Introduction. Understanding the genetic architecture of scleroderma (SSc) susceptibility is particularly important in understanding disease mechanism in a disease with few therapies and great morbidity and mortality.
Methods. We selected 557 cases from the Australian Scleroderma Cohort Study for genotyping with the Immunochip, a custom Illumina Infinium genotyping array containing 196 524 rare and common variants important in a wide variety of autoimmune disorders. 4537 controls were taken from the British Birth cohort. Genotype data were analysed with PLINK. The final data set consisted of 505 cases, 4491 controls and 146 867 SNPs. Allelic association analyses were conducted using Fisher’s exact test. Genotype clusters were manually examined for all associations of P<105.
Results. Significant associations were detected at seven loci. HLA-DRB1 and STAT4 have been previously implicated in scleroderma susceptibility. Several are novel, including SNPs near PXK (P=4.4x106) and CFDP1(P=2.6x106). The strongest associations were with SNPs in the Class II region of the MHC. One of the most strongly associated SNPs [rs4639334;P=1.6x108; odds ratio (OR)=1.8] is in linkage disequilibrium (r2=0.46) with the Class II allele HLA-DRB1*11:01. This allele hasbeen associated with SSc. Another strongly associated SNP is rs2857130 (P=1.6x108; OR=0.67), which lies in the promoter region of HLA-DRB1, but is not in LD with any classical MHC alleles. Outside the MHC, there were six regions of association with P<105, including the confirmed SSc locus at STAT4. Several SNPs implicate a locus at PXK, which has been previously associated with SLE but not with SSc. The remaining associations are novel for both SSc and SLE and require replication. Of particular interest is a rare variant located within a non-coding RNA on chromosome 6q21 whichwas 20 times more frequent in cases than controls.
Conclusions. This pilot study has confirmed previously reported SSc associations, revealed further genetic overlap between SSc and SLE, and identified putative novel SSc susceptibility loci including a rare allele with major effect size.