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Previous Volume 357:977-986 September 6, 2007 Number 10 Next

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ABSTRACT

Background Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.

Methods We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1–STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case–control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus.

Results A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10^–7; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10^–9; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis.

Conclusions A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.

Source Information

From the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD (E.F.R., J.M.L., S.L.M., M.G.B., D.L.K.); the Broad Institute, Cambridge, MA (R.M.P., R.R.G., P.I.W.B.); Brigham and Women's Hospital (R.M.P.); the Feinstein Institute for Medical Research, Manhasset, NY (A.T.L., H.-S.L., F.B., W.L., P.K.G.); Genentech, South San Francisco, CA (G.H., T.W.B.); Hanyang University College of Medicine, Seoul, South Korea (H.-S.L.); Biogen Idec, Cambridge, MA (J.P.C.); the Karolinska Institutet, Stockholm (L.P., L.A., L.K.); University of Texas M.D. Anderson Cancer Center, Houston (W.V.C., C.I.A.); the University of California at San Francisco, San Francisco (L.A.C.); and the University of California at Davis, Davis (M.F.S.).

Drs. Remmers and Plenge contributed equally to this article.

Address reprint requests to Dr. Gregersen at the Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030, or at peterg{at}nshs.edu.

Full Text of this Article

Related Letters:

Rheumatoid Arthritis, Systemic Lupus Erythematosus, and STAT4
Dagna L., Frontino G., Praderio L., Remmers E. F., Plenge R. M., Gregersen P. K.
Extract | Full Text | PDF  
N Engl J Med 2007; 357:2517-2518, Dec 13, 2007. Correspondence

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