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Zochling2014ART Scleroderma Immunochip.pdf (681.28 kB)

An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3

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posted on 2023-05-18, 05:29 authored by Zochling, J, Newell, F, Jac CharlesworthJac Charlesworth, Leo, P, Jim Stankovich, Cortes, A, Yuan ZhouYuan Zhou, Stevens, W, Sahhar, J, Roddy, J, Nash, P, Tymms, K, Rischmueller, M, Lester, S, Proudman, S, Brown, MA
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 1938 controls.

Results: A total of 8 loci with suggestive association (P <10-4.5) were identified, of which 5 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.

History

Publication title

Arthritis Research & Therapy

Volume

16

Issue

5

Article number

438

Number

438

Pagination

1-7

ISSN

1478-6362

Department/School

Menzies Institute for Medical Research

Publisher

Biomed Central Ltd

Place of publication

Middlesex House, 34-42 Cleveland St, London, England, W1T 4Lb

Rights statement

Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/

Repository Status

  • Open

Socio-economic Objectives

Clinical health not elsewhere classified

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