Genetics of Pediatric Inflammatory Bowel Disease

Size: px

Start display at page:

Download "Genetics of Pediatric Inflammatory Bowel Disease"

Marjorie Doyle
6 years ago
Views:

1 Genetics of Pediatric Inflammatory Bowel Disease Judith Kelsen MD Assistant Professor of Pediatrics Division of Gastroenterology, Hepatology, and Nutrition IBD Education Day 2/9/2014

2 Objectives Brief overview of role of genetics and IBD Brief review of DNA Evolution of genetic technology How we can apply these findings to disease Specific considerations Very early-onset IBD Pediatrics: burden of disease

3 IBD Susceptibility Adapted from Inflamm Bowel Dis 2010:16;152

IBD Genetics of Complex Disease IBD Mendelian Diseases Genotype Genotype Common and complex diseases Environmental factors Phenotype Phenotype Complex

4 IBD Genetics of Complex Disease IBD Mendelian Diseases Genotype Genotype Common and complex diseases Environmental factors Phenotype Phenotype Complex Disease: Several genes involved in the expression of the clinical trait Gene-gene interactions and geneenvironment intreractions Incomplete penetrance agedependent

5 Genetic Susceptibility There is strong link between genetics and IBD Identical twins studies show concordance rates of % in CD Non-identical twins studies show much lower concordance rates of about 4% in both CD and UC

6 DNA

7 Chromosome, DNA and Genes

8 Progression of Genomic Technology

9 Battle For the Human Genome

10 Beginning..

11 First Phase: Sanger Sequencing

12 GeneChip

13 GWAS studies in IBD As of the beginning of 2011, 99 IBD susceptibility gene loci had been identified 71 associated with Crohn s disease 47 associated with ulcerative colitis 28 associated with both

14 Next Generation Sequencing

15 And Beyond

DGKD IL12B CDKAL1 6q21 12q12 13q14 17q21 17q21 MTMR3, LIF HORMAD2 ZMIZ1 Many New Loci from meta analysis NOD2 OCTN 1/2 TNFSF15 IL23R

16 Timeline of confirmed IBD Loci / genes in children and adults with IBD Confirmed in both adults & children 6p21 9q32 To date only confirmed in adults 1q13 8q24 To date only confirmed in children 1q23 9p24 1q24 10p11 3p21 1q32 c11orf30 IRGM NKX2-3 PTPN2 ATG16L1 DGKD IL12B CDKAL1 6q21 12q12 13q14 17q21 17q21 MTMR3, LIF HORMAD2 ZMIZ1 Many New Loci from meta analysis NOD2 OCTN 1/2 TNFSF15 IL23R 10q21 5p13 6q27 7p12 21q21 ICOSLG TLR cluster IL Year of gene discovery in chronological order

susceptibility Other immunemediated disease UC genes 23 UC specific

17 Genetics of IBD: 163 confirmed loci NOD2 PTPN22 CD genes 30 CD specific loci 110 IBD loci Common pathways: Leprosy Mycobacterial susceptibility Other immunemediated disease UC genes 23 UC specific loci MHC Genes in common Jostins, L. et al. Nature 491, (01 November 2012)

18 Identification of Disease Associated Pathways Xavier 2011

19 Bacterially -Generated Phenotypes IL-10 -/- Germ-Free IL-10 -/- Commensal Bacteria IL-10 -/- E. faecalis IL-10 -/- E. coli Kim SC et al. Gastroenterology 2005:128(4):

20 Genetic Differences and Host Response to Bacteria IL-10 deficient B. vulgatus Minimally inflamed HLA-B27 2 transgenic B. vulgatus Inflamed

21 Innate and Adaptive Immunity are Linked Threat Detection Pattern Recognition Receptors 0-6 Hours Immediate Responses Innate Immunity Broad Action PRIME 1-5 Days Longer-Term Mobilization Adaptive Immunity Antigen-Specific Cytokines And Chemokines ACTIVATE MODULATE TLRs, NODs Release of anti-microbials Recruitment of cells Localized Inflammation B cell or T cell KILL PATHOGENS CLEAR INFECTION Mahida Y. Rolfe N. Clinical Science 2004;1007:

22 Nature 2001;411:604

23 NOD2 Contributes to Normal Mucosal Defenses Normal villi/ low NOD2 Paneth cells Paneth cells NOD2 expression increased with inflammatory mediators Antigens Bacteria NOD2

