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Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk

Abstract

To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls1. We used Gene Relationships Across Implicated Loci (GRAIL)2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3,4,5,6,7,8,9,10,11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 × 10−6 replication, P = 1 × 10−9 overall), CD28 (rs1980422, P = 5 × 10−6 replication, P = 1 × 10−9 overall) and PRDM1 (rs548234, P = 1 × 10−5 replication, P = 2 × 10−8 overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 × 10−7 overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 × 10−7 overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 × 10−6 overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 × 10−5 overall). Many of these loci are also associated to other immunologic diseases.

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Figure 1: Using Gene Relationships Across Implicated Loci (GRAIL) to prioritize candidate RA SNPs.
Figure 2: GRAIL identified interconnectivity among genes in RA loci.
Figure 3: GRAIL identifies new RA risk loci that replicate when genotyped in independent case-control samples.

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References

  1. Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Raychaudhuri, S. et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gregersen, P.K., Silver, J. & Winchester, R.J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. Begovich, A.B. 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. 75, 330–337 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Plenge, R.M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Thomson, W. et al. Rheumatoid arthritis association at 6q23. Nat. Genet. 39, 1431–1433 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Suzuki, A. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Suzuki, A. et al. Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population. Nat. Genet. 40, 1224–1229 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Barton, A. et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat. Genet. 40, 1156–1159 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhernakova, A. et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am. J. Hum. Genet. 81, 1284–1288 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Plenge, R.M. et al. Replication of putative candidate-gene associations with rheumatoid arthritis in &gt;4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am. J. Hum. Genet. 77, 1044–1060 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Isenberg, D. Oxford Textbook of Rheumatology (Oxford University Press, Oxford, UK, and New York, 2004).

  13. Gregersen, P.K. et al. REL, encoding a member of the NF-κB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat. Genet. 41, 820–823 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Raychaudhuri, S. Computational Text Analysis for Functional Genomics and Bioinformatics (Oxford University Press, Oxford, 2006).

  15. Arnett, F.C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).

    Article  CAS  PubMed  Google Scholar 

  16. Kuritz, S.J., Landis, J.R. & Koch, G.G. A general overview of Mantel-Haenszel methods: applications and recent developments. Annu. Rev. Public Health 9, 123–160 (1988).

    Article  CAS  PubMed  Google Scholar 

  17. Duits, A.J. et al. Skewed distribution of IgG Fc receptor IIa (CD32) polymorphism is associated with renal disease in systemic lupus erythematosus patients. Arthritis Rheum. 38, 1832–1836 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Harley, J.B. et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hunt, K.A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smyth, D.J. et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N. Engl. J. Med. 359, 2767–2777 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tchilian, E.Z. et al. The exon A (C77G) mutation is a common cause of abnormal CD45 splicing in humans. J. Immunol. 166, 6144–6148 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Barcellos, L.F. et al. PTPRC (CD45) is not associated with the development of multiple sclerosis in U.S. patients. Nat. Genet. 29, 23–24 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Jacobsen, M. et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat. Genet. 26, 495–499 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Vorechovsky, I. et al. Does 77C→G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus? Nat. Genet. 29, 22–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. De Jager, P.L. et al. The role of the CD58 locus in multiple sclerosis. Proc. Natl. Acad. Sci. USA 106, 5264–5269 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rubio, J.P. et al. Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians. Genes Immun. 9, 624–630 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Schraven, B., Samstag, Y., Altevogt, P. & Meuer, S.C. Association of CD2 and CD45 on human T lymphocytes. Nature 345, 71–74 (1990).

    Article  CAS  PubMed  Google Scholar 

  29. Ishida, T. et al. Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J. Biol. Chem. 271, 28745–28748 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Calame, K. Activation-dependent induction of Blimp-1. Curr. Opin. Immunol. 20, 259–264 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Sato, M. et al. The validity of a rheumatoid arthritis medical records-based index of severity compared with the DAS28. Arthritis Res. Ther. 8, R57 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  32. De Jager, P.L. et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat. Genet. 41, 776–782 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kathiresan, S. et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat. Genet. 41, 334–341 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Amos, C.I. et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat. Genet. 40, 616–622 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Plenge, R.M. et al. TRAF1–C5 as a risk locus for rheumatoid arthritis–a genomewide study. N. Engl. J. Med. 357, 1199–1209 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nielen, M.M. et al. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis. Ann. Rheum. Dis. 64, 1199–1204 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wijbrandts, C.A. et al. The clinical response to infliximab in rheumatoid arthritis is in part dependent on pre-treatment TNFα expression in the synovium. Ann. Rheum. Dis. (2007).

