HLA contributions to risk and protection for anti-centromere autoantibody-positive scleroderma
Arthritis and Rheumatology
Background/Purpose: Anti-nuclear autoantibodies are a hallmark of scleroderma with anti-centromere antibody (ACA) recognizing centromeric antigens. ACA-positive patients have longstanding Raynaud's, limited cutaneous disease and increased risk for pulmonary arterial hypertension. We investigated the role of HLA classical genes and alleles on risk for ACA-positive scleroderma in a large collection of patients with scleroderma and genetically matched controls. Methods: SNP genotypes of 723 scleroderma cases and 5,561 controls, all of European ancestry, were obtained from dbGaP. Classical HLA types were imputed with SNP2HLA using the Type I Diabetes Genetic Consortium reference of 5,225 individuals. Association of HLA classical alleles was tested by a dominant model regression analysis coding the HLA types as numeric values (1 for present, 0 for absent). Regression tests were corrected for genetic dissimilarity by including the top 5 principal components as covariates. Results: Of the 723 scleroderma cases, 238 (32.9%) were positive for ACA. The most significantly ACA-positive scleroderma-associated HLA allele was HLA-DRB1∗07:01, which was disease protective (P-value=1.8x10-18, odds ratio (OR)=0.11 (95%CI=0.05 to 0.22)). This allele was found in only 3.4% of the ACA-positive cases versus 23.6% of controls and 20.8% of the ACA-negative cases. Regression analysis conditioning on the disease-associated alleles identified HLADQB1∗ 05:01 as the most significantly associated disease risk allele (P-value= 3.3x10-08, OR=2.18 (1.66-2.86)) with additional independent risk effects of HLA-DQA1∗04:01 and HLA-DQA1∗03:01). A two-locus analysis of the DQB1∗05:01 disease-risk and the DRB1∗07:01 disease-protective alleles suggested the risk effect of DQB1∗05:01 is overridden by the protective effect of DRB1∗07:01(Figure 1). The odds ratio for ACA-positive disease in individuals carrying both alleles was 0.14, similar to that in individuals carrying DRB1∗07:01 without DQB1∗05:01 (0.15). No effect of DRB1∗07:01 or DQB1∗05:01 was found in the anti-topoisomerase I autoantibody subset (P=0.98 and P=0.054, respectively). For validation, 62 African American ACA-positive cases and 946 matched controls from the Genomic Research in African American Scleroderma Patients (GRASP) Collection, were similarly analyzed. DQB1∗05:01 was associated with disease risk (P=3.6x10-4, OR=2.68 (1.57-4.58)) and DRB1∗07:01 was protective (P=8.6x10-3, OR=0.33 (0.13-0.85)) in the African American sample. Conclusion: HLA-DQB1∗05:01 is associated with risk and HLA-DRB1∗07:01 is associated with protection for ACA-positive scleroderma. The mechanisms responsible for these effects could be exploited to prevent or treat scleroderma. (Figure Presented).