1. Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene
- Author
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Michou, Laëtitia, Lasbleiz, Sandra, Rat, Anne-Christine, Migliorini, Paola, Balsa, Alejandro, Westhovens, René, Barrera, Pilar, Alves, Helena, Pierlot, Céline, Glikmans, Elodie, Garnier, Sophie, Dausset, Jean, Vaz, Carlos, Fernandes, Manuela, Petit-Teixeira, Elisabeth, Lemaire, Isabelle, Pascual-Salcedo, Dora, Bombardieri, Stefano, Dequeker, Jan, Radstake, Timothy R., van Riel, Piet, Putte, Leo, Lopes-Vaz, Antonio, Prum, Bernard, Bardin, Thomas, Dieudé, Philippe, Cornélis, François, Families, European Consortium, Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel - EA 3886), Université d'Évry-Val-d'Essonne (UEVE), Service de Rhumatologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), La Paz Hospital, IdiPAZ, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Unité de Catalyse et de Chimie du Solide - UMR 8181 (UCCS), Université d'Artois (UA)-Ecole Centrale de Lille-Ecole Nationale Supérieure de Chimie de Lille (ENSCL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, ENITA LEMPDES, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Service de Recherche en Hémato-Immunologie (SRHI - UMR_E 05), Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Center for Research in Ceramic and Composite Materials (CICECO), Universidade de Aveiro, Université de Pise, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Service de Rhumatologie [CHU Lariboisière], Hôpital Lariboisière, Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel), Unité de Génétique Clinique Adulte, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospital La Paz, Madrid, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Biologie, Centre Hospitalier Sud Francilien, Laboratoire Statistique et Génome (SG), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), and CH Evry-Corbeil-CH Evry-Corbeil
- Subjects
Male ,Linkage disequilibrium ,Genetic Linkage ,Autoimmunity ,Linkage Disequilibrium ,Arthritis, Rheumatoid ,0302 clinical medicine ,Gene Frequency ,Rheumatoid ,Genotype ,transmission disequilibrium ,Non-Receptor Type 1 ,ComputingMilieux_MISCELLANEOUS ,Genetics ,Chronic inflammation and autoimmunity [UMCN 4.2] ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,0303 health sciences ,education.field_of_study ,Multidisciplinary ,Biological Sciences ,Non-Receptor Type 22 ,3. Good health ,Pathogenesis and modulation of inflammation [N4i 1] ,[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,linkage analysis ,R620W polymorphism ,rheumatoid factor ,LYP protein ,Female ,Infection and autoimmunity [NCMLS 1] ,Adult ,Population ,Biology ,Auto-immunity, transplantation and immunotherapy [N4i 4] ,PTPN22 ,03 medical and health sciences ,Genetic ,Genetic linkage ,Rheumatoid Factor ,Rheumatoid factor ,Humans ,Genetic Predisposition to Disease ,Allele ,Polymorphism ,education ,Allele frequency ,Alleles ,030304 developmental biology ,030203 arthritis & rheumatology ,Polymorphism, Genetic ,Arthritis ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,HLA-DR Antigens ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Evaluation of complex medical interventions [NCEBP 2] ,Immunology ,Protein Tyrosine Phosphatase ,Protein Tyrosine Phosphatases ,Immunity, infection and tissue repair [NCMLS 1] ,HLA-DRB1 Chains - Abstract
The tyrosine phosphatase PTPN22 allele 1858T has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. RA is the most frequent of those multifactorial diseases. The RA association was usually restricted to serum rheumatoid factor positive disease (RF + ). No interaction was shown with HLA-DRB1 , the first RA gene. Many case-control studies replicated the RA association, showing an allele frequency increase of ≈5% on average and large variations of population allele frequencies (2.1–15.5%). In multifactorial diseases, the final proof for a new susceptibility allele is provided by departure from Mendel's law (50% transmission from heterozygous parents). For PTPN22–1858T allele, convincing linkage proof was available only for type 1 diabetes. We aimed at providing this proof for RA. We analyzed 1,395 West European Caucasian individuals from 465 “trio” families. We replicated evidence for linkage, demonstrating departure from Mendel's law in this subset of early RA onset patients. We estimated the overtransmission of the 1858T allele in RF + families: T = 63%, P < 0.0007. The 1858T allele frequency increased from 11.0% in controls to 17.4% in RF + RA for the French Caucasian population and the susceptibility genotype ( 1858T / T or T / C ) from 20.2% to 31.6% [odds ratio (OR) = 1.8 (1.2–2.8)]. In conclusion, we provided the linkage proof for the PTPN22–1858T allele and RF + RA. With diabetes and RA, PTPN22 is therefore a “linkage-proven” autoimmunity gene. PTPN22 accounting for ≈1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.
- Published
- 2007
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