a gene-environment interaction for SZ in the form of immune challenge. We used month of birth as a proxy for environmental immune challenge and estimated the genetic correlation between winter-born and non-winter born SZ to be significantly less than 1 for coding/regulatory region SNPs (0.56, s.e. 0.14, P = 0.00090). Our results are consistent with epidemiological observations of a negative relationship between SZ and RA reflecting, at least in part, genetic factors. Results of the month of birth analysis are consistent with pleiotropic effects of genetic variants dependent on environmental context. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
    International Journal of Epidemiology 08/2015; DOI:10.1093/ije/dyv136 · 9.18 Impact Factor
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    ABSTRACT: Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10(-12); T1D, P = 2.4 × 10(-10); psoriasis, P = 5.9 × 10(-6); celiac disease, P = 1.2 × 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10(-3); T1D, P = 8.6 × 10(-27); celiac disease, P = 6.0 × 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.
    Nature Genetics 08/2015; 47(9). DOI:10.1038/ng.3379 · 29.35 Impact Factor
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    ABSTRACT: Determining whether potential causal variants for related diseases are shared can identify overlapping etiologies of multifactorial disorders. Colocalization methods disentangle shared and distinct causal variants. However, existing approaches require independent data sets. Here we extend two colocalization methods to allow for the shared-control design commonly used in comparison of genome-wide association study results across diseases. Our analysis of four autoimmune diseases-type 1 diabetes (T1D), rheumatoid arthritis, celiac disease and multiple sclerosis-identified 90 regions that were associated with at least one disease, 33 (37%) of which were associated with 2 or more disorders. Nevertheless, for 14 of these 33 shared regions, there was evidence that the causal variants differed. We identified new disease associations in 11 regions previously associated with one or more of the other 3 disorders. Four of eight T1D-specific regions contained known type 2 diabetes (T2D) candidate genes (COBL, GLIS3, RNLS and BCAR1), suggesting a shared cellular etiology.
    Nature Genetics 06/2015; 47(8). DOI:10.1038/ng.3330 · 29.35 Impact Factor
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    ABSTRACT: Background Systemic sclerosis (SSc) is a chronic connective tissue disorder with the highest mortality of any autoimmune disease. SSc is a complex disease with a clear genetic component. This genetic susceptibility has been supported by a number of well-powered genetic association studies. In this regard, it is remarkable that several SSc genetic markers have been reported in the IL-12 pathway (IL12A, STAT4, IL12RB2, IL12RB1). Furthermore, multiple clinical and experimental evidences have shown that this pathway is altered in SSc patients. TYK2 encodes the Tyrosine kinase 2 enzyme, which mediates the signaling of IL-12 receptor. Objectives We aimed to analyze the association of the TYK2 locus with SSc susceptibility. Methods The complete set of individuals included in this study reached 4,985 SSc patients and 11,621 healthy controls of European ancestry from Spain, Germany, The Netherlands, USA, Italy and United Kingdom. Initially, we analyzed all the polymorphisms located in the region that encompasses the TYK2 coding sequence and 20 kb up and downstream, in a previously published Immunochip-based dense genotyping study. We identified a common single nucleotide polymorphism (SNP), the V362F variant (rs2304256) and three rare variants: P1104A (rs34536443), A928V (rs35018800) and I684S (rs12720356), as the genetic markers that better explained the observed association in the region. Then, these variants were followed up in additional cohorts. Association and dependence relations were tested using logistic regression and conditional logistic regression, and pooled analyses were performed using the inverse variance method. Results Our pooled analysis showed that V362F variant reached the genome-wide significance level (P=2.00x10-10, OR =0.84), while P1104A (rs34536443), A928V (rs35018800) and I684S (rs12720356) remained significant (P=8.61x10-3, OR=0.79; P=1.95x10-4, OR=0.49; Prandom=0.016, OR=0.84, respectively). The analyses carried out for the main clinical features revealed that the observed association signals relied on the whole disease. Furthermore, our results revealed that the association of TYK2 with SSc was dependent on the interaction between the P1104A, A928V and I684S rare variants and that the previously observed association for the autoimmune related V362F variant, corresponded to a synthetic association dependent on the association of the three previously mentioned rare variants. Conclusions We report for the first time the association of TYK2 variants with SSc. Moreover, our data support that the highly significant association of a previously known autoimmune disease marker, the V362F variant (rs2304256), is dependent on the effect of three non-synonymous rare variants in this locus. Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):116.2-116. DOI:10.1136/annrheumdis-2015-eular.3859 · 10.38 Impact Factor
