Deep Resequencing of GWAS Loci Identifies Rare Variants in , and That Are Associated with Ulcerative Colitis

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Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (∼14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

Vyšlo v časopise: Deep Resequencing of GWAS Loci Identifies Rare Variants in , and That Are Associated with Ulcerative Colitis. PLoS Genet 9(9): e32767. doi:10.1371/journal.pgen.1003723
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003723

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Zdroje

1. XavierRJ, PodolskyDK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448 : 427–434.

2. AndersonCA, BoucherG, LeesCW, FrankeA, D'AmatoM, et al. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43 : 246–252.

3. JostinsL, RipkeS, WeersmaRK, DuerrRH, McGovernDP, et al. (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491 : 119–124.

4. DuerrRH, TaylorKD, BrantSR, RiouxJD, SilverbergMS, et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314 : 1461–1463.

5. RiouxJD, XavierRJ, TaylorKD, SilverbergMS, GoyetteP, et al. (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39 : 596–604.

6. HampeJ, FrankeA, RosenstielP, TillA, TeuberM, et al. (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genetics 39 : 207–211.

7. RivasMA, BeaudoinM, GardetA, StevensC, SharmaY, et al. (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43 : 1066–1073.

8. McGovernDP, GardetA, TorkvistL, GoyetteP, EssersJ, et al. (2010) Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42 : 332–337.

9. BarrettJC, HansoulS, NicolaeDL, ChoJH, DuerrRH, et al. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 40 : 955–962.

10. FestenEA, GoyetteP, ScottR, AnneseV, ZhernakovaA, et al. (2009) Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 58 : 799–804.

11. MomozawaY, MniM, NakamuraK, CoppietersW, AlmerS, et al. (2011) Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat Genet 43 : 43–47.

12. AdzhubeiIA, SchmidtS, PeshkinL, RamenskyVE, GerasimovaA, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7 : 248–249.

13. WilliamsIR (2004) Chemokine receptors and leukocyte trafficking in the mucosal immune system. Immunol Res 29 : 283–292.

14. MoffattMF, KabeschM, LiangL, DixonAL, StrachanD, et al. (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448 : 470–473.

15. NatoliG, ChioccaS (2008) Nuclear ubiquitin ligases, NF-kappaB degradation, and the control of inflammation. Science signaling 1: pe1.

16. ZhaoW, WangL, ZhangM, YuanC, GaoC (2012) E3 Ubiquitin Ligase Tripartite Motif 38 Negatively Regulates TLR-Mediated Immune Responses by Proteasomal Degradation of TNF Receptor-Associated Factor 6 in Macrophages. J Immunol 188 : 2567–2574.

17. JinW, ChangM, SunSC (2012) Peli: a family of signal-responsive E3 ubiquitin ligases mediating TLR signaling and T-cell tolerance. Cell Mol Immunol 9 : 113–122.

18. FernandezMI, RegnaultB, MuletC, TanguyM, JayP, et al. (2008) Maturation of paneth cells induces the refractory state of newborn mice to Shigella infection. J Immunol 180 : 4924–4930.

19. LiX, MadisonBB, ZachariasW, KolterudA, StatesD, et al. (2007) Deconvoluting the intestine: molecular evidence for a major role of the mesenchyme in the modulation of signaling cross talk. Physiol Genomics 29 : 290–301.

20. BoydM, BressendorffS, MollerJ, OlsenJ, TroelsenJT (2009) Mapping of HNF4alpha target genes in intestinal epithelial cells. BMC Gastroenterol 9 : 68.

21. FangB, Mane-PadrosD, BolotinE, JiangT, SladekFM (2012) Identification of a binding motif specific to HNF4 by comparative analysis of multiple nuclear receptors. Nucleic Acids Res 40 : 5343–5356.

22. KtistakiE, TalianidisI (1997) Modulation of hepatic gene expression by hepatocyte nuclear factor 1. Science 277 : 109–112.

23. KyrmiziI, HatzisP, KatrakiliN, TroncheF, GonzalezFJ, et al. (2006) Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev 20 : 2293–2305.

