Genes, Genes, Everywhere! The key to a cure for IBD
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1 Genes, Genes, Everywhere! The key to a cure for IBD Dermot McGovern MD, PhD, FRCP Director, Translational Medicine Professor of Medicine Joshua L and Lisa Z Greer Endowed Chair in IBD Genetics F. Widjaja Foundation IBRI Cedars-Sinai Medical Center
2 Familial occurrences of ulcerative colitis, regional enteritis and ileocolitis Post 2001 Professor Joseph B. Kirsner Annals of internal medicine 1963:59:133
3 Genetics 101 Human Genome Book
4 Genetics Chapters 23 Chromosomes
5 Genetics 101 Each chapter contains several thousand stories Genes Each story is made up of Exons paragraphs Interrupted by commercials (junk DNA) Introns
6 Genetics 101 Each paragraph is made up of words Each word is written in letters Codons Bases
7 What is a polymorphism or mutation? Also known as a SNP Single Nucleotide Polymorphism
8 Chip Technology Dual Color: One Color:
9
10 CD Genes Linkage Initial GWAS 2008 meta-analysis Individual GWAS/candidate gene 2010 meta-analysis NKX2-3 PTPN2 ZNF365 NOD2 5q31 IL23R IRGM PTGER4 MHC TNFSF15 ATG16L1 MST1 1q24 1q32 6q21 7p12 8q24 10p11 13q14 19p13 21q21 ITLN1 PTPN22 IL12B CDKAL1 CCR6 JAK2 C11orf30 LRRK2/MUC19 MAP3K7IP1 19q13 IL27 ORMDL3 ZMIZ1 STAT3 CARD9 ICOSLG IL18RAP 8q24 TAGAP BACH2 6p25 CPEB4 NDFIP1 ERAP2 5q13 3p24 SP140 PLCL1 VAMP3 C2orf74 THADA GCKR DNMT3A IL10 DENND1B SCAMP3/MUC1 FUT2 Prior ICAM1/3 CCL2/7 EIF3C/CD19 YDJC SMAD3 GALC ZFP36L1 TNFSF11 MTMR3 TNFRSF6B PRDX5/ESRRA UBE2D1 IL2RA FADS1
11 47 Confirmed UC Genes IL7R IL8RA/B DAP IL1R2/1 SATB2 PRKRIR TYK2 16q24 STAT3 13q12 11q23 13q13 ETS1 RTEL1 21q IL10 IL23R 12q15 1p36 IL17REL NKX2-3 ORMDL3 21q22 5p15 REL FCGR2A CDH1 HNF4A MST1 KIF1A LAMB1 IL2/IL21 7q22 TNFRSF14 TNFRSF9 1q32 Ip36 PTGER4 IL12B JAK2 TNFSF15 GNA12 PRDM1 6q23 5q31 LSP1 CREM MHC CARD9
12 New loci bring the count from IBD Genetics 2011
13 to ~160 IBD associated loci IBD Genetics 2012
14 Defining the genetic architecture of CD vs. UC > UC specific loci MHC IL23R 110 IBD loci NOD2 30 CD specific loci PTPN >1.5 Nature, In press
15 IBD - A complex trait? Lung Cancer Blood Group Car crash IBD Eye Colour "It isn't pollution that's harming the environment. It's the impurities in our air Diabetes and water that are doing Cystic it." Fibrosis - George W. Bush Malaria 100% Environment 100% Genetic
16
17 IBD - A complex trait? UC IBDU CD
18 Shared genes immune-mediated diseases Lees et al Gut 2011
19 Population Structure
20 How will genetics help in IBD? Diagnosis? Increased understanding of underlying causes Novel therapeutic pathways Molecular classification Development of Biomarkers Disease severity Response to therapy? CURE
21 An estimate, based on currently available information, on whether your genetic risk of Crohn's Disease is higher or lower than average. NOD2, ATG16L1, IL23R, NKX2, IBD5, PTPN2 One's lifetime odds of getting Crohn's Disease range between 0% and 1%, based on genotype.? Useful in General population FHx Symptomatic individual..sort of the modern version of genetic snake oil Francis Collins
22 How will genetics help in IBD? Diagnosis? Increased understanding of underlying causes Novel therapeutic pathways Molecular classification Development of Biomarkers Disease severity Response to therapy? CURE
23 Genetic heterogeneity Epithelial integrity IL23/IL17 CD Innate Immunity Autophagy
