International IBD Genetics Consortium Identifies over 50 Genetic Risk Factors for Ulcerative Colitis.

Transcription

1 DDW2010, New Orleans Clinical Prac5ce Dis5nguished Abstract Plenary Session May 4 th, 2010 (5:15pm), Rm 348/349 International IBD Genetics Consortium Identifies over 50 Genetic Risk Factors for Ulcerative Colitis. Presented on behalf of the Interna0onal IBD Gene0cs Consor0um (IIBDGC) and the IIBDGC UC Meta- analysis Wri0ng Group IIBDGC will make all slides available at Presented by: John D. Rioux, Ph.D. Associate Professor of Medicine, Université de Montréal Canada Research Chair - GeneBcs and Genomic Medicine

2 Independent GWA Studies Iden5fy Mul5ple Risk Factors for Crohn s Duerr et. al. (2006) Science, Libioulle et. al. (2007) Plos Gene,cs,3:e58 Rioux et. al. (2007) Nature Gene,cs, 39:596 WTCCC (2007) Nature, June, 447:661

3 Meta- analysis of GWAS Iden5fies >30 Risk Factors for Crohn s Interna,onal IBD Gene,cs Consor,um (IIBDGC) Combined GWAS: Tested top 74 regions: ~3200 cases + ~4800 controls ~3600 cases (trios & C/C) 10% overall risk 20% genebc risk PTPN22 ITLN1 IL12B CDKAL1 CCR6 JAK2 C10orf30 MUC19 ORMDL3 STAT3 ICOSLG 2008 BarreT et al. (2008) Nat. Gene,cs 40(8):955

4 Meta- analysis of GWAS Iden5fies >30 Risk Factors for Crohn s Interna,onal IBD Gene,cs Consor,um (IIBDGC) Combined GWAS: Tested top 74 regions: ~3200 cases + ~4800 controls ~3600 cases (trios & C/C) PTPN22 JAK2 10% overall risk 20% genebc risk IL23R signaling ITLN1 C10orf30 MUC19 MST1 autophagy CDKAL1 ORMDL3 STAT3 CCR6 ICOSLG 2008 BarreT et al. (2008) Nat. Gene,cs 40(8):955

5 Individual Genome- wide AssociaBon Studies IdenBfy 18 Genes for UC (5 x 10-8 ) Duerr et al. (2006) Science;314:1461 GoyeTe et al (2008) Mucosal Immunol;1:131 Franke et al. (2008) Nat Genet; Silverberg et al. (2009) Nat Genet; 41:216 WTCCC2 (2009) Nat Genet; AOP November 15 Imielinski (2009) Nat Genet; 41:1335 Asano and al (2009) Nat Genet; 41:1325 McGovern et al (2010) Nat Genet; 42:332 FcGR2A SLC26A3 13q12 21q21 KIF21B ORMDL3 IL23R MST1 OTUD3/ PLA2G2E IFN gamma /IL26/IL22 IL10 KIF1A CDH1/3 HNF4 DLD/LAMB1 NKX2-3 BTNL2 CEP72/TPPP REL/PUS

6 InternaBonal IBD GeneBcs ConsorBum UlceraBve ColiBs Meta- Analysis Project 80+ researchers from >15 countries

7 InternaBonal IBD GeneBcs ConsorBum UlceraBve ColiBs Meta- Analysis Project STEP #1 : Combine genome- wide (GWA) data ~6,433 pa5ents with UC ~20,099 controls STEP #2 : Perform QC and associa5on analyses Iden5fy SNP markers Pvalue < 10-5 STEP #3 : Test top SNPs in independent cohort ~12,000 pa5ents with UC ~16,000 healthy controls

8 ReplicaBon phase of Meta- Analysis Study 75 independent regions with P value < /75 known loci no need to replicate further 57/75 potentially novel loci need to replicate TODAY: Preliminary results on 52/57 regions * 3614 patients with UC * 3397 controls (unpublished)

9 Meta- Analysis of UC GWA Studies Detects the 18 Known UC Loci (5 x 10-8 ) Genes within Associated Region Chrom # First Identified META-ANALYSIS P-value C1orf192,FCGR2C,FCGR3A,MPZ,FCGR2A,SDHC,FCGR3B, HSPA6, 1 Asano et. al IL19,DYRK3,IL20,IL10,MAPKAPK2, 1 Franke et al C1orf106,GPR25,KIF21B,CACNA1S,CAMSAP1L1, 1 McGovern et al IL23R,C1orf141, 1 Silverberg et. al RNF186,TMCO4,OTUD3,PLA2G2E,PLA2G2A, 1 Silverberg et. al DUSP28,RNPEPL1,CAPN10,ANKMY1,Q8TAU7_HUMAN,AQ P12A,AQP12B,GPR35,Q8TAU7_HUMAN,KIF1A, 2 Imielinski et. al Q96HQ8_HUMAN,REL,CCDC139,XPO1,KIAA1841,PEX13,A HSA2,USP34,PAPOLG, 2 McGovern et al MST1 region 3 Goyette et al IL21,ADAD1,KIAA1109,IL2, 4 Festen et. al Q9NX68_HUMAN,CEP72,PDCD6,Q71RB1_HUMAN,EXOC3,TPPP,SLC9A3,Q8N2X6_HUMAN,Q6P7N6_HUMAN, 5 McGovern et al MHC region 6 Multiple SLC26A3,DLD,LAMB1, 7 WTCCC NKX2-3, 10 McGovern et al IFNG,IL26, 12 Silverberg Multiple (incl CDH1) 16 WTCCC PERLD1,ZPBP2,NR1D1,GSDML,FBXL20,PSMD3,THRA,ST ARD3,ERBB2,NEUROD2,IKZF3,GSDM1,PPP1R1B,TCAP,M ED1,GRB7,STAC2,CSF3,MED24,PNMT,ORMDL3,C17orf37, CRKRS, 17 McGovern et al Q6ZRQ9_HUMAN,C20orf62,ADA,SERINC3,HNF4A,C20orf1 21,PKIG, 20 WTCCC gene desert near to PSMG1 21 McGovern et al (unpublished)

