Presentation is loading. Please wait.

Presentation is loading. Please wait.

Understanding the Next Steps in Determining the Role of the Genome in IBD Judy H. Cho, M.D. Ward-Coleman Professor of Translational Genetics and Medicine,

Similar presentations


Presentation on theme: "Understanding the Next Steps in Determining the Role of the Genome in IBD Judy H. Cho, M.D. Ward-Coleman Professor of Translational Genetics and Medicine,"— Presentation transcript:

1 Understanding the Next Steps in Determining the Role of the Genome in IBD Judy H. Cho, M.D. Ward-Coleman Professor of Translational Genetics and Medicine, Icahn School of Medicine at Mount Sinai December 6th, 2014

2 Questions  What naturally occurring genetic polymorphisms are associated with IBD?

3 What naturally occurring genetic polymorphisms are associated with IBD?  Value: molecular insight  profoundly shaped the landscape of IBD research  What’s worked and what hasn’t  Family-based: linkage  NOD2. Otherwise, family-based studies have not worked—re-vist with microbiome-based studies & genetic counseling  Case-control:  163 loci and counting  Surprises & advances  Magnitude of sample sizes required unexpected: NOD2 (Nature 2001) involved 416 CD samples -  > 30,000 cases  Number of significant loci larger than expected: 163 and counting  Advances: autophagy, IL-23 pathway, M1-M2 macrophage subsets  Challenges: long journey from genes  biology  drug targeting  new drugs Assessment

4 Questions  What naturally occurring genetic polymorphisms are associated with IBD?  What are the functional consequences of IBD- associated polymorphisms?

5 What are the functional consequences of IBD- associated polymorphisms?  Altered cytokine responses to microbial stimulation : NOD2, XIAP (direct); many indirect effects  Genotype-dependent variable bacterial clearance: autophagy, NADPH oxidase  Direct ex vivo analyses  IL23R and Th17/Tc17 cells (Sarin et al., PNAS 2011)  NOD2 & Paneth cell morphologies (Van Dussen Gastroenterology 2014)  Altered regulation of gene expression

6 What are the functional consequences of IBD- associated polymorphisms?  Altered cytokine responses to microbial stimulation : NOD2, XIAP  Genotype-dependent variable bacterial clearance: autophagy, NADPH oxidase  Direct ex vivo analyses  IL23R and Th17/Tc17 cells (Sarin et al., PNAS 2011)  NOD2 & Paneth cell morphologies (Van Dussen Gastroenterology 2014)  Altered regulation of gene expression

7 Expression quantitative trait loci (eQTL) mapping  mRNA expression as a continous trait  Heritable  Mappable to specific SNPs  Cell lines, tissues and context- specificity  Presently defined eQTLs likely only a subset of genuine eQTLs  LPS- & IFN  stimulated monocytes define more eQTLs  80% of transcripts with eQTLs Morley, et al., Nature 2004; 430: 743 Dixon, et al., Nature Genetics 3007; 39: 1202 Fairfax et al., Science 2014

8 Fine-mapping in autoimmunity  Fine-mapped autoimmune loci  90% are non-coding  60% map to immune enhancers  Histone marks: greatest enrichment seen for H3K27ac—active/stimulated enhancers  Disease-associated SNPs in enhancers are near, but not within consensus transcription factor binding sites Farh et al., Nature 2014

9 Enrichment of CD loci genes in open chromatin regions of Th17 cells, but not monocytes  Apples to oranges: Th17 cells vs. monocytes  Pending: tissue-specific enhancer landscape of organ- and context-specific tissue macrophages

10 From co-expression to (genetic) causal networks Gene in IBD- associated locus Highly correlated RNA expression between NOD2, IL10 & HCK (hematopoietic cell kinase)  HCK: key for differentiation of M2 macrophages  Cis eQTL in HCK: variable HCK expression is driving variable NOD2 & IL10 expression aka NRAMP Jostins et al, Nature 2012 Eric Schadt

11 Primary value of direct ex-vivo analyses: pathogenic & protective cells  High dimensional analyses needs to be matched to deep clinical information  Basic science questions  Cellular plasticity and diffentiation  DNA-RNA-protein Defining innate cell hierarchies by high-dimensional Cytof analysis

