TY - JOUR
T1 - Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis
AU - Juvenile Dermatomyositis Cohort Biomarker Study and Repository (UK and Ireland)
AU - The Myositis Genetics Consortium (MYOGEN)
AU - Childhood Myositis Heterogeneity Study Group
AU - Deakin, Claire T
AU - Bowes, John
AU - Rider, Lisa G
AU - Miller, Frederick W
AU - Pachman, Lauren M
AU - Sanner, Helga
AU - Rouster-Stevens, Kelly
AU - Mamyrova, Gulnara
AU - Curiel, Rodolfo
AU - Feldman, Brian M
AU - Huber, Adam M
AU - Reed, Ann M
AU - Schmeling, Heinrike
AU - Cook, Charlotte G
AU - Marshall, Lucy R
AU - Ll Wilkinson, Meredyth G
AU - Eyre, Stephen
AU - Raychaudhuri, Soumya
AU - Wedderburn, Lucy R
N1 - © The Author(s) 2022. Published by Oxford University Press.
PY - 2022/7/15
Y1 - 2022/7/15
N2 - 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.
AB - 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.
KW - Adult
KW - Alleles
KW - Amino Acids/genetics
KW - Child
KW - Dermatomyositis/diagnosis
KW - Genetic Predisposition to Disease
KW - HLA-C Antigens/genetics
KW - HLA-DRB1 Chains/genetics
KW - Haplotypes/genetics
KW - Humans
KW - Myositis/diagnosis
U2 - 10.1093/hmg/ddac019
DO - 10.1093/hmg/ddac019
M3 - Article
C2 - 35094092
SN - 0964-6906
VL - 31
SP - 2471
EP - 2481
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 14
ER -