24 Innate Immunity: NOD2 Signaling Activates Proinflammatory Cytokines INTRACELLULAR BACTERIA NF-kB PROINFLAMMATORY RESPONSE NOD2 SENSES PEPTIDOGLYCANS (MDP)

25 Innate Immunity: Failure of NOD2 Signaling alters cell function PERSISTENCE OF INTRACELLULAR BACTERIA INTRACELLULAR BACTERIA NF-kB DEFENSIN DEFICIENCY (LOSS OF STERILE CRYPTS) NOD2 SENSES PEPTIDOGLYCANS (MDP) ALTERED EPITHELIAL CELL FUNCTION (? INCREASED PERMEAILITY)

26 ATGL1 and Autophagy: More Defense Functional autophagy Absence of autophagy

27 Adaptive Immunity

28 Model for Crohn s Disease Genotype- Phenotype associations Normal

29 Model for Crohn s Disease Genotype-Phenotype associations Inflammation NOD2 and other genes (location)

30 Model for Crohn s Disease Genotype- Phenotype associations Fibrostenosis NOD2/CARD15 Earlier surgery

31 Model for Crohn s Disease Genotype- Phenotype associations Aggressive disease more surgeries NOD2 Atg16L1 Smoking ASCA/I2/OmpC expression

32 Therapies Directed at These Pathways

33 Biology of Interleukins 12 and 23 Stimulus TLR? IL-12 p35 p40 Anti- IL-12/23 Anti-IL-12/23 Antigen Presenting Cell MHCII Ag 2 TCR IL-23R IL-12R 1 CD4 + X IFNg (Th1) IL-17 (Th17) IL-12R 1 p19 p40 IL-23 Anti- IL-12/23

34 Imielinski, et al. Nature Genetics 2009;41:1335 Are there novel genes that confer susceptibility to pediatric onset IBD? International Pediatric IBD GWAS Most genes identified in adult GWAS show association with pediatric IBD Novel genes subsequently confirmed in adult cohorts Shows similarity in pathways in both adult and pediatric onset IBD Included patients were predominantly older children or adolescents at time of diagnosis (A1b or A2)

35 IL27 and IBD

Inflammatory Bowel Disease (IBD) We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 and 21q22 located close to the TNFRSF6B and PSMG1 genes,

36 Inflammatory Bowel Disease (IBD) We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 and 21q22 located close to the TNFRSF6B and PSMG1 genes, respectively Gene discovery studies in childhood-onset disease have unveiled genetic factors that are less likely to surface in adult studies We have identified six other novel IBD loci and replicated the vast majority of loci discovered in adult onset IBD

37 Very Early-Onset IBD: The Challenge Diagnosed 5 years of age Frequently different phenotype and more severe disease presentation Often unresponsive to conventional therapy

38 Genomics and VEO-IBD GWAS approach Primarily included adults and children>10 Frequently misses rare variants, MAF <5% Role of primary immunodeficiency Are we missing important pathways in this cohort?

39 WES: The Low-Hanging Fruit? Muise Gastroenterology 2012

40 Identified Rare Variants in Candidate Genes Chr Position dbsnp ID Ref Alt DNA Alteration Gene Immunodeficiency rs C G p.t43r TNFRSF18 CVID Novel G C p.s554t MSH5 CVID rs G A p.r514h CD19 CVID rs A G p. T1724V LRBA CVID rs C T p. R702W NOD2 IBD risk loci rs T A p.n419i NCF2 CGD CYBA CGD rs A G p.1591t MEFV FMF rs C T p.r412w IL10RA IL-10R (see IL10) rs rs C G T C p.v7221 JAK3 Primary immunodeficiency; Multiple immunodeficiency pathways

Loss of protective flora Crohn specific genes (Nod2) Core genes

41 IBD pathogenesis Crohn disease-like Ulcerative colitis-like Crohn activating infections Colonization (bacteria, viruses, fungi, worms) Loss of protective flora Crohn specific genes (Nod2) Core genes Regulating Inflammation, Epithelial barrier, autophagy, etc UC specific genes

42 The microbiome shapes the innate immune response and vice versa Microbiome Innate immune responses

43 Conclusions Genomics of IBD is evolving Newer technology has allowed us to identify pathways critical in the development of IBD Candidate causative mutations in early-onset IBD can be identified by exome sequencing Goal is combine our findings in genomics and microbiome and target therapy for the individual patient

44 Thank You

Genes, Genes, Everywhere! The key to a cure for IBD

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