title: The HLA-DRβ1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations.
abstract: Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRβ1 (P=2.48 × 10(-17)) and its proxy position 11 (P=4.15 × 10(-17)), followed by position 26 in a stepwise conditional analysis (P=2.42 × 10(-9)). Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRβ1 that are responsible for most of the association between SLE and MHC.
authors.affiliation: 1] Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea [2] Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Bang
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.affiliation: 1] Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA [4] Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-0034, Japan [5] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: 1] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA [3] Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore.
authors.forename: Woei-Yuh
authors.initials: WY
authors.lastname: Saw
authors.affiliation: 1] Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore [2] Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore [3] Department of Statistics and Applied Probability, National University of Singapore, Singapore 117546, Singapore [4] NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore 117456, Singapore [5] Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672, Singapore.
authors.forename: Yik-Ying
authors.initials: YY
authors.lastname: Teo
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011485:Protein Binding; D056910:Republic of Korea
chemical_list: D059811:HLA-DRB1 Chains