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

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-on...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307311/
https://www.ncbi.nlm.nih.gov/pubmed/35094092
http://dx.doi.org/10.1093/hmg/ddac019
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author 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
author_facet 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
author_sort Deakin, Claire T
collection PubMed
description 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.
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spelling pubmed-93073112022-07-25 Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis 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 Hum Mol Genet Association Studies 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. Oxford University Press 2022-01-31 /pmc/articles/PMC9307311/ /pubmed/35094092 http://dx.doi.org/10.1093/hmg/ddac019 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Association Studies Article
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
Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis
title Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis
title_full Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis
title_fullStr Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis
title_full_unstemmed Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis
title_short Association with HLA-DRβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis
title_sort association with hla-drβ1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis
topic Association Studies Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9307311/
https://www.ncbi.nlm.nih.gov/pubmed/35094092
http://dx.doi.org/10.1093/hmg/ddac019
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