title: Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene.
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 approximately 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 approximately 1% of the RA familial aggregation, many new genes could be expected that are as many leads to definitive therapy for autoimmune diseases.
authors.affiliation: GenHotel-EA 3886, University Evry-Paris 7 Medical School, Member of the AutoCure European Consortium, CP5727, 91057 Evry-Genopole Cedex, France. michou@polyarthrite.net
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Michou
authors.forename: Sandra
authors.initials: S
authors.lastname: Lasbleiz
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Rat
authors.forename: Paola
authors.initials: P
authors.lastname: Migliorini
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: René
authors.initials: R
authors.lastname: Westhovens
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Helena
authors.initials: H
authors.lastname: Alves
authors.forename: Céline
authors.initials: C
authors.lastname: Pierlot
authors.forename: Elodie
authors.initials: E
authors.lastname: Glikmans
authors.forename: Sophie
authors.initials: S
authors.lastname: Garnier
authors.forename: Jean
authors.initials: J
authors.lastname: Dausset
authors.forename: Carlos
authors.initials: C
authors.lastname: Vaz
authors.forename: Manuela
authors.initials: M
authors.lastname: Fernandes
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petit-Teixeira
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lemaire
authors.forename: Dora
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.forename: Stefano
authors.initials: S
authors.lastname: Bombardieri
authors.forename: Jan
authors.initials: J
authors.lastname: Dequeker
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Radstake
authors.forename: Piet
authors.initials: P
authors.lastname: Van Riel
authors.forename: Leo
authors.initials: L
authors.lastname: van de Putte
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopes-Vaz
authors.forename: Bernard
authors.initials: B
authors.lastname: Prum
authors.forename: Thomas
authors.initials: T
authors.lastname: Bardin
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.forename: François
authors.initials: F
authors.lastname: Cornélis
mesh_terms: D000328:Adult; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D015551:Autoimmunity / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012217:Rheumatoid Factor / Q000235:genetics
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D012217:Rheumatoid Factor; C516765:PTPN22 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases