TY - JOUR
T1 - An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3
AU - Zochling, Jane
AU - Newell, Felicity
AU - Charlesworth, Jac C.
AU - Leo, Paul
AU - Stankovich, Jim
AU - Cortes, Adrian
AU - Zhou, Yuan
AU - Stevens, Wendy
AU - Sahhar, Joanne
AU - Roddy, Janet
AU - Nash, Peter
AU - Tymms, Kathleen
AU - Rischmueller, Maureen
AU - Lester, Sue
AU - Proudman, Susanna
AU - Brown, Matthew A.
N1 - Publisher Copyright:
© 2014 Zochling et al.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84988843948&partnerID=8YFLogxK
U2 - 10.1186/s13075-014-0438-8
DO - 10.1186/s13075-014-0438-8
M3 - Article
SN - 1478-6354
VL - 16
JO - Arthritis Research and Therapy
JF - Arthritis Research and Therapy
IS - 1
M1 - 438
ER -