title: Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity.
abstract: Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA(-) RA and observed independent associations for serine and leucine at position 11 in HLA-DRβ1 (p = 1.4 × 10(-13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 × 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1(∗)03 (encoding serine at 11) and HLA-B(∗)08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DRβ1 Ser11+Leu11: p = 5.8 × 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 × 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DRβ1 position 11 were distinct (p < 2.9 × 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 × 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.
authors.affiliation: Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA.
authors.forename: Buhm
authors.initials: B
authors.lastname: Han
authors.affiliation: Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Diogo
authors.affiliation: Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Kallberg
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands; Department of Genetics, University Medical Center Groningen and University of Groningen, 9700 RB Groningen, the Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Rheumatology Division, Hospital Universitario Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, 39008 Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: González-Gay
authors.affiliation: Department of Public Health and Clinical Medicine and Department of Rheumatology, Umeå University, 901 85 Umeå, Sweden.
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.affiliation: Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, 18100 Armilla, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: Merck Research Laboratories, Merck & Co. Inc., Boston, MA 02115, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.affiliation: Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Departments of Epidemiology and Medical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA; Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK. Electronic address: soumya@broadinstitute.org.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D018740:Genetic Heterogeneity; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans
chemical_list: D006680:HLA Antigens