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    ABSTRACT: Advances have been made in identifying genetic susceptibility loci for autoimmune diseases, but evidence is needed regarding their association with prognosis and treatment response. To assess whether specific HLA-DRB1 haplotypes associated with rheumatoid arthritis (RA) susceptibility are also associated with radiological severity, mortality, and response to tumor necrosis factor (TNF) inhibitor drugs. The Norfolk Arthritis Register (NOAR; 1691 patients and 2811 radiographs; recruitment: 1989-2008; 2008 as final follow-up) was used as a discovery cohort and the Early Rheumatoid Arthritis Study (421 patients and 3758 radiographs; recruitment: 1986-1999; 2005 as final follow-up) as an independent replication cohort for studies of radiographic outcome. Mortality studies were performed in the NOAR cohort (2432 patients; recruitment: 1990-2007; 2011 as final follow-up) and studies of treatment response in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort (1846 patients enrolled at initiation of TNF inhibitor; recruitment: 2006-2010; 2011 as final follow-up). Longitudinal statistical modeling was performed to integrate multiple radiograph records per patient over time. All patients were from the United Kingdom and had self-reported white ancestry. Sixteen HLA-DRB1 haplotypes defined by amino acids at positions 11, 71, and 74. Radiological outcome using the Larsen score (range: 0 [none] to 200 [severe joint damage]) and erosions of the hands and feet on radiographs, all-cause mortality, and treatment response measured by change in Disease Activity Score based on 28 joint counts and European League Against Rheumatism (EULAR) response. Patients with RA and valine at position 11 of HLA-DRB1 had the strongest association with radiological damage (OR, 1.75 [95% CI, 1.51-2.05], P = 4.6E-13). By year 5, the percentages of patients with erosions of the hands and feet were 48% of noncarriers (150/314) of valine at position 11, 61% of heterozygote carriers (130/213), and 74% of homozygote carriers (43/58). Valine at position 11 also was associated with higher all-cause mortality in patients with inflammatory polyarthritis (hazard ratio, 1.16 [95% CI, 1.03-1.31], P = .01) (noncarriers: 319 deaths in 1398 patients over 17 196 person-years, mortality rate of 1.9% per year; carriers: 324 deaths in 1116 patients in 13 208 person-years, mortality rate of 2.5% per year) and with better EULAR response to TNF inhibitor therapy (OR, 1.14 [95% CI, 1.01-1.30], P = .04) (noncarriers: 78% [439/561 patients] with moderate or good EULAR response; heterozygote carriers: 81% [698/866]; and homozygote carriers: 86% [277/322]). The risk hierarchy defined by HLA-DRB1 haplotypes was correlated between disease susceptibility, severity, and mortality, but inversely correlated with TNF inhibitor treatment response. Among patients with RA, the HLA-DRB1 locus, which is associated with disease susceptibility, was also associated with radiological severity, mortality, and treatment response. Replication of these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRB1 haplotype analysis for management of RA.
    JAMA The Journal of the American Medical Association 04/2015; 313(16):1645-1656. DOI:10.1001/jama.2015.3435 · 35.29 Impact Factor
  • J. Ding · S. Eyre · J. Worthington
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    ABSTRACT: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
    04/2015; 1(1):e000028-e000028. DOI:10.1136/rmdopen-2014-000028
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    ABSTRACT: Despite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three pro-tein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3×10-21), A928V (rs35018800, OR = 0.53, P = 1.2×10-9), and I684S (rs12720356, OR = 0.86, P = 4.6×10-7). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6×10-18 ), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; Pomnibus = 0.005). Finally, in a phenomewide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.
    PLoS ONE 04/2015; 10(4):e0122271. DOI:10.1371/journal.pone.0122271 · 3.23 Impact Factor
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    ABSTRACT: We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; 96(4). DOI:10.1016/j.ajhg.2015.02.009 · 10.93 Impact Factor
  • Stephen Eyre · Jane Worthington
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    ABSTRACT: Many of the hits identified through genome-wide association studies are located outside protein-coding regions, making it difficult to define mechanism. In Nature, Farh et al., (2014) describe an approach to identify causal variants in autoimmune disease as first step to assigning function. Copyright © 2014 Elsevier Inc. All rights reserved.
