Association with HLA-DRβ1 position 37 distinguishes juvenile Dermatomyositis from adult-onset myositis
Human molecular genetics
OBJECTIVES: Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease and the most common idiopathic inflammatory myopathy (IIM) 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 age of disease onset may influence pathogenesis. Therefore, a JDM-focused genetic analysis was performed using the largest collection of JDM samples to date. METHODS: Caucasian JDM samples (n = 952) obtained via international collaboration were genotyped using the Illumina HumanCoreExome chip. Additional non-assayed HLA loci and genome-wide SNPs were imputed. RESULTS: HLA-DRB1*03:01 was confirmed as the classical HLA allele most strongly associated with JDM (OR 1.66; 95% 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 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 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. CONCLUSIONS: 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.
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.; Wilkinson, Meredyth G.; Eyre, Stephen; Raychaudhuri, Soumya; and Wedderburn, Lucy R., "Association with HLA-DRβ1 position 37 distinguishes juvenile Dermatomyositis from adult-onset myositis" (2022). GW Authored Works. Paper 207.