title: Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations.
abstract: Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope (Pomnibus = 6.9 × 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)--but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional Pomnibus = 2.2 × 10(-33)) and 74 (conditional Pomnibus = 1.1 × 10(-8)). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 × 10(-6)) and HLA-DPβ1 (Phe9, conditional P = 3.0 × 10(-5)) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.
authors: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan Division of Rheumatology, Immunology, and Allergy and Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors: Yukinori
authors: Y
authors: Okada
authors: Division of Rheumatology, Immunology, and Allergy and Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.
authors: Kwangwoo
authors: K
authors: Kim
authors: Division of Rheumatology, Immunology, and Allergy and Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
authors: Buhm
authors: B
authors: Han
authors: Saw Swee Hock School of Public Health.
authors: Nisha E
authors: NE
authors: Pillai
authors: Saw Swee Hock School of Public Health.
authors: Rick T-H
authors: RT
authors: Ong
authors: Saw Swee Hock School of Public Health.
authors: Woei-Yuh
authors: WY
authors: Saw
authors: Department of Medical Microbiology, University of Manitoba, Winnepeg, Canada National Microbiology Laboratory, Winnipeg, Canada.
authors: Ma
authors: M
authors: Luo
authors: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
authors: Lei
authors: L
authors: Jiang
authors: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
authors: Jian
authors: J
authors: Yin
authors: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.
authors: So-Young
authors: SY
authors: Bang
authors: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.
authors: Hye-Soon
authors: HS
authors: Lee
authors: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia.
authors: Matthew A
authors: MA
authors: Brown
authors: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea.
authors: Sang-Cheol
authors: SC
authors: Bae
authors: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.
authors: Huji
authors: H
authors: Xu
authors: Saw Swee Hock School of Public Health Life Sciences Institute Department of Statistics and Applied Probability and NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
authors: Yik-Ying
authors: YY
authors: Teo
authors: Department of Medical Genetics, Center for Molecular Medicine and Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands and.
authors: Paul I W
authors: PI
authors: de Bakker
authors: Division of Rheumatology, Immunology, and Allergy and Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK soumya@broadinstitute.org.
authors: Soumya
authors: S
authors: Raychaudhuri
mesh_terms: D000483:Alleles; D000596:Amino Acids / Q000235:genetics / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000208:ethnology* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D044466:Asian People; D001323:Autoantibodies / Q000096:biosynthesis; D002874:Chromosome Mapping; D002956:Citrulline / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015870:Gene Expression; D005787:Gene Frequency; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D059868:HLA-DP beta-Chains / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006801:Humans; D011110:Polymorphism, Genetic; D012306:Risk; D044465:White People
chemical_list: D000596:Amino Acids; D001323:Autoantibodies; D000939:Epitopes; D015235:HLA-B Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059811:HLA-DRB1 Chains; D002956:Citrulline