    Immunity 12/2014; 41(6). DOI:10.1016/j.immuni.2014.12.014 · 21.56 Impact Factor
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    ABSTRACT: A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell–derived neurons for the L-type calciumchannel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.
    Cell Reports 11/2014; 9(4):1-13. DOI:10.1016/j.celrep.2014.10.015 · 8.36 Impact Factor
  • Annie Yarwood · Tom W J Huizinga · Jane Worthington
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    ABSTRACT: There is now a general consensus that RA has a spectrum of disease stages that can begin many years before the onset of clinical symptoms. It is widely thought that understanding the complex interplay between genetics and environment, and their role in pathogenesis, is essential in gaining further insight into the mechanisms that drive disease development and progression. More than 100 genetic susceptibility loci have now been identified for RA through studies that have focused on patients with established RA compared with healthy controls. Studying the early preclinical phases of disease will provide valuable insights into the biological events that precede disease and could potentially identify biomarkers to predict disease onset and future therapeutic targets. In this review we will cover recent advances in the knowledge of genetic and environmental risk factors and speculate on how these factors may influence the transition from one stage of disease to another.
    Rheumatology (Oxford, England) 09/2014; DOI:10.1093/rheumatology/keu323 · 4.48 Impact Factor
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    Arthritis and Rheumatology 09/2014; 66(12). DOI:10.1002/art.38870
  • A. Webster · D. Plant · S. Eyre · G. Wilson · A. Morgan · J. Isaacs · J. Worthington · A. Barton
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    ABSTRACT: Background Anti-TNF therapies have proved a huge advance for the treatment of rheumatoid arthritis (RA), however very good disease control or remission is achieved in just 30% of patients. This makes the identification of biomarkers predictive of response an important area of research. Such predictive biomarkers would allow the most effective treatment for a patient to be identified early in disease course. An increasing number of studies have identified a role for epigenetics in RA and other autoimmune disorders, thus we hypothesised that epigenetic changes, such as DNA methylation, may provide potential biomarkers of response to anti-TNFs. Objectives To identify methylation signatures predictive of response to anti-TNF therapies in patients with RA. Methods Patients were selected from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) longitudinal cohort. Patients (n=119) were selected based on having an extreme response phenotype after 3 months of treatment with etanercept or adalimumab; 36 were good responders to etanercept and 30 to adalimumab defined as having an endpoint DAS28<2.6, and 35 were poor responders to etanercept and 18 to adalimumab defined as having an improvement of <0.6 or between 0.6-1.2 with an endpoint DAS28 of >5.1. DNA from each patient, sampled before initiation of therapy, was bisulfite converted and an epigenome-wide association study was conducted using the HumanMethylation450 BeadChip (Illumina). The results from each drug were analysed separately using the minfi package in R and probes with a detection-p value >0.01 were removed. Differentially methylated positions between responders and non-responders were identified using the F-test following quantile normalisation. Results In the etanercept study, four CpG sites showed differential DNA methylation that passed a false discovery rate of 0.05, while in the adalimumab study, two CpG sites passed this threshold. The most differentially methylated position in etanercept patients mapped to the LRPAP1 gene (p=1.46×10-8). This gene encodes a chaperone of low density lipoprotein receptor-related protein 1 (LRP1) which is known to influence TGF-β activity. Technical validation of methylation at this site by pyrosequencing showed very good correlation (Spearmans r=0.8). In the adalimumab patients, the most differentially methylated position maps to the MAD2L2 gene. Conclusions This is one of the largest methylome-wide investigations of treatment response to anti-TNF therapies in RA. These preliminary results identify DNA methylation as a potential biomarker of response for etanercept and adalimumab. Acknowledgements This work was supported by the innovative medicines initiative joint undertaking (IMI JU) funded project BeTheCure, (contract number 115142-2). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4104
    Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):158-159. DOI:10.1136/annrheumdis-2014-eular.4104 · 10.38 Impact Factor
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    ABSTRACT: Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA(-) RA and observed independent associations for serine and leucine at position 11 in HLA-DRβ1 (p = 1.4 × 10(-13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 × 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1(∗)03 (encoding serine at 11) and HLA-B(∗)08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DRβ1 Ser11+Leu11: p = 5.8 × 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 × 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DRβ1 position 11 were distinct (p < 2.9 × 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 × 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.
