Molecular typing of HLA-class II alleles reveals an association with autoantibodies and disease subsets of systemic sclerosis in a North Indian (Kashmir) population

Abstract

Aim of the work

To identify specific human leukocyte antigen (HLA)-Class II (DRB/DQB1/DPB1) alleles associated with systemic sclerosis (SSc) and to explore their relation with SSc autoantibodies, clinical manifestations, and disease subsets.

Patients and methods

HLA-class II alleles (DRB1/DRB3/DRB4/DRB5/DQB1) were determined by DNA typing in 80 SSc cases and 60 matched controls and HLA-DPB1 in 40 SSc patients and 30 controls by allele-specific-polymerase chain reaction with sequence-specific primers (PCR-SSP).

Results

The mean age of SSc patients was 36.9 ± 9.4 years; 76 females and 4 males (F:M 19:1) and a disease duration of 5.3 ± 3.3 years, they were 43(53.7%) limited and 37(46.2%) diffuse subtypes. SSc was significantly associated with DRB1*11, DRB1*01, DQB1*04, and DQB1*03*03 in a >4-fold manner, whereas DPB1*04 had a >7-fold increased risk compared to controls. There was a strong association between DRB1*11 (p = 0.04), DQB1*03*03 (p = 0.005), and DPB1*13 (p = 0.009) with anti-topoisomerase I (anti-topoI) whereas the frequency of DRB1*01 (p < 0.0001) was increased in patients with anti-centromere (ACA) positive SSc compared those negative (56% vs 25%; p < 0.0001). DRB1*03, DRB1*15, and DQB1*03*01 were SSc protective alleles in patients with positive ACA. Anti-topo I was associated with interstitial lung disease (ILD) (p < 0.01), whereas ACA with pulmonary arterial hypertension (PAH) (p = 0.01) and protection against ILD (p < 0.001). In addition, HLA-DRB1*03, DQB1*03*01and DPB1*03 were more frequent in patients with ILD than in patients without.

Conclusion

Associations between specific HLA-class II alleles with certain SSc-specific autoantibodies (anti-topo I and ACA) were identified. Specific HLA associations with clinical and serological subtypes could serve as biomarkers of disease severity and progression in SSc.