Analysis of TNFAIP3, a feedback inhibitor of nuclear factor-kappaB and the neighbor intergenic 6q23 region in rheumatoid arthritis susceptibility.
BACKGROUND
Genome-wide association studies of rheumatoid arthritis (RA) have identified an association of the disease with a 6q23 region devoid of genes. TNFAIP3, an RA candidate gene, flanks this region, and polymorphisms in both the TNFAIP3 gene and the intergenic region are associated with systemic lupus erythematosus. We hypothesized that there is a similar association with RA, including polymorphisms in TNFAIP3 and the intergenic region.


METHODS
To test this hypothesis, we selected tag-single nucleotide polymorphisms (SNPs) in both loci. They were analyzed in 1,651 patients with RA and 1,619 control individuals of Spanish ancestry.


RESULTS
Weak evidence of association was found both in the 6q23 intergenic region and in the TNFAIP3 locus. The rs582757 SNP and a common haplotype in the TNFAIP3 locus exhibited association with RA. In the intergenic region, two SNPs were associated, namely rs609438 and rs13207033. The latter was only associated in patients with anti-citrullinated peptide antibodies. Overall, statistical association was best explained by the interdependent contribution of SNPs from the two loci TNFAIP3 and the 6q23 intergenic region.


CONCLUSIONS
Our data are consistent with the hypothesis that several RA genetic factors exist in the 6q23 region, including polymorphisms in the TNFAIP3 gene, like that previously described for systemic lupus erythematosus.
Dieguez-Gonzalez
Rebeca
R
Laboratorio de Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain. rebeca.dieguez@usc.es
Calaza
Manuel
M
Perez-Pampin
Eva
E
Balsa
Alejandro
A
Blanco
Francisco J
FJ
Cañete
Juan D
JD
Caliz
Rafael
R
Carreño
Luis
L
de la Serna
Arturo R
AR
Fernandez-Gutierrez
Benjamin
B
Ortiz
Ana Maria
AM
Herrero-Beaumont
Gabriel
G
Pablos
Jose L
JL
Narvaez
Javier
J
Navarro
Federico
F
Marenco
Jose L
JL
Gomez-Reino
Juan J
JJ
Gonzalez
Antonio
A
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D021901:DNA, Intergenic / Q000235:genetics*; D004268:DNA-Binding Proteins; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D021901:DNA, Intergenic; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3