Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis

• Published in: Human molecular genetics 2022-07, Vol.31 (14), p.2471-2481
• Main Authors: Deakin, Claire T, Bowes, John, Rider, Lisa G, Miller, Frederick W, Pachman, Lauren M, Sanner, Helga, Rouster-Stevens, Kelly, Mamyrova, Gulnara, Curiel, Rodolfo, Feldman, Brian M, Huber, Adam M, Reed, Ann M, Schmeling, Heinrike, Cook, Charlotte G, Marshall, Lucy R, Ll Wilkinson, Meredyth G, Eyre, Stephen, Raychaudhuri, Soumya, Wedderburn, Lucy R
• Format: Article
• Language: English
• Subjects: Association Studies
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddac019

Abstract Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease and the most common idiopathic inflammatory myopathy of children. JDM and adult-onset dermatomyositis (DM) have similar clinical, biological and serological features, although these features differ in prevalence between childhood-onset and adult-onset disease, suggesting that age of disease onset may influence pathogenesis. Therefore, a JDM-focused genetic analysis was performed using the largest collection of JDM samples to date. Caucasian JDM samples (n = 952) obtained via international collaboration were genotyped using the Illumina HumanCoreExome chip. Additional non-assayed human leukocyte antigen (HLA) loci and genome-wide single-nucleotide polymorphisms (SNPs) were imputed. HLA-DRB1*03:01 was confirmed as the classical HLA allele most strongly associated with JDM [odds ratio (OR) 1.66; 95% confidence interval (CI) 1.46, 1.89; P = 1.4 × 10−14], with an independent association at HLA-C*02:02 (OR = 1.74; 95% CI 1.42, 2.13, P = 7.13 × 10−8). Analyses of amino acid positions within HLA-DRB1 indicated that the strongest association was at position 37 (omnibus P = 3.3 × 10−19), with suggestive evidence this association was independent of position 74 (omnibus P = 5.1 × 10−5), the position most strongly associated with adult-onset DM. Conditional analyses also suggested that the association at position 37 of HLA-DRB1 was independent of some alleles of the Caucasian HLA 8.1 ancestral haplotype (AH8.1) such as HLA-DQB1*02:01 (OR = 1.62; 95% CI 1.36, 1.93; P = 8.70 × 10−8), but not HLA-DRB1*03:01 (OR = 1.49; 95% CR 1.24, 1.80; P = 2.24 × 10−5). No associations outside the HLA region were identified. Our findings confirm previous associations with AH8.1 and HLA-DRB1*03:01, HLA-C*02:02 and identify a novel association with amino acid position 37 within HLA-DRB1, which may distinguish JDM from adult DM.