12 What are the functional consequences of IBD- associated polymorphisms?  Altered cytokine responses to microbial stimulation : NOD2, XIAP  Genotype-dependent variable bacterial clearance: autophagy, NADPH oxidase  Direct ex vivo analyses  IL23R and Th17/Tc17 cells (Sarin et al., PNAS 2011)  NOD2 & Paneth cell morphologies (Van Dussen Gastroenterology 2014)  Altered regulation of gene expression Acceleration of in vitro & in vivo studies with CRISPR/CAS9 technologies: refined genetic & molecular definition will improve modeling

13 Questions  What naturally occurring genetic polymorphisms are associated with IBD?  What are the functional consequences of IBD- associated polymorphisms?  Why do Ashkenazi Jewish populations have a higher IBD prevalence?  Rare variants  Common variants

14 Rare variants are “less rare” in AJs  128 whole genome sequenced in AJs  Rare variants are “less rare” in AJs compared to Flemish  Profound population bottleneck in AJs Derived allele frequency AJ Flemish Carmi et al., Nature Commun 2014

15 IBD Genetic Burden Score Ashkenazi Jews with a higher composite burden score than non-Jewish European ancestry Developing integrative models of common variant risk?

16 Striking overlap between IBD & mycobacterial susceptibility 163 IBD loci 6/7 7 multigenic leprosy GWAS loci 7/9 9 single gene mycobacterial (Tb) genes NOD2 RIPK2 **TNFSF15 LRRK2 IL23R C13orf31 IL12B STAT1 IRF8 TYK2 STAT3 IFNGR2 IFNGR1 Anti-TNF treatment of IBD associated with re-activation of latent mycobacterial disease NEJM 2001; 345: 1098

17 Epidemiologic support for the Jewish-Tb hypothesis PopulationDeaths per 100,000 Mussulman Arabs1130 Europeans513 Jews75 Deaths from tuberculosis, London PopulationNYBrooklyn African-American Ireland Bohemia Russia and Poland (mostly Jews) Scotland Scandinavia Canada Germany France England and Wales Italy United States (White) Hungary (mostly Jews) Jacobs J. The Jewish Encyclopedia; a guide to its contents, an aid to its use. New York, London: Funk & Wagnalls company; NYC, 6 years before 1890 per 100,000 Polygenic adaptation: positive selection at scores to hundreds of genes that confer selective advantage

18 Questions  What naturally occurring genetic polymorphisms are associated with IBD?  What are the functional consequences of IBD- associated polymorphisms?  Why do Ashkenazi Jewish populations have a higher IBD prevalence?  What factors are genetic and what are non- genetic/stochastic/developmental?  Better modeling of genetic contributions  More frequent modeling of environmental/stochastic factors

19 Systematic analysis of rare variants via enteroids Bank of rare variants broadly amenable for study Stem cells Biopsy Add growth factors Stem cells > Ascertaining by genotypes > CRISPR-CAS9

20 IgA-coating enriches for colitogenic bacteria  Stool-based collections: IgA enrichment may identify functionally important bacteria—reducing microbial complexity  Frequent sampling Palm et al., Cell 2014

21 Questions  What naturally occurring genetic polymorphisms are associated with IBD?  What are the functional consequences of IBD- associated polymorphisms?  Why do Ashkenazi Jewish populations have a higher IBD prevalence?  What factors are genetic and what are non- genetic/stochastic/developmental?  UC: limited vs. extensive disease  CD: ileal post-op—modeling first steps of disease recurrence  Age-dependent effects: disease severity & age of onset

22 Acknowledgements  Cho lab  Ken Hui  Monica Bowen  Kyle Gettler  Kaida Ning  Nai-Yun Hsu  Felix Chuang  Yashoda Sharma  Mount Sinai collaborators  Inga Peter  Eric Schadt  Miriam Merad  Bruce Sands  Jean-Fred Colombel  NIDDK IBD Genetics Consortium  Steve Brant  Richard Duerr  Dermot McGovern  John Rioux  Mark Silverberg  Mark Daly  Phil Schumm  Thad Stappenbeck-Wash U: enteroids  Yale University  Clara Abraham  Richard Flavell  RISK Pediatric Consortium  Subra Kugathasan  Ted Denson


Download ppt "Understanding the Next Steps in Determining the Role of the Genome in IBD Judy H. Cho, M.D. Ward-Coleman Professor of Translational Genetics and Medicine,"

Similar presentations


Ads by Google