10 Preliminary Results 21 Novel Loci Reach Genome- wide Significance Genes within Associated Region Chrom # META-ANALYSIS REPLICATION COMBINED E E E-11 PLCH2,Q6ZV91_HUMAN,MMEL1,PANK4,Q6ZP28_HUMAN, C1orf93,HES5,TNFRSF14, E E E-08 Q6ZUN9_HUMAN,TNFRSF9,ERRFI1,UTS2,PARK7, E E E-08 TMBIM1,ARPC2,AAMP,GPBAR1,PNKD,IL8RA,IL8RB,SLC11 A1,C2orf62,RUFY4, E E E-10 RNF145,IL12B,UBLCP1, E E E-12 DAP, E E E E E E E E E-12 GNA12,AMZ1_HUMAN, E E E-10 SEC16A,C9orf151,C9orf163,CARD9,SNAPC4,Q9Y4N2_HU MAN,QSOX2,PMPCA,INPP5E,SDCCAG3,NOTCH1,GPSM1, E E E-15 INSL4,INSL6,JAK2, E E E-15 TNFSF8,TNFSF15, E E E-10 NP_ ,CREM,Q8IV12_HUMAN,CUL2,CCNY, E E E-09 C11orf71,REXO2,FAM55D,FAM55A,FAM55B,RBM7, E E E-12 C11orf30,Q3ZCU0_HUMAN,PRKRIR, E E E-10 ETS E E E E E E E E E-13 WSB1,Q2M1I1_HUMAN,KSR1, E E E-08 ARFRP1,PR285_HUMAN,Q6ZN89_HUMAN,STMN3,RTEL1, ZGPAT,ZBTB46,SLC2A4RG,LIME1,GMEB2,TPD52L2,C20or f135,zbtb46,c20orf181, E E E E E E-09 (unpublished)

11 FOUR AddiBonal Novel Loci Reach Nominal Significance in ReplicaBon Study Genes within Associated Region Chrom # META- ANALYSIS REPLICATION COMBINED CAPSL,IL7R,SPEF2,UGT3A1, E E E E E E-07 Q8NEU3_HUMAN, E E E-08 EDG8,ICAM5,RAVER1,ICAM3, CDC37,TYK2,KEAP1,PDE4A E E E-07 (unpublished)

12 Many UC GeneBc Risk Factors are shared with CD and other Inflammatory Diseases Category Shared with CD Shared with other Inflammatory Dx % Shared 18 known loci % 21 novel loci % 4 nominal loci % 43 TOTAL % 26 not yet replicated % *** Predict 52 UC loci from this study ~50% shared with CD; ~20% with other Inflamm Dx (unpublished)

13 Each New UC Gene Contributes to the Puzzle ETS1 (chr. 11) All Th subsets (Th0, Th1, Th2 and Th17) express: full length (p55) and alternabvely spliced (p42) isoforms Profound impact on Th1 immune responses required for opbmal producbon of inflammatory cytokines suppresses IL10 levels Adop5ve transfer of Ets1 - /- Th cells does NOT induce coli5s in SCID mice Ets1 - /- Th17 cells have IL17 producbon and enhanced Th17 differenbabon

14 Analysis of Literature Suggests Novel UC Genes Pinpoint PotenBal Molecular Mechanisms DAP (chr. 5) DEATH- ASSOCIATED PROTEIN DAP kinases modulate mtor acbvity (upstream regulator of autophagy) Altered expression in UC GA12 (chr. 7) Regulates protein interacbons wbhin MDCK cell Bght juncbon Inhibits Bgh- juncbon assembly WSB1 (chr. 17) Hedgehog inducible ubiquibn ligase loss of funcbonal hedgehog results in spontaneous intesbnal inflammabon but this work has just begun and

15 GRAIL Network Analysis of UC Genes Soumya Raychaudhuri & Mark Daly The Broad InsBtute (unpublished)

16 Molecular Function Enrichment Kinase Signaling molecule Aylwin Ng & Ramnik Xavier, MGH

17 InternaBonal IBD GeneBcs ConsorBum DramaBcally Increases Knowledge of UC Risk and Pathways IL2/21 CREM STAT3 IL10 TNFSF8/15 PRDM1 IRF5 JAK2 IL7R CARD9 PTGER4 ADCY2 GNA12 KIF5A RBPJ FCGR2A 21q21 LPP SLC26A3 KIF21B WSB1 FOXP1 13q12 ORMDL3 DAP IL1R KIF1A NKX2-3 IL12B OTUD3/ PLA2G2E CDH1/3 BTNL2 IL8RA/B ETS1 IFN gamma /IL26/IL22 HNF4 CEP72/TPPP TNFRSF9 SLC23A2 IL23R MST1 IL10 DLD/LAMB1 REL/PUS10 TNFRSF14 FAM55 TYK

18 GeneBc AssociaBons IdenBfy Key Pathways Provide TherapeuBc & PGx Targets Budarf et al. (2009) TIG, 25:137-46

19 Interna5onal IBD Gene5cs Consor5um UC Meta- analysis Wri5ng Group IIBDGC will make all slides available at