24. TomaruY, NakanishiM, MiuraH, KimuraY, OhkawaH, et al. (2009) Identification of an inter-transcription factor regulatory network in human hepatoma cells by Matrix RNAi. Nucleic Acids Res 37 : 1049–1060.

25. BandyopadhyayS, ChiangCY, SrivastavaJ, GerstenM, WhiteS, et al. (2010) A human MAP kinase interactome. Nat Methods 7 : 801–805.

26. DasD, NahleZ, ZhangMQ (2006) Adaptively inferring human transcriptional subnetworks. Mol Syst Biol 2 : 2006 0029.

27. OdomDT, ZizlspergerN, GordonDB, BellGW, RinaldiNJ, et al. (2004) Control of pancreas and liver gene expression by HNF transcription factors. Science 303 : 1378–1381.

28. GarrisonWD, BattleMA, YangC, KaestnerKH, SladekFM, et al. (2006) Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology 130 : 1207–1220.

29. DarsignyM, BabeuJP, DupuisAA, FurthEE, SeidmanEG, et al. (2009) Loss of hepatocyte-nuclear-factor-4alpha affects colonic ion transport and causes chronic inflammation resembling inflammatory bowel disease in mice. PLoS One 4: e7609.

30. MarcilV, SeidmanE, SinnettD, BoudreauF, GendronFP, et al. (2010) Modification in oxidative stress, inflammation, and lipoprotein assembly in response to hepatocyte nuclear factor 4alpha knockdown in intestinal epithelial cells. J Biol Chem 285 : 40448–40460.

31. GoyetteP, LefebvreC, NgA, BrantSR, ChoJH, et al. (2008) Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol 1 : 131–138.

32. AsanoK, MatsushitaT, UmenoJ, HosonoN, TakahashiA, et al. (2009) A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 41 : 1325–1329.

33. DassopoulosT, NguyenGC, BittonA, BromfieldGP, SchummLP, et al. (2007) Assessment of reliability and validity of IBD phenotyping within the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium (IBDGC). Inflamm Bowel Dis 13 : 975–983.

34. FisherSA, TremellingM, AndersonCA, GwilliamR, BumpsteadS, et al. (2008) Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet 40 : 710–712.

35. BrownAM, LoKS, GuelpaP, BeaudoinM, RiouxJD, et al. (2010) Optimus Primer: A PCR enrichment primer design program for next-generation sequencing of human exonic regions. BMC Res Notes 3 : 185.

36. GnirkeA, MelnikovA, MaguireJ, RogovP, LeProustEM, et al. (2009) Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol 27 : 182–189.

37. LiH, RuanJ, DurbinR (2008) Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res 18 : 1851–1858.

38. McKennaA, HannaM, BanksE, SivachenkoA, CibulskisK, et al. (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20 : 1297–1303.

39. CajaL, BertranE, CampbellJ, FaustoN, FabregatI (2011) The transforming growth factor-beta (TGF-beta) mediates acquisition of a mesenchymal stem cell-like phenotype in human liver cells. J Cell Physiol 226 : 1214–1223.

40. HongMH, ChouYC, WuYC, TsaiKN, HuCP, et al. (2012) Transforming growth factor-beta1 suppresses hepatitis B virus replication by the reduction of hepatocyte nuclear factor-4alpha expression. PLoS One 7: e30360.

41. WangB, CaiSR, GaoC, SladekFM, PonderKP (2001) Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4 alpha in rat liver. Hepatology 34 : 979–989.

42. BoydM, HansenM, JensenTG, PerearnauA, OlsenAK, et al. (2010) Genome-wide analysis of CDX2 binding in intestinal epithelial cells (Caco-2). J Biol Chem 285 : 25115–25125.

43. McKinney-FreemanSL, LengerkeC, JangIH, SchmittS, WangY, et al. (2008) Modulation of murine embryonic stem cell-derived CD41+c-kit+ hematopoietic progenitors by ectopic expression of Cdx genes. Blood 111 : 4944–4953.