Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups.
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Rothwell Simon, Chinoy Hector, Lamb Janine A, Miller Frederick W, Rider Lisa G, Wedderburn Lucy R, McHugh Neil J, Mammen Andrew L, Betteridge Zoe E, Tansley Sarah L, Bowes John, Vencovský Jiří, Deakin Claire T, Dankó Katalin, Vidya Limaye, Selva-O'Callaghan Albert, Pachman Lauren M, Reed Ann M, Molberg Øyvind, Benveniste Olivier, Mathiesen Pernille R, Radstake Timothy R D J, Doria Andrea, de Bleecker Jan, Lee Annette T, Hanna Michael G, Machado Pedro M, Ollier William E, Gregersen Peter K, Padyukov Leonid, O'Hanlon Terrance P, Cooper Robert G, Lundberg Ingrid E, Myositis Genetics Consortium (MYOGEN)
Аннотация
METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups.
RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10-5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10-53 and HLA-DRB1*03:01, p=3.25×10-9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10-26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10-11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10-13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10-6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10-64) and position 9 of HLA-B (p=7.03×10-11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies.
CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.