The Prospective Registry of MyositIS (PROMIS): I. Next-generation sequencing identifies HLA-DQA1 as a novel genetic risk of anti-MDA5 antibody-positive dermatomyositis

Antimelanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM) is a rare subtype of myositis with a poor prognosis and insufficient genetic understanding. Our study aimed to identify risk variants associated with anti-MDA5+ DM and to assess their correlation with clinical outcomes. We enrolled 231 anti-MDA5+ DM patients, 127 anti-MDA5⁻ DM patients, 1468 patients with non-DM rheumatic disease, and 1027 healthy controls, with an additional 51 anti-MDA5+ DM patients for validation. Whole-exome sequencing was used to identify human leukocyte antigen (HLA) alleles, amino acids, and single nucleotide polymorphisms (SNPs) in major histocompatibility complex (MHC) and non-MHC regions. Association studies were performed to identify genetic variants associated with anti-MDA5+ DM by comparing different sets of control groups. A clinical association study was conducted to further explore the influence of genetic factors on clinical manifestations. Two novel genetic risks, HLA-DQA1*06:01 and HLA-DQB1*06:09, were significantly associated with anti-MDA5+ DM in both the discovery and validation cohorts. HLA-DQA1*06:01 was particularly prevalent in anti-MDA5+ DM (20.4%) compared with anti-MDA5⁻ DM (6.69%) and non-DM rheumatic disease (5.93%). Besides, the strongest associated amino acid was HLA-DQα1:69 (P = 3.27 × 10-11), and 1 SNP in the ARHGAP22 gene (rs76208937) showed suggestive significance (P = 7.99 × 10-6). In addition, HLA-DQA1*06:01 was linked to acute rapidly progressive interstitial lung disease (P < .001), elevated levels of lactate dehydrogenase (P = .026), and death (P = .049) in patients with anti-MDA5+ DM. HLA-DQA1*06:01 is a new genetic and prognostic factor for anti-MDA5+ DM, potentially serving as a biomarker for early diagnosis and intervention.