  38. Kurreeman, F.A. et al. A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med. 4, e278 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wesoly, J. et al. Association of the PTPN22 C1858T single-nucleotide polymorphism with rheumatoid arthritis phenotypes in an inception cohort. Arthritis Rheum. 52, 2948–2950 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Fung, H.C. et al. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol. 5, 911–916 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Costenbader, K.H., Chang, S.C., De Vivo, I., Plenge, R. & Karlson, E.W. Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking. Arthritis Res. Ther. 10, R52 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Germer, S., Holland, M.J. & Higuchi, R. High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res. 10, 258–266 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

S.R. is supported by a US National Institutes of Health (NIH) Career Development Award (1K08AR055688-01A1) and an American College of Rheumatology Bridge Grant. R.M.P. is supported by a K08 grant from the NIH (AI55314-3), a private donation from the Fox Trot Fund, the William Randolph Hearst Fund of Harvard University, the American College of Rheumatology 'Within Our Reach' campaign and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. M.J.D. is supported by NIH grants through the U01 (HG004171, DK62432) and R01 (DK083756-1, DK64869) mechanisms. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. The Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry is supported by a grant from Millennium Pharmaceuticals and Biogen-Idec. The North American Rheumatoid Arthritis Consortium (NARAC) is supported by the NIH (NO1-AR-2-2263 and RO1 AR44422). This research was also supported in part by the Intramural Research Program of the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the NIH. This research was also supported in part by grants to KAS from the Canadian Institutes for Health Research (MOP79321 and IIN - 84042) and the Ontario Research Fund (RE01061) and by a Canada Research Chair. We acknowledge the help of C.E. van der Schoot for healthy control samples for the Genetics Network Rheumatology Amsterdam (GENRA) and the help of B.A.C. Dijkmans, D. van Schaardenburg, A.S. Peña, P.L. Klarenbeek, Z. Zhang, M.T. Nurmohammed, W.F. Lems, R.R.J. van de Stadt, W.H. Bos, J. Ursum, M.G.M. Bartelds, D.M. Gerlag, M.G.H. van der Sande, C.A. Wijbrandts and M.M.J. Herenius in gathering GENRA patient samples and data. We thank the Myocardial Infarction Genetics Consortium (MIGen) study for the use of genotype data from their healthy controls in our study. The MIGen study was funded by the US NIH and National Heart, Lung, and Blood Institute's SNP Typing for Association with Multiple Phenotypes from Existing Epidemiologic Data (STAMPEED) genomics research program R01HL087676 and a grant from the National Center for Research Resources. We thank the Johanna Seddon Progression of AMD Study, AMD Registry Study, Family Study of AMD, The US Twin Study of AMD and the Age-Related Eye Disease Study (AREDS) for use of genotype data from their healthy controls in our study. We thank D. Hafler and the Multiple Sclerosis collaborative for use of genotype data from their healthy controls recruited at Brigham and Women's Hospital.

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S.R., M.J.D., D.A. and R.M.P. designed the study, conducted the statistical analysis, interpreted the primary data and wrote the initial manuscript. All authors contributed to the final manuscript. B.P.T., E.F.R., S.E., A.H., C.G., J.J.C., G.X., E.A.S., R.C., N.P.B. and M.S. were involved directly in genotyping samples or extracting genotypes for this study. The BRASS genetic study was coordinated by E.A.S., P.L.d.J., J.C., S.R. and R.M.P. under the direction of M.E.W. and N.A.S. The CANADA genetic study was coordinated by C.I.A., X.L. and G.X. under the direction of K.A.S. The Epidemiological Investigation of Rheumatoid Arthritis (EIRA) genetic study was coordinated by L.A., B.D., L.P. and M.S. under the direction of L.K. The Genomics Collaborative Initiative (GCI) genetic study was coordinated by K.G.A., J.J.C., M.C. and Y.L. under the direction of A.B.B. The GENRA genetic study was coordinated by J.B.A.C., P.P.T., I.E.v.d.H.-B. and G.J.W. under the direction of N.d.V. The Leiden University Medical Center (LUMC) genetic study was coordinated by T.W.J.H., F.A.S.K., Y.L. and A.H.M.v.d.H.-v.M. under the direction of R.E.M.T. The NARAC genetic study was coordinated by E.F.R., C.I.A., M.C., L.A.C., D.L.K., A.T.L. and M.F.S. under the direction of P.K.G. The NHS genetic study was coordinated by K.H.C. and J.C. under the direction of E.W.K. The UK Rheumatoid Arthritis Genetics (UKRAG) genetic study was coordinated by S.E., B.I.R.A.C., A.B., J.B., P.E., E.F., P.H., A.H., L.J.H., X.K., P.M., A.W.M., D.M.R., S.S., W.T., A.G.W., P.W. and Y.E.A.R. under the direction of J.W.

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Correspondence to Soumya Raychaudhuri or Robert M Plenge.

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A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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Raychaudhuri, S., Thomson, B., Remmers, E. et al. Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nat Genet 41, 1313–1318 (2009). https://doi.org/10.1038/ng.479

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