Objective: A case-control association study was conducted to determine HLA-class II (DRB1, DQB1, DQA1, and DPB1) alleles, haplotypes and shared epitopes associated with scleroderma (systemic sclerosis or SSc) and its sub-phenotypes in a large multi-ethnic US cohort.
Patients and methods: 1300 SSc cases (961 whites, 178 blacks and 161 Hispanics) characterized for clinical skin forms (limited vs diffuse), SSc- specific autoantibodies (anti-centromere (ACA), anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 RNP (fibrillarin), and others were studied using molecular genotyping. Statistical analyses in SSc itself by ethnicity, gender, skin type and autoantibodies were performed using exact logistic regression modeling for dominant (D), additive (A) and recessive (R) effects from HLA.
Results: The strongest positive class II associations with SSc in whites and Hispanics were the DRB1*1104, DQA1*0501, DQB1*0301 haplotype, and DQB1 alleles encoding a non-leucine residue at position 26 (DQB1 26 epi), while the DRB1*0701, DQA1*0201, DQB1*0202 haplotype and DRB1*1501 haplotype were negatively correlated and possibly protective in dominant and recessive models, respectively. These associations did not discriminate limited SSc from diffuse SSc. SSc in blacks was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles. DPB1*1301 showed the highest odds ratio for ATA (OR=14). Moreover, it showed no LD or gene interaction with DR/DQ. ACA was best explainable by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and DQB1*03 alleles in whites and Hispanics but DRB1*08 in blacks. These data indicate unique and multiple HLA class II effects in SSc, especially on autoantibody markers of different sub-phenotypes.