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Zervou M.I.,Laboratory of Molecular Medicine and Human Genetics | Myrthianou E.,Laboratory of Molecular Medicine and Human Genetics | Flouri I.,Clinical Immunology and Allergy | Plant D.,Manchester Academy of Health science | And 10 more authors.
PLoS ONE | Year: 2013

Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece. © 2013 Zervou et al.


Carmona F.D.,Institute Parasitologia y Biomedicina Lopez Neyra | Mackie S.L.,University of Leeds | Martin J.-E.,Institute Parasitologia y Biomedicina Lopez Neyra | Taylor J.C.,University of Leeds | And 70 more authors.
American Journal of Human Genetics | Year: 2015

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. © 2015 The American Society of Human Genetics.


Banka S.,Genomic Health | Cain S.A.,University of Manchester | Carim S.,Genomic Health | Daly S.B.,Genomic Health | And 16 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objectives: Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. Methods and results: Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-ß pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p. Ser71Thr, could confer protection against disease (p<1×10-5). Conclusions: Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-ß/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-ß-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiffskin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.


Cordingley L.,University of Manchester | Prajapati R.,University of Manchester | Plant D.,Manchester Academy of Health science | Maskell D.,Manchester Academy of Health science | And 6 more authors.
Arthritis Care and Research | Year: 2014

Objective. The Disease Activity Score in 28 joints (DAS28), used to assess disease activity in rheumatoid arthritis (RA), is a composite score comprising clinical, biochemical, and patient self-report measures. We hypothesized that psychological factors (cognitions and mood) would be more strongly associated with patient-reported components of the DAS28 than clinical or biochemical components. Methods. A cross-sectional, observational study of 322 RA patients with active disease (mean DAS28 6.0) awaiting therapy with a biologic agent was undertaken. Patients' illness beliefs, treatment beliefs, and mood were measured using the Brief Illness Perception Questionnaire (IPQ), the Beliefs about Medicines Questionnaire (BMQ), and the Hospital Anxiety and Depression Scale (HADS), respectively. Relationships between psychological factors and 1) total DAS28 and 2) individual components of the DAS28 were analyzed using linear regression. Results. Total DAS28 produced significant but weak associations with 2 of the Brief IPQ items, but no associations with BMQ or HADS scores. There were larger significant associations between the patient-reported visual analog scale (VAS) with 5 items of the Brief IPQ and with HADS depression. Low illness coherence was associated with higher tender joint count. Three Brief IPQ items and HADS anxiety scores were significantly associated with C-reactive protein level or erythrocyte sedimentation rate. No psychological factors were associated with the swollen joint count. Conclusion. One of the subjective components of the DAS28, patient VAS, was highly correlated with cognitive factors and depression in those with severe RA. By reporting individual DAS28 components, clinicians may be better able to assess the impact of therapies on each component, adjusting approaches according to patients' needs. © 2014 The Authors. Arthritis Care & Research is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.


Plant D.,Manchester Academy of Health science | Webster A.,University of Manchester | Nair N.,University of Manchester | Oliver J.,University of Manchester | And 8 more authors.
Arthritis and Rheumatology | Year: 2016

Objective Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. Methods An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. Results Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10-8 and cg26401028, P = 1.69 × 10-8). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10-7 and P = 1.05 × 10-6, respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204). Conclusion We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor-related protein 1. Additional replication experiments in independent sample collections are now needed. © 2016, American College of Rheumatology.


Banka S.,Institute of Human Development | Banka S.,University of Manchester | Cain S.A.,University of Manchester | Carim S.,Institute of Human Development | And 22 more authors.
Annals of the Rheumatic Diseases | Year: 2015

Objectives: Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. Methods: and results Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p. Ser71Thr, could confer protection against disease (p<1×10∼5). Conclusions: Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-β-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.


Oliver J.,University of Manchester | Plant D.,Manchester Academy of Health science | Webster A.P.,University of Manchester | Barton A.,University of Manchester | Barton A.,Manchester Academy of Health science
Biomarkers in Medicine | Year: 2015

Despite the success of anti-TNF drugs in the treatment of rheumatoid arthritis, a significant rate of nonresponse remains. Current clinical factors confer little power for predicting response and, in current practice, an unsatisfactory 'trial and error' approach governs therapeutic decisions. Candidate gene and unbiased genome-wide investigations have sought to identify genetic biomarkers that predict who will respond to anti-TNF drugs before the drug is administered. To date, few studies have yielded robust associations; herein, we discuss currently identified associations and the issues that need to be addressed in future investigations including insufficient power and an inadequate measure of disease activity. The potential for alternative predictors of anti-TNF therapy response from transcriptomic and epigenetic data will also be explored. © 2015 Future Medicine Ltd.


PubMed | University of Manchester and Manchester Academy of Health science
Type: Journal Article | Journal: Biomarkers in medicine | Year: 2015

Despite the success of anti-TNF drugs in the treatment of rheumatoid arthritis, a significant rate of nonresponse remains. Current clinical factors confer little power for predicting response and, in current practice, an unsatisfactory trial and error approach governs therapeutic decisions. Candidate gene and unbiased genome-wide investigations have sought to identify genetic biomarkers that predict who will respond to anti-TNF drugs before the drug is administered. To date, few studies have yielded robust associations; herein, we discuss currently identified associations and the issues that need to be addressed in future investigations including insufficient power and an inadequate measure of disease activity. The potential for alternative predictors of anti-TNF therapy response from transcriptomic and epigenetic data will also be explored.

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