Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci
Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10−8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (Pcombined = 1.2×10−12), rs864537 near CD247 (Pcombined = 2.2×10−11), rs2298428 near UBE2L3 (Pcombined = 2.5×10−10), and rs11203203 near UBASH3A (Pcombined = 1.1×10−8). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10−8 (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
Vyšlo v časopise:
Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1002004
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002004
Souhrn
Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10−8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (Pcombined = 1.2×10−12), rs864537 near CD247 (Pcombined = 2.2×10−11), rs2298428 near UBE2L3 (Pcombined = 2.5×10−10), and rs11203203 near UBASH3A (Pcombined = 1.1×10−8). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10−8 (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
Zdroje
1. HemminkiKLiXSundquistKSundquistJ 2009 Shared familial aggregation of susceptibility to autoimmune diseases. Arthritis Rheum 60 2845 2847
2. DuboisPCTrynkaGFrankeLHuntKARomanosJ Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42 295 302
3. StahlEARaychaudhuriSRemmersEFXieGEyreS Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42 508 514
4. RaychaudhuriSThomsonBPRemmersEFEyreSHinksA 2009 Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nat Genet 41 1313 1318
5. GregersenPKAmosCILeeATLuYRemmersEF 2009 REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis. Nat Genet 41 820 823
6. TrynkaGZhernakovaARomanosJFrankeLHuntK 2009 Coeliac disease associated risk variants in TNFAIP3 and REL implicate altered NF-{kappa}B signalling. Gut
7. SmythDJPlagnolVWalkerNMCooperJDDownesK 2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359 2767 2777
8. HuntKAZhernakovaATurnerGHeapGAFrankeL 2008 Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40 395 402
9. van HeelDAFrankeLHuntKAGwilliamRZhernakovaA 2007 A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39 827 829
10. ZhernakovaAAlizadehBZBevovaMvan LeeuwenMACoenenMJ 2007 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
11. PlengeRMCotsapasCDaviesLPriceALde BakkerPI 2007 Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet 39 1477 1482
12. Lango AllenHEstradaKLettreGBerndtSIWeedonMN 2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467 832 838
13. TeslovichTMMusunuruKSmithAVEdmondsonACStylianouIM 2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466 707 713
14. SpeliotesEKWillerCJBerndtSIMondaKLThorleifssonG 2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet
15. ImielinskiMBaldassanoRNGriffithsARussellRKAnneseV 2009 Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 41 1335 1340
16. 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678
17. PearsonTAManolioTA 2008 How to interpret a genome-wide association study. JAMA 299 1335 1344
18. ZhernakovaAvan DiemenCCWijmengaC 2009 Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10 43 55
19. CoenenMJTrynkaGHeskampSFrankeBvan DiemenCC 2009 Common and different genetic background for rheumatoid arthritis and coeliac disease. Hum Mol Genet 18 4195 4203
20. de BakkerPIFerreiraMAJiaXNealeBMRaychaudhuriS 2008 Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet 17 R122 128
21. HanJWZhengHFCuiYSunLDYeDQ 2009 Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41 1234 1237
22. FransenKVisschedijkMCvan SommerenSFuJYFrankeL 2010 Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease. Hum Mol Genet 19 3482 3488
23. RadstakeTRGorlovaORuedaBMartinJEAlizadehBZ 2010 Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 42 426 429
24. BarrettJCHansoulSNicolaeDLChoJHDuerrRH 2008 Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40 955 962
25. BegovichABCarltonVEHonigbergLASchrodiSJChokkalingamAP 2004 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
26. BottiniNMusumeciLAlonsoARahmouniSNikaK 2004 A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36 337 338
27. RaychaudhuriSPlengeRMRossinEJNgACPurcellSM 2009 Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet 5 e1000534 doi:10.1371/journal.pgen.1000534
28. CallMEWucherpfennigKW 2004 Molecular mechanisms for the assembly of the T cell receptor-CD3 complex. Mol Immunol 40 1295 1305
29. TsygankovAY 2008 Multidomain STS/TULA proteins are novel cellular regulators. IUBMB Life 60 224 231
30. EgenJGKuhnsMSAllisonJP 2002 CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 3 611 618
31. HutloffADittrichAMBeierKCEljaschewitschBKraftR 1999 ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397 263 266
32. MaoMBieryMCKobayashiSVWardTSchimmackG 2004 T lymphocyte activation gene identification by coregulated expression on DNA microarrays. Genomics 83 989 999
33. LiYHeXSchembri-KingJJakesSHayashiJ 2000 Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Src homology 2 domains that can inhibit T cell activation. J Immunol 164 5199 5206
34. YaoBBNiuPSurowyCSFaltynekCR 1999 Direct interaction of STAT4 with the IL-12 receptor. Arch Biochem Biophys 368 147 155
35. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
36. MarchiniJHowieBMyersSMcVeanGDonnellyP 2007 A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39 906 913
37. EyreSHinksABowesJFlynnEMartinP 2010 Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease. Arthritis Res Ther 12 R175
38. AulchenkoYSRipkeSIsaacsAvan DuijnCM 2007 GenABEL: an R library for genome-wide association analysis. Bioinformatics 23 1294 1296
39. BartonAThomsonWKeXEyreSHinksA 2008 Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat Genet 40 1156 1159
40. PlengeRMSeielstadMPadyukovLLeeATRemmersEF 2007 TRAF1-C5 as a risk locus for rheumatoid arthritis–a genomewide study. N Engl J Med 357 1199 1209
41. RaychaudhuriSRemmersEFLeeATHackettRGuiducciC 2008 Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 40 1216 1223
42. RemmersEFPlengeRMLeeATGrahamRRHomG 2007 STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357 977 986
43. PlantDFlynnEMbarekHDieudePCornelisF 2010 Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers. Ann Rheum Dis 69 1548 1553
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 2
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci
- MiRNA Control of Vegetative Phase Change in Trees
- The Cardiac Transcription Network Modulated by Gata4, Mef2a, Nkx2.5, Srf, Histone Modifications, and MicroRNAs
- Break to Make a Connection