<em>STAT4</em> and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus

Elaine Remmers

Robert Plenge

Annette Lee

Robert Graham

Hye Lee+14 authors

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.).

^{Corresponding author.}

Address reprint requests to Dr. Gregersen at the Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030, or at ude.shsn@gretep

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 = 2.81×10^{; 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 = 1.87×10}^{; 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.

Abstract

RHEUMATOID ARTHRITIS IS THE MOST common cause of adult inflammatory arthritis and is associated with considerable disability and early mortality.¹ Studies of twins clearly show a genetic contribution to disease susceptibility,² and the siblings of patients with seropositive, erosive rheumatoid arthritis have an estimated risk of developing the disease of between 5 and 10 times that of the general population.³ The highly polymorphic HLA region is a major contributor to genetic risk of rheumatoid arthritis.⁴ Several other genes associated with more modest risks have recently been identified, including the Arg620→Trp variant of the intracellular phosphatase gene PTPN22.⁵6 However, the definitive identification of additional risk genes outside the HLA region has been challenging.

We recently described a linkage peak with nearly genomewide significance on the long (q) arm of chromosome 2 in 642 families of European ancestry⁷ collected by the North American Rheumatoid Arthritis Consortium (NARAC).⁸ The region encompasses more than 50 million base pairs (Mb) of genomic DNA and has also been implicated in previous meta-analyses of linkage-study data.⁹10 In the current study, we undertook a large case-control disease-association analysis of 13 selected candidate genes within the chromosome 2q linkage region.

Footnotes

Drs. Remmers and Plenge contributed equally to this article.

