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IBD genetics in children across diverse populations

IBD genetics in children across diverse populations. Subra Kugathasan, MD Professor of Pediatrics and Human Genetics Emory University . The predictive power of genetic markers should be integrated into the management of IBD.

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IBD genetics in children across diverse populations

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  1. IBD genetics in children across diverse populations Subra Kugathasan, MD Professor of Pediatrics and Human Genetics Emory University

  2. The predictive power of genetic markers should be integrated into the management of IBD Biology (genetics, serology andmicrobial markers vary greatly across populations

  3. US Population at Glance Projected By Race: Foreign-Born by Race: Projected http://www.usc.edu/schools/price/futures/pdf/2011_Pitkin-Myers_Projections-Immigrant-Generations-and-Foreign-Born.pdf

  4. IBD phenotypes in different populations Multi-center US populations N=138 N=1,406 White et al., Clinical Gastroenterology and Hepatology, 2008

  5. Why study IBD studies across populations? • Most genetic studies of IBD to date have mainly been conducted in Caucasians. Finding of Caucasians (West Europeans) cannot be extrapolated to non-Caucasians. Most results found in Caucasians do not have prognostic utility in other minority population. • Emerging data support the hypothesis that the prevalence and disease burden among African Americans (AA) is similar to that of Caucasians. • The disease pathogenesis, disease course and treatment responses could vary with Race/Ethnicity genetics

  6. NIH/NIDDK Genetic consortium – ancillary R01 Progress to data • Goal: • 1500 African American IBD subjects from multiple sites • 1150 African American control subjects • Detailed phenotypic characterization • Collection of whole blood for DNA and serum Total CASES: 905 Total CONTROLS: 238

  7. Genesis AA Enrollment by Site

  8. IBD phenotypes in African Americans Our current data from over 900 subjects

  9. Age of onset among African Americans Over 900 subjects, not population based

  10. Prevalence of CD and UC in the US by Age

  11. Age of Onset among Subjects AA enrolled at 18 years of age and older

  12. Why study genetics across populations? • Non-Africans and Non Europeans represent an admixed population, with founders from West Africa and Europe. • They have a different genetic diversity and a various lenghtLD block than their founders. This makes genetic studies ideal for identifying population specific disease variants. • It is mandatory to perform GWAS in minority population to test the hypothesis that specific disease susceptibility SNPs exist either within the known IBD loci, or in undiscovered loci. • Most results found in Caucasians do not have prognostic utility in other minority population Tishkoff SA et al. Science. 2009 May 22;324(5930):1035-44

  13. Admixture African American = 80% African + 20% Caucasian loci Based on 1327 nuclear microsatellite and insertion/deletion markers used to asses the genetic ancestry of populations VS. VS. Modified from Tishkoff SA et al. Science. 2009 May 22;324(5930):1035-44

  14. Ancestry Informative Markers can Confirm Self-reported Ethnicity 4 clusters distinguishes between 4 US populations Divers et al., BMC Genet. 2011 Mar 4;12:28

  15. Populations Admixture vary within the US African American = 80% African + 20% Caucasian ancestry VS. VS. http://en.wikipedia.org/wiki/Mexican_American Modified from Tishkoff SA et al. Science. 2009 May 22;324(5930):1035-44

  16. Admixture can vary between individual of the same family Mother 93% African, 6% European and 1% Asian Sister 1 84% African, 13% European and 3% Asian Sister 2 78% African, 18% European and 4% Asian African Ancestry European Ancestry Asian Ancestry Not genotyped or too little data http://www.taneya-kalonji.com/genblog/category/23andme/page/2

  17. An admixture mapping scan is typical Percent Ancestry from Caucasian population Chromosome position High proportion of ancestry from the Caucasian population Patients inherited high-risk alleles from Caucasian Nature Reviews Genetics6, 623-632 (August 2005)

  18. Representative AA admixture at NOD2 loci African Ancestry European Ancestry Asian Ancestry Not genotyped or too little data http://blog.openhelix.eu/?p=6906

  19. Adeyanju et al. InflammBowel Dis. 2012 Dec;18(12):2357-9

  20. Common NOD2 risk variants in AA with CD are due to recent Caucasian admixture 20% European Ancestry 100% European Ancestry 100% African Ancestry 80% African Ancestry Carrier of NOD2 variants (1000fs, R702W, G908R) Adeyanju et al. InflammBowel Dis. 2012 Dec;18(12):2357-9

  21. First Collaborative AA Immunochip Removed SNPs with low genotyping quality or errors in duplicates/parent-offspring trios • Allele frequencies of Yoruba's (YRI) and Caucasians (CEU) HapMap used to estimate ancestry. • Joint admixture/association tests (logistic regressions) were implemented: • Estimate test burdens for admixture and association mapping • Genotypic association stratified by local ancestry • Combined regression coefficient in each strata and calculated pooled p-values • Converted pooled p-values into posterior probability (pp) by using pp from admixture mapping as prior and test burden from association mapping. • 2,236 AA IBD 192,402 SNPs • 1770 AA IBD 136,497 SNPs QC filtering

  22. Second Collaborative AA Immunochip ~ 500 pediatric cases (2 to 17 years); include ~200 early onset (2 to 10 years)

  23. Second Collaborative AA ichip QC Process • 4,048 Samples (2025 cases and 2023 controls) • All genotypes jointly called with Illumina tools • Samples with <98.5% call rate temporarily removed • Remaining samples (n=~3,100) reclustered • 4,048 samples re-called using clusters from best performing samples • Final call rate >97.7%. Only 85 samples having call rates <92%. • Mendelian inconsistencies and gender mismatches still being resolved.

  24. Minor Allele Frequencies of Selected SNPs *Jostins L et al. Nature. 2012 Nov 1;491(7422):119-24

  25. ExomeSequencing –A pilot project • Sample size: 27 CD patients • 20 samples with severe perianal disease phenotype • 7 samples with of early onset disease • 17 novel functional variants in 16 genes could be implicated in neutrophil dysfunction (validation in progress)

  26. Conclusions & Future directions • Through collaborations, we have assembled a well powered, well phenotyped a understudied US population (AA, both adults and children) for genetic studies • Immunochip studies, GWAS and sequencing (exome & whole genome) studies in AA are underway in both adult and children. • Admixture analysis is a powerful way to narrow down the causatice loci when admixed population like AA is studied. • We will be able to these results in risk stratification and prognostic utility in minority population directly rather than extrapolating the Caucasian found results.

  27. Acknowledgements to our partners NIH/NIDDK Genetic consortium

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