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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Deakin, CT; Bowes, J; Rider, LG; Miller, FW; Pachman, LM; Sanner, H; Rouster-Stevens, K; Mamyrova, G; Curiel, R; Feldman, BM; Huber, AM; Reed, AM; Schmeling, H; Cook, CG; Marshall, LR; Ll Wilkinson, MG; Eyre, S; Raychaudhuri, S; Wedderburn, LR; Juvenile Dermatomyositis Cohort and Biomarker Study, the Childhood Myositis Heterogeneity Study Group, and the Myositis Genetics Consortium (MYOGEN),

Published Date

  • July 21, 2022

Published In

Volume / Issue

  • 31 / 14

Start / End Page

  • 2471 - 2481

PubMed ID

  • 35094092

Pubmed Central ID

  • PMC9307311

Electronic International Standard Serial Number (EISSN)

  • 1460-2083

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddac019

Language

  • eng

Conference Location

  • England