Footnotes

References

1. Goronzy J, Weyand C. Rheumatoid arthritis. A. Epidemiology, pathology, and pathogenesis. In: Klippel J, Crofford L, Stone J, Weyand C, editors. Primer on the rheumatic diseases. 12th ed. Arthritis Foundation; Atlanta: 2001. pp. 209–17. [PubMed]
2. MacGregor AJ, Snieder H, Rigby AS, et al Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000;43:30–7.[PubMed][Google Scholar]
3. Seldin MF, Amos CI, Ward R, Gregersen PKThe genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum. 1999;42:1071–9.[PubMed][Google Scholar]
4. Wordsworth BP, Bell JIThe immunogenetics of rheumatoid arthritis. Springer Semin Immunopathol. 1992;14:59–78.[PubMed][Google Scholar]
5. Begovich AB, Carlton VE, Honigberg LA, et al A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004;75:330–7.[Google Scholar]
6. Gregersen PK, Lee HS, Batliwalla F, Begovich ABPTPN22: setting thresholds for autoimmunity. Semin Immunol. 2006;18:214–23.[PubMed][Google Scholar]
7. Amos CI, Chen WV, Lee A, et al High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33. Genes Immun. 2006;7:277–86.[PubMed][Google Scholar]
8. Jawaheer D, Seldin MF, Amos CI, et al Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families. Arthritis Rheum. 2003;48:906–16.[PubMed][Google Scholar]
9. Choi SJ, Rho YH, Ji JD, Song GG, Lee YHGenome scan meta-analysis of rheumatoid arthritis. Rheumatology (Oxford) 2006;45:166–70.[PubMed][Google Scholar]
10. Etzel CJ, Chen WV, Shepard N, et al Genome-wide meta-analysis for rheumatoid arthritis. Hum Genet. 2006;119:634–41.[PubMed][Google Scholar]
11. Mitchell MK, Gregersen PK, Johnson S, Parsons R, Vlahov DThe New York Cancer Project: rationale, organization, design, and baseline characteristics. J Urban Health. 2004;81:301–10.[Google Scholar]
12. Wolfe F, Michaud K, Gefeller O, Choi HKPredicting mortality in patients with rheumatoid arthritis. Arthritis Rheum. 2003;48:1530–42.[PubMed][Google Scholar]
13. Fries JF, Wolfe F, Apple R, et al HLADRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity, and treatment bias. Arthritis Rheum. 2002;46:2320–9.[PubMed][Google Scholar]
14. Irigoyen P, Lee AT, Wener MH, et al Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles. Arthritis Rheum. 2005;52:3813–8.[PubMed][Google Scholar]
15. Stolt P, Bengtsson C, Nordmark B, et al Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003;62:835–41.[Google Scholar]
16. Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog LA gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 2004;50:3085–92.[PubMed][Google Scholar]
17. Thorburn CM, Prokunina-Olsson L, Sterba KA, et al Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun. 2007;8:279–87.[Google Scholar]
18. Tan EM, Cohen AS, Fries JF, et al The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–7.[PubMed][Google Scholar]
19. Petri MHopkins Lupus Cohort: 1999 update. Rheum Dis Clin North Am. 2000;26:199–213.[PubMed][Google Scholar]
20. Bauer JW, Baechler EC, Petri M, et al Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med. 2006;3(12):e491.[Google Scholar]
21. Criswell LA, Pfeiffer KA, Lum RF, et al Analysis of families in the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet. 2005;76:561–71.[Google Scholar]
22. de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler DEfficiency and power in genetic association studies. Nat Genet. 2005;37:1217–23.[PubMed][Google Scholar]
23. Bland JM, Altman DGStatistics notes: the odds ratio. BMJ. 2000;320:1468.[Google Scholar]
24. Barrett JC, Fry B, Maller J, Daly MJHaploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.[PubMed][Google Scholar]
25. Seldin MF, Shigeta R, Villoslada P, et al European population substructure: clustering of northern and southern populations. PLoS Genet. 2006;2(9):e143.[Google Scholar]
26. Pritchard JK, Stephens M, Rosenberg NA, Donnelly PAssociation mapping in structured populations. Am J Hum Genet. 2000;67:170–81.[Google Scholar]
27. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich DPrincipal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–9.[PubMed][Google Scholar]
28. Plenge RM, Padyukov L, Remmers EF, et al Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet. 2005;77:1044–60.[Google Scholar]
29. Moser KL, Neas BR, Salmon JE, et al Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci U S A. 1998;95:14869–74.[Google Scholar]
30. Gray-McGuire C, Moser KL, Gaffney PM, et al Genome scan of human systemic lupus erythematosus by regression modeling: evidence of linkage and epistasis at 4p16-15.2. Am J Hum Genet. 2000;67:1460–9.[Google Scholar]
31. Cantor RM, Yuan J, Napier S, et al Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33, 16q12-13, and 17q21-23 and novel evidence at 3p24, 10q23-24, 13q32, and 18q22-23. Arthritis Rheum. 2004;50:3203–10.[PubMed][Google Scholar]
32. Gregersen PK, Behrens TWGenetics of autoimmune disease — disorders of immune homeostasis. Nat Rev Genet. 2006;7:917–28.[PubMed][Google Scholar]
33. Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O'Shea JJSignaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004;202:139–56.[PubMed][Google Scholar]
34. Morinobu A, Gadina M, Strober W, et al STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A. 2002;99:12281–6.[Google Scholar]
35. Nishikomori R, Usui T, Wu CY, Morinobu A, O'Shea JJ, Strober WActivated STAT4 has an essential role in Th1 differentiation and proliferation that is independent of its role in the maintenance of IL-12R beta 2 chain expression and signaling. J Immunol. 2002;169:4388–98.[PubMed][Google Scholar]
36. Mathur AN, Chang HC, Zisoulis DG, et al Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol. 2007;178:4901–7.[PubMed][Google Scholar]
37. Bettelli E, Oukka M, Kuchroo VKTT(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–50.[PubMed][Google Scholar]
38. Finnegan A, Grusby MJ, Kaplan CD, et al IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms. J Immunol. 2002;169:3345–52.[PubMed][Google Scholar]
39. Klinman DM, Gursel I, Klaschik S, Dong L, Currie D, Shirota HTherapeutic potential of oligonucleotides expressing immunosuppressive TTAGGG motifs. Ann N Y Acad Sci. 2005;1058:87–95.[PubMed][Google Scholar]
40. Hildner KM, Schirmacher P, Atreya I, et al Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis. J Immunol. 2007;178:3427–36.[PubMed][Google Scholar]
41. Duerr RH, Taylor KD, Brant SR, et al A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–3.[Google Scholar]
42. Cargill M, Schrodi SJ, Chang M, et al A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80:273–90.[Google Scholar]
43. Tsunemi Y, Saeki H, Nakamura K, et al Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci. 2002;30:161–6.[PubMed][Google Scholar]
44. Fukao T, Frucht DM, Yap G, Gadina M, O'Shea JJ, Koyasu SInducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. J Immunol. 2001;166:4446–55.[PubMed][Google Scholar]
45. Remoli ME, Ragimbeau J, Giacomini E, et al NF-κB is required for STAT-4 expression during dendritic cell maturation. J Leukoc Biol. 2007;81:355–63.[PubMed][Google Scholar]
46. Jacob CO, Zang S, Li L, et al Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice. J Immunol. 2003;171:1564–71.[PubMed][Google Scholar]
47. Bottini N, Musumeci L, Alonso A, et al A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36:337–8.[PubMed][Google Scholar]
48. Vandiedonck C, Capdevielle C, Giraud M, et al Association of the PTPN22* R620W polymorphism with autoimmune myasthenia gravis. Ann Neurol. 2006;59:404–7.[PubMed][Google Scholar]
49. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JNMeta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003;33:177–82.[PubMed][Google Scholar]
50. Campbell CD, Ogburn EL, Lunetta KL, et al Demonstrating stratification in a European American population. Nat Genet. 2005;37:868–72.[PubMed][Google Scholar]
51. Lee H-S, Remmers EF, Le JM, Kastner DL, Bae S-C, Gregersen PKAssociation of STAT4 with rheumatoid arthritis in the Korean population. Mol Med. (in press)