title: An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3.
abstract: BACKGROUND
  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.
authors.forename: Jane
authors.initials: J
authors.lastname: Zochling
authors.forename: Felicity
authors.initials: F
authors.lastname: Newell
authors.forename: Jac C
authors.initials: JC
authors.lastname: Charlesworth
authors.forename: Paul
authors.initials: P
authors.lastname: Leo
authors.forename: Jim
authors.initials: J
authors.lastname: Stankovich
authors.forename: Adrian
authors.initials: A
authors.lastname: Cortes
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Wendy
authors.initials: W
authors.lastname: Stevens
authors.forename: Joanne
authors.initials: J
authors.lastname: Sahhar
authors.forename: Janet
authors.initials: J
authors.lastname: Roddy
authors.forename: Peter
authors.initials: P
authors.lastname: Nash
authors.forename: Kathleen
authors.initials: K
authors.lastname: Tymms
authors.forename: Maureen
authors.initials: M
authors.lastname: Rischmueller
authors.forename: Sue
authors.initials: S
authors.lastname: Lester
authors.forename: Susanna
authors.initials: S
authors.lastname: Proudman
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D002503:Centromere / Q000276:immunology; D015331:Cohort Studies; D004706:Endodeoxyribonucleases / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology
chemical_list: D001323:Autoantibodies; C485421:DNASE1L3 protein, human; D004706:Endodeoxyribonucleases