24 CD Genetics 2010 Linkage Initial GWAS 2008 meta-analysis Individual GWAS/candidate gene 2010 meta-analysis NKX2-3 PTPN2 ZNF365 NOD2 5q31 IL23R IRGM PTGER4 MHC TNFSF15 ATG16L1 MST1 Prior q24 1q32 6q21 7p12 8q24 10p11 13q14 19p13 21q21 ITLN1 PTPN22 IL12B CDKAL1 CCR6 JAK2 C11orf30 LRRK2/MUC19 MAP3K7IP1 19q13 IL27 ORMDL3 ZMIZ1 STAT3 CARD9 ICOSLG IL18RAP 8q24 TAGAP BACH2 6p25 CPEB4 NDFIP1 ERAP2 5q13 3p24 SP140 PLCL1 VAMP3 C2orf74 THADA GCKR DNMT3A IL10 DENND1B SCAMP3/MUC1 FUT ICAM1/3 CCL2/7 EIF3C/CD19 YDJC SMAD3 GALC ZFP36L1 TNFSF11 MTMR3 TNFRSF6B PRDX5/ESRRA UBE2D1 IL2RA FADS1
25
26 Over-Expression of TNFSF15 in Mouse Generates Severe SB/Colonic Disease with Strictures Normal Expression Over-Expression Small Bowel Colon Strictures Strictures Is TNFSF15 a target to alter disease progression? Barrett, R.... Shih, D. DDW 2011, Abstract #925
27 TNFSF15 Antibody Healed Histologic Inflammation Day 32 Day 56 Day 56 Rectum Mid-Colon Cecum Before Treatment Isotype Ab TNFSF15 Ab
28 Hypothetical TNFSF15 Trial Efficac cy (%) % anti-tnfsf15 Therapeutic % 0 All Subjects 5 % Low TNFSF15 Producers High TNFSF15 Producers as defined by antibodies and genes
29 How will genetics help in IBD? Diagnosis? Increased understanding of underlying causes Novel therapeutic pathways Molecular classification Development of Biomarkers Disease severity Response to therapy? CURE
30
31 IBD How many diseases?
32 We propose to describe, in its pathologic and clinical details, a disease of the terminal ileum, affecting mainly young adults, characterized by subacute or chronic necrotizing inflammation. Crohn, Ginzburg and Oppenheimer JAMA 1932
33 NOD2 & ileal disease Relative risk ileal disease Any variant allele 4.1 ( ) Simple heterozygote 2.8 ( ) Homozygote 30.3 ( ) PAR ileal disease 40% Ahmad et al Gastroenterology 2002
34 Crohn s ( Segmental ) colitis I am prepared to believe that this segmental colitis is a colonic form of Crohn s disease. Crohn himself does not sanction this extension of the entity to which we give his name Ulcerative colitis and Crohn s disease Lecture delivered to the Royal College of Surgeons of England by Charles Wells, FRCS, October 1952
35 HLA & IBD phenotype Colonic CD - HLA A1B8DR3DQ2 RR=3.2 DRB1*0103 RR=5.1 Ahmad et al Tissue Antigens 2003
36 Defining IBD: 1996 vs 2016? Names UC CD vs Molecular Mechanisms IBD1 IBD2 IBD3 IBD4 Disease location and behavior
37 How will genetics help in IBD? Diagnosis? Increased understanding of underlying causes Novel therapeutic pathways Molecular classification Development of Biomarkers Disease severity Response to therapy? CURE
38 Higher Risk Score Associated with need for surgery in UC (MR-UC) p-value Chi-squared test for trend < Non-MR-UC MR-UC 100 Proportion (%) Risk Score Categories 53-60
39 CD Genetics 2010 Linkage Initial GWAS 2008 meta-analysis Individual GWAS/candidate gene 2010 meta-analysis NKX2-3 PTPN2 ZNF365 NOD2 5q31 IL23R IRGM PTGER4 MHC TNFSF15 ATG16L1 MST1 Prior q24 1q32 6q21 7p12 8q24 10p11 13q14 19p13 21q21 ITLN1 PTPN22 IL12B CDKAL1 CCR6 JAK2 C11orf30 LRRK2/MUC19 MAP3K7IP1 19q13 IL27 ORMDL3 ZMIZ1 STAT3 CARD9 ICOSLG IL18RAP 8q24 TAGAP BACH2 6p25 CPEB4 NDFIP1 ERAP2 5q13 3p24 SP140 PLCL1 VAMP3 C2orf74 THADA GCKR DNMT3A IL10 DENND1B SCAMP3/MUC1 FUT ICAM1/3 CCL2/7 EIF3C/CD19 YDJC SMAD3 GALC ZFP36L1 TNFSF11 MTMR3 TNFRSF6B PRDX5/ESRRA UBE2D1 IL2RA FADS1
40 42 year old pt, 1 st surgery
41 42 year old pt, different genetics
42 Same patient, now a current smoker
43 Qin et al, Nature 2010
44 How will genetics help in IBD? Diagnosis? Increased understanding of underlying causes Novel therapeutic pathways Molecular classification Development of Biomarkers Disease severity Response to therapy? CURE
45
46
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