    The American Journal of Human Genetics 03/2014; 94(4). DOI:10.1016/j.ajhg.2014.02.013 · 10.93 Impact Factor
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    ABSTRACT: A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45 790 European case-control samples. We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
    Annals of the rheumatic diseases 02/2014; 74(3). DOI:10.1136/annrheumdis-2013-204749 · 10.38 Impact Factor
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    ABSTRACT: Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
    PLoS ONE 02/2014; 9(2):e87645. DOI:10.1371/journal.pone.0087645 · 3.23 Impact Factor
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    ABSTRACT: Background Since 2007 over 30 genetic loci have been associated with susceptibility to rheumatoid arthritis (RA). The functional consequences of many loci are unknown, in particular their role on disease severity. Recently, several studies have investigated these variants in the development and progression of radiographic joint damage in early and established RA [1-4], highlighting their potential as severity markers. Objectives We aimed to probe the impact of RA susceptibility loci on baseline radiographic joint damage measured using the total modified Sharp/van der Heijde score (TSS) in a RA inception cohort. Methods Radiographic damage was assessed from plain x-rays of the hands and feet at baseline on 721 patients recruited into the Yorkshire Early Arthritis Register (YEAR) using the modified Sharp/van der Heijde scoring system. Genotyping was performed on 41 single nucleotide polymorphisms (SNP) covering 34 genomic loci associated with RA susceptibility. Matched baseline TSS and genotype data were available on 411 patients with a symptom duration ≤24months. Zero-inflated negative binomial regression was used to model the TSS as count data, estimate incidence rate ratios (IRR) and perform univariate association under a log additive model for each SNP. A p-value threshold for nominal association was set at p<0.05 with a Bonferroni adjusted threshold for 34 loci at p<1.47×10-3. Results The mean symptom duration was 7.4 months (SD 4.2), mean age at onset 58.9 years, 70.8% were female, 13.7% had recorded radiographic damage (TSS>0) and 58.3% were seropositive (ACPA and/or RF). The strongest association mapped to the C8ORF13-BLK locus (rs13277113 p=3.7×10-5 IRR 2.3 95%CI[1.6-3.4]) and remained significant at 2years (n=313 p=0.016 IRR 1.6 95%CI[1.1-2.3]). Increased TSS was nominally associated with minor alleles at the KIF5A-PIP4K2C and PTPN2 loci (rs1678542 p=0.006 IRR 2.2 95%CI[1.3-4.0] & rs7234029 p=0.03 IRR 1.7 95%CI[1.1-2.7]). Reduced TSS was nominally associated with minor alleles at the TNIP2 and IL2RB loci (rs231707 p=0.03 IRR 0.6 95%CI[0.4-0.9] & rs3218258 p=0.001 IRR 0.5 95%CI[0.4-0.8]). In addition to these findings, we replicated an association with the minor allele of rs26232 in the first intron of c5orf30 (p=0.002 IRR 0.4 95%CI[0.2-0.7]) associated with a lower median Larsen score in a cross-sectional cohort of established RA patients [4]. Conclusions Investigation of RA susceptibility loci and radiographic joint damage of early RA patients has highlighted several genomic regions of interest as markers of erosive damage at disease onset. The strongest association lies close to a known expression variant in BLK [5], a B-cell specific tyrosine kinase involved in BCR and pre-BCR signaling. Replication in comparable early RA cohorts is now warranted. Disclosure of Interest None Declared
    Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):472-472. DOI:10.1136/annrheumdis-2012-eular.2953 · 10.38 Impact Factor

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15k Citations
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  • 1996–2015
    • The University of Manchester
      • • Institute of Inflammation and Repair
      • • Centre for Integrated Genomic Medical Research (CIGMR)
      Manchester, England, United Kingdom
  • 2014
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2013
    • Spanish National Research Council
      • Institute of Parasitology and Biomedicine "López-Neyra"
      Madrid, Madrid, Spain
  • 2009
    • The University of Sheffield
      • Academic Unit of Rheumatology
      Sheffield, ENG, United Kingdom
  • 1991–2009
    • Manchester University
      North Manchester, Indiana, United States