Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.
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.
National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
F W
FW
Miller
M.D. Anderson Cancer Center, Houston, TX, USA.
W
W
Chen
National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
T P
TP
O'Hanlon
MRC/ARUK Institute for Ageing and Chronic Disease, University of Liverpool, UK.
R G
RG
Cooper
Institute of Rheumatology, Charles University, Prague, Czech Republic.
J
J
Vencovsky
National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
L G
LG
Rider
3rd Department of Internal Medicine, Division of Immunology University of Debrecen, Debrecen, Hungary.
K
K
Danko
Institute of Child Health, University College London, London, UK.
L R
LR
Wedderburn
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
I E
IE
Lundberg
Department of Pediatric Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
L M
LM
Pachman
Mayo Clinic, Rochester, MN, USA.
A M
AM
Reed
Mayo Clinic, Rochester, MN, USA.
S R
SR
Ytterberg
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
L
L
Padyukov
Vall d'Hebron General Hospital, Barcelona, Spain.
A
A
Selva-O'Callaghan
Department of Rheumatology and Clinical Immunology, Laboratory for Translational Immunology, Utrecht University Medical Center; and Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands.
T R
TR
Radstake
Division of Medicine, University College London, London, UK.
D A
DA
Isenberg
The National Institute for Health Research Manchester Musculoskeletal Biomedical Research Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK.
H
H
Chinoy
Centre for Integrated Genomic Medical Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
W E R
WE
Ollier
M.D. Anderson Cancer Center, Houston, TX, USA.
P
P
Scheet
M.D. Anderson Cancer Center, Houston, TX, USA.
B
B
Peng
Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, USA.
A
A
Lee
Department of Community and Family Medicine, Dartmouth College, Hanover, NH, USA.
J
J
Byun
Centre for Integrated Genomic Medical Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
J A
JA
Lamb
Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, USA.
P K
PK
Gregersen
Department of Community and Family Medicine, Dartmouth College, Hanover, NH, USA.
C I
CI
Amos
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001323:Autoantibodies / Q000276:immunology; D016022:Case-Control Studies; D003882:Dermatomyositis / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009220:Myositis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017285:Polymyositis / Q000235:genetics; D012307:Risk Factors; D044465:White People
D001323:Autoantibodies; D006680:HLA Antigens