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Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.
Okada, Yukinori; Han, Buhm; Tsoi, Lam C; Stuart, Philip E; Ellinghaus, Eva; Tejasvi, Trilokraj; Chandran, Vinod; Pellett, Fawnda; Pollock, Remy; Bowcock, Anne M; Krueger, Gerald G; Weichenthal, Michael; Voorhees, John J; Rahman, Proton; Gregersen, Peter K; Franke, Andre; Nair, Rajan P; Abecasis, Gonçalo R; Gladman, Dafna D; Elder, James T; de Bakker, Paul I W; Raychaudhuri, Soumya.
Afiliación
  • Okada Y; Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-0085, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Division of Rheumatology, Immu
  • Han B; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambri
  • Tsoi LC; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Stuart PE; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Ellinghaus E; Institute of Clinical Molecular Biology, Kiel University, Kiel 24105, Germany.
  • Tejasvi T; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Chandran V; Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON M5T 2S8, Canada; Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada.
  • Pellett F; Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada.
  • Pollock R; Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada.
  • Bowcock AM; National Heart and Lung Institute, Imperial College, London SW7 2AZ, UK.
  • Krueger GG; Department of Dermatology, University of Utah, Salt Lake City, UT 84112, USA.
  • Weichenthal M; Department of Dermatology, Christian-Albrechts-Universität zu Kiel, Kiel 24105, Germany.
  • Voorhees JJ; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Rahman P; Memorial University of Newfoundland, St. John's, NL A1C5S7, Canada.
  • Gregersen PK; The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA.
  • Franke A; Institute of Clinical Molecular Biology, Kiel University, Kiel 24105, Germany.
  • Nair RP; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Abecasis GR; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Gladman DD; Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, ON M5T 2S8, Canada; Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University of Toronto, Toronto, ON M5T 2S8, Canada; Toronto Western Research Institute, University of Toro
  • Elder JT; Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA.
  • de Bakker PI; Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands. Electronic address:
  • Raychaudhuri S; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambri
Am J Hum Genet ; 95(2): 162-72, 2014 Aug 07.
Article en En | MEDLINE | ID: mdl-25087609
ABSTRACT
Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)0602 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)0602-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)1203, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Psoriasis / Antígenos de Histocompatibilidad Clase I / Antígenos de Histocompatibilidad Clase II / Complejo Mayor de Histocompatibilidad Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2014 Tipo del documento: Article
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Psoriasis / Antígenos de Histocompatibilidad Clase I / Antígenos de Histocompatibilidad Clase II / Complejo Mayor de Histocompatibilidad Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2014 Tipo del documento: Article