Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

F. W. Miller; W. Chen; T. P. O'Hanlon; R. G. Cooper; J. Vencovsky; L. G. Rider; K. Danko; L. R. Wedderburn; I. E. Lundberg; L. M. Pachman; A. M. Reed; S. R. Ytterberg; L. Padyukov; A. Selva-O'Callaghan; T. R. Radstake; D. A. Isenberg; H. Chinoy; W. E.R. Ollier; P. Scheet; B. Peng; A. Lee; J. Byun; J. A. Lamb; P. K. Gregersen; C. I. Amos

doi:10.1038/gene.2015.28

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

F. W. Miller, W. Chen, T. P. O'Hanlon, R. G. Cooper, J. Vencovsky, L. G. Rider, K. Danko, L. R. Wedderburn, I. E. Lundberg, L. M. Pachman, A. M. Reed, S. R. Ytterberg, L. Padyukov, A. Selva-O'Callaghan, T. R. Radstake, D. A. Isenberg, H. Chinoy, W. E.R. Ollier, P. Scheet, B. PengA. Lee, J. Byun, J. A. Lamb, P. K. Gregersen, C. I. Amos

Rheumatology

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Abstract

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10-8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1∗03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B∗08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

Original language	English (US)
Pages (from-to)	470-480
Number of pages	11
Journal	Genes and Immunity
Volume	16
Issue number	7
DOIs	https://doi.org/10.1038/gene.2015.28
State	Published - Oct 1 2015

ASJC Scopus subject areas

Immunology
Genetics
Genetics(clinical)

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Miller, F. W., Chen, W., O'Hanlon, T. P., Cooper, R. G., Vencovsky, J., Rider, L. G., Danko, K., Wedderburn, L. R., Lundberg, I. E., Pachman, L. M., Reed, A. M., Ytterberg, S. R., Padyukov, L., Selva-O'Callaghan, A., Radstake, T. R., Isenberg, D. A., Chinoy, H., Ollier, W. E. R., Scheet, P., ... Amos, C. I. (2015). Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes. Genes and Immunity, 16(7), 470-480. https://doi.org/10.1038/gene.2015.28

Miller, FW, Chen, W, O'Hanlon, TP, Cooper, RG, Vencovsky, J, Rider, LG, Danko, K, Wedderburn, LR, Lundberg, IE, Pachman, LM, Reed, AM, Ytterberg, SR, Padyukov, L, Selva-O'Callaghan, A, Radstake, TR, Isenberg, DA, Chinoy, H, Ollier, WER, Scheet, P, Peng, B, Lee, A, Byun, J, Lamb, JA, Gregersen, PK & Amos, CI 2015, 'Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes', Genes and Immunity, vol. 16, no. 7, pp. 470-480. https://doi.org/10.1038/gene.2015.28

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title = "Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes",

abstract = "Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10-8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1∗03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B∗08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.",

author = "Miller, {F. W.} and W. Chen and O'Hanlon, {T. P.} and Cooper, {R. G.} and J. Vencovsky and Rider, {L. G.} and K. Danko and Wedderburn, {L. R.} and Lundberg, {I. E.} and Pachman, {L. M.} and Reed, {A. M.} and Ytterberg, {S. R.} and L. Padyukov and A. Selva-O'Callaghan and Radstake, {T. R.} and Isenberg, {D. A.} and H. Chinoy and Ollier, {W. E.R.} and P. Scheet and B. Peng and A. Lee and J. Byun and Lamb, {J. A.} and Gregersen, {P. K.} and Amos, {C. I.}",

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AU - Miller, F. W.

AU - Chen, W.

AU - O'Hanlon, T. P.

AU - Cooper, R. G.

AU - Vencovsky, J.

AU - Rider, L. G.

AU - Danko, K.

AU - Wedderburn, L. R.

AU - Lundberg, I. E.

AU - Pachman, L. M.

AU - Reed, A. M.

AU - Ytterberg, S. R.

AU - Padyukov, L.

AU - Selva-O'Callaghan, A.

AU - Radstake, T. R.

AU - Isenberg, D. A.

AU - Chinoy, H.

AU - Ollier, W. E.R.

AU - Scheet, P.

AU - Peng, B.

AU - Lee, A.

AU - Byun, J.

AU - Lamb, J. A.

AU - Gregersen, P. K.

AU - Amos, C. I.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10-8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1∗03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B∗08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

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Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

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