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State of the Art in IBD Genetics

State of the Art in IBD Genetics . Judy H. Cho, M.D. Ward-Coleman Professor of Medicine and Genetics, Icahn School of Medicine at Mount Sinai. Central importance of human genetics. Germline DNA variants  disease susceptibility Primary causality

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State of the Art in IBD Genetics

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  1. State of the Art in IBD Genetics Judy H. Cho, M.D. Ward-Coleman Professor of Medicine and Genetics, Icahn School of Medicine at Mount Sinai

  2. Central importance of human genetics • Germline DNA variants disease susceptibility • Primary causality • Immediate molecular insight—genes, increased/decreased function • Humans as your experimental system—natural pertubagens relevance for patients • Genome-wide genetic approaches are unbiased • Novel, unexpected insight—autophagy • Promise of new therapy development—major challenge for the field

  3. Genetics: enormous impact on IBD research—autophagy & Paneth cells Cell 2010 Critical role for the Paneth cell Nature 2013

  4. Genetics impact: IL-23 pathway & treatment Science 2006 PNAS 2011 Salt increases IL23R expression Nature 2013 NEJM 2012

  5. IBD Immunochip: 163 loci associated to IBD 150 GWAS meta-analyses Immunochip163 loci NOD2 Single-center GWAS 100 Cumulative IBD loci MHC in UC 50 0 2000 2002 2004 2006 2008 2010 2012 Nature, 2012 Year

  6. Major genetics concepts: functional variants and evolutionary selection • Overlap of major loci between related diseases—motivation for development of Immunochip • Most GWAS-identified variants are non-coding and affect gene expression (eQTLs) • Immune-mediated disease loci: evolved in response to historically significant pathogens • Population differences: may provide major insight • Common vs. rare variants

  7. Genetic architecture: Crohn’s disease vs. ulcerative colitis in European ancestry cohorts • IL23R in both • MHC major in UC • Crohn’sdisease-uniquely lacks a dominant MHC signal • Instead, innate immune defects: NOD2 & ATG16L1 Crohn’s disease Arg381Gln Ulcerative colitis Nature 2001;411:603 Science 2006;314:1461 Nat Genet. 2009;41:216 **Nat Genet. 2011;43:246 **Nat Genet. 2010;42:1118 Nat Genet. 2011;43:1066

  8. The Immunochip effort in IBD: international collaboration on a grand scale • 38,565 cases & 37,747 controls • Combined 15 separate European ancestry IBD GWAS 25,075 SNPs with p < 0.01 • Meta-analysis: • GWAS + • New cases genotyped on Immunochip • 14,763 CD cases • 10,920 UC cases • 15,977 controls genotyped • 71 new loci163 genome-wide significant loci

  9. Defining the genetic architecture of CD vs. UC IL23R NOD2 110 IBD loci 23 UC specific loci >1.5 1.4 30 CD specific loci MHC 1.3 IBD vs. control odds ratio 1.2 PTPN22 1.1 CD vs. UC odds ratio 0.67 1.0 >1.5

  10. Inflammatory bowel disease: 163 loci genes & alleles • Annotation approaches for “hit SNPs”: • cSNPs: 24 loci (15%) • eQTLs: 64 loci (39%)** • Dapple (protein-protein interaction): 30 loci • Grail (literature mining): 87 loci • Bayesian network analysis: 43 loci • 52 loci contain genes implicated by two or more annotation approaches

  11. Striking overlap of IBD loci between diseases IBD loci 82 53 MSMD 82 Primary immune deficiencies 82 Immune-mediated diseases CMC v Chronic mucocutaneouscandidiasis (CMC): CARD9, STAT3 Mycobacterial disease

  12. Striking overlap between IBD & mycobacterial susceptibility IL12B STAT1 IRF8 TYK2 STAT3 IFNGR2 IFNGR1 NOD2 RIPK2 TNFSF15 LRRK2 IL23R C13orf31 * 163 IBD loci 7/9 6/7 9 single gene mycobacterial (Tb) genes 7 leprosy GWAS loci

  13. Why the specificity between IBD & mycobacterial infection? • NOD2 & glycolyl MDP: mycobacteria & Actinomycetes contain enzyme (NamH) which converts acetyl MDP to glycolyl MDP (Coulombe, JEM 2009) • TNF & IBD: • Over-expression of TNF ileitis & arthritis (Kontoyiannis, Immunity 1999) • Anti-TNF highly effective in the treatment of Crohn’s disease & ulcerative colitis • Anti-TNF treatment reactivation of latent Tb (Keane et al, NEJM 2001) • Ashkenazim, Crohn’s disease & mycobacterial susceptibility

  14. Epidemiologic support for the Jewish-Tb hypothesis NYC, 6 years before 1890 per 100,000 Deaths from tuberculosis, London 1894-1900 Jacobs J. The Jewish Encyclopedia; a guide to its contents, an aid to its use. New York, London: Funk & Wagnalls company; 1906.

  15. Tissue-based co-expression modules define genes with correlated gene expression Module with greatest enrichment for IBD genes: 523 module from adipose tissue Gene in IBD-associated locus Highly correlated RNA expression between NOD2, IL10 & HCK (hematopoietic cell kinase) NOD2 • - HCK: key for differentiation of M2 macrophages

  16. Unexpected relationship between abdominal fat and IBD Creeping fat Transmural disease complications Adipose tissue an abundant source of TNF

  17. Rare variants--less power to detect association, but greater effect sizes (i.e., odds ratios, OR) 0.50 Protective Risk Not typically present Common variation of small effects GWAS Most associations with small effects, OR < 1.1 Negative selection: deleterious alleles are low frequency Frequency of genetic variation 1% vs. 0.3% OR ~3 Uncommon variation of large effect (Mendelian) Not identifiable 1 (baseline risk) Magnitude of effect

  18. At least 3 of 4 components of Mendelian susceptibility to Mycobacterial diseases (MSMD) genes also associated to IBD * * * * Key components: IL12/23 signaling IFNg signaling CD40-CD40L interaction NADPH oxidase system * * * * * * What about the NADPH oxidase system?? * * * * * * IBD-associated gene * Casanova et al., Immunity 2012 36: 515

  19. NADPH oxidase deficiency & IBD • Autosomal recessive mutations in NCF2 (p67phox) associated with chronic granulomatous disease • NCF4: nominal association to IBD by GWAS (association signal stronger in AJs) • NCF2 mutations at Arg38 • Arg38Gln: 0.5% allele in very-early onset IBD with 24x increased risk (Muise et al, Gut 2012) • Ashkenazi Jewish exome sequencing: identified an AJ-specific, distinct mutation Arg38Trp (0.51% allele, 4.4x increased risk) • Both mutations, Arg38Gln, Arg38Trp impaired binding to RAC2 • Implicates impaired NADPH oxidase function in adolescent/adult-onset IBD as well as very-early onset IBD

  20. Conclusions & future directions • IBD genetics: foundation for many of the most impactful publications in IBD research • Genetic architecture of IBD shaped in response to mycobacterial infections—implications • Host-microbiomeinteractions • Can leverage the enormous existing biologic understanding of innate responses to mycobacteria • Leverage evolution and population differences • Rare mutations have higher effect sizes and may provide a more direct route to new therapies • Early onset • Population differences

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