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Type: Journal article
Title: An immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3
Author: Zochling, J.
Newell, F.
Charlesworth, J.
Leo, P.
Stankovich, J.
Cortes, A.
Zhou, Y.
Stevens, W.
Sahhar, J.
Roddy, J.
Nash, P.
Tymms, K.
Rischmueller, M.
Lester, S.
Proudman, S.
Brown, M.
Citation: Arthritis Research and Therapy, 2014; 16(5):438-1-438-7
Publisher: BioMed Central
Issue Date: 2014
ISSN: 1478-6354
Statement of
Jane Zochling, Felicity Newell, Jac C Charlesworth, Paul Leo, Jim Stankovich, Adrian Cortes, Yuan Zhou, Wendy Stevens, Joanne Sahhar, Janet Roddy, Peter Nash, Kathleen Tymms, Maureen Rischmueller, Sue Lester, Susanna Proudman, and Matthew A Brown
Abstract: INTRODUCTION: The aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population. METHODS: We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls. RESULTS: A total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 × 10(-10)) in anti-centromere antibody (ACA) positive cases. CONCLUSIONS: This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.
Keywords: Centromere
Scleroderma, Systemic
Genetic Predisposition to Disease
Logistic Models
Odds Ratio
Cohort Studies
Pilot Projects
Gene Frequency
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Middle Aged
Genetic Pleiotropy
Rights: © 2014 Zochling et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
DOI: 10.1186/s13075-014-0438-8
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