Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes.

Objective: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes.

Methods: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA).

Results: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with and , and revealed a novel association of . Stratified analyses showed specific associations of with lcSSc, and an exclusive association of with dcSSc. Similarly, private associations were detected in and confirmed the previously reported association of with ACA-positive patients, as opposed to the and alleles associated with ATA presentation.

Conclusions: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.