Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene.
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.
Michou
Laëtitia
L
GenHotel-EA 3886, University Evry-Paris 7 Medical School, Member of the AutoCure European Consortium, CP5727, 91057 Evry-Genopole Cedex, France. michou@polyarthrite.net
Lasbleiz
Sandra
S
Rat
Anne-Christine
AC
Migliorini
Paola
P
Balsa
Alejandro
A
Westhovens
René
R
Barrera
Pilar
P
Alves
Helena
H
Pierlot
Céline
C
Glikmans
Elodie
E
Garnier
Sophie
S
Dausset
Jean
J
Vaz
Carlos
C
Fernandes
Manuela
M
Petit-Teixeira
Elisabeth
E
Lemaire
Isabelle
I
Pascual-Salcedo
Dora
D
Bombardieri
Stefano
S
Dequeker
Jan
J
Radstake
Timothy R
TR
Van Riel
Piet
P
van de Putte
Leo
L
Lopes-Vaz
Antonio
A
Prum
Bernard
B
Bardin
Thomas
T
Dieudé
Philippe
P
Cornélis
François
F
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
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