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


Zochling, J and Newell, F and Charlesworth, JC and Leo, P and Stankovich, J and Cortes, A and Zhou, Y and Stevens, W and Sahhar, J and Roddy, J and Nash, P and Tymms, K and Rischmueller, M and Lester, S and Proudman, S and Brown, MA, An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3, Arthritis Research & Therapy, 16, (5) Article 438. ISSN 1478-6362 (2014) [Refereed Article]


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Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

DOI: doi:10.1186/s13075-014-0438-8


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׿1010) 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.

Item Details

Item Type:Refereed Article
Keywords:scleroderma genetics
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Rheumatology and arthritis
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Zochling, J (Dr Jane Zochling)
UTAS Author:Charlesworth, JC (Dr Jac Charlesworth)
UTAS Author:Stankovich, J (Dr Jim Stankovich)
UTAS Author:Zhou, Y (Mr Yuan Zhou)
ID Code:96990
Year Published:2014
Web of Science® Times Cited:44
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-11-27
Last Modified:2017-11-03
Downloads:333 View Download Statistics

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