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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. - PowerPoint PPT Presentation
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IBD genetics in children across diverse populations
Subra Kugathasan, MDProfessor of Pediatrics and Human Genetics
Emory University
The predictive power of genetic markers should be integrated into the management of IBD
Biology (genetics, serology andmicrobial markers vary greatly across populations
US Population at Glance
By Race:
Foreign-Born by Race:
Projected
Projected
http://www.usc.edu/schools/price/futures/pdf/2011_Pitkin-Myers_Projections-Immigrant-Generations-and-Foreign-Born.pdf
White et al., Clinical Gastroenterology and Hepatology, 2008
N=138 N=1,406
IBD phenotypes in different populationsMulti-center US 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
Why study IBD studies across populations?
CASE ENROLLMENT
CASE GOAL
CONTROL ENROLLMENT
CONTROL GOAL
0 200 400 600 800 1000 1200 1400 1600
570
105
129
133
55 150
1500
1150
Enrollment Goals and Progress to Date
Genesis AA Cohort
Previously recruited at Emory
Wisconsin Cohort
CHOP Cohort
Final Goal
• 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
NIH/NIDDK Genetic consortium – ancillary R01 Progress to data
Total CASES: 905Total CONTROLS: 238
Genesis AA Enrollment by Site
Previously recruited at Emory
Wisconsin Cohort
Emory University
University Hospitals Case Western Medical Center
University of Maryland School of Medicine
LSU Health Science Center
Children's Hospital of Philadelphia
Cincinnati Children's Hospital Medical Center
Vanderbilt-Monroe Carell Jr. Children's Hospital
UT Southwestern Children's Medical Center
UNC Chapel Hill Children's Hospital
University of Chicago Children's Hospital
Cook Children's Medical Center
Willis-Knighton Physician Network
University of Mississippi Children's Medical Center
Atlanta VA Medical Center
Montefiore Medical Center
0 20 40 60 80 100 120 140
CONTROL ENROLLMENTCASE ENROLLMENT
Ilecolonic41%
Colon52%
Ileal6%
Uppper GI1%
Disease Location
Male43%
Female57%
Gender Difference Fibrostenotic Penetrating Perianal 0%
5%
10%
15%
20%
25%
30%
25% 24%20%
Disease Behaviour
CD68%
UC28%
IBDU4%
Disease Type
IBD phenotypes in African AmericansOur current data from over 900 subjects
Age of onset among African Americans Over 900 subjects, not population based
less than 10 years
10 to 19 20 to 29 30 to 39 40 to 49 50 to 59 60 years of age and above
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
UC (%)
Crohn's (%)
Prevalence of CD and UC in the US by Age
<10 10 to 19 20 to 29 30 to 39 40 to 49 50 to 59 60 and above
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
CD (%) UC (%)
Age of Onset among Subjects AA enrolled at 18 years of age and older
<5 5 to 9 10 to 14
15 to 19
20 to 24
25 to 29
30 to 34
35 to 39
40 to 44
45 to 49
50 to 54
55 to 59
>=600
10
20
30
40
50
60
70
Crohn'sUC
Num
ber o
f Sub
ject
s Dia
gnos
ed
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 lenght LD 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
AdmixtureAfrican American = 80% African + 20% Caucasian loci
Based on 1327 nuclear microsatellite and insertion/deletion markers used to asses the genetic ancestry of populations
Modified from Tishkoff SA et al. Science. 2009 May 22;324(5930):1035-44
VS. VS.
Ancestry Informative Markers can Confirm Self-reported Ethnicity
Divers et al., BMC Genet. 2011 Mar 4;12:28
4 clusters distinguishes between 4 US populations
Populations Admixture vary within the US
Modified from Tishkoff SA et al. Science. 2009 May 22;324(5930):1035-44
VS. VS.
http://en.wikipedia.org/wiki/Mexican_American
African American = 80% African + 20% Caucasian ancestry
Sister 1 84% African, 13% European
and 3% Asian
Sister 2 78% African, 18% European
and 4% Asian
http://www.taneya-kalonji.com/genblog/category/23andme/page/2
Admixture can vary between individual of the same family
Mother93% African, 6% European
and 1% Asian
African AncestryEuropean AncestryAsian AncestryNot genotyped or too little data
An admixture mapping scan is typical
Nature Reviews Genetics 6, 623-632 (August 2005)
Perc
ent A
nces
try
from
Cau
casia
n po
pula
tion
Chromosome position
Patients inherited high-risk alleles from Caucasian
High proportion of ancestry from the Caucasian population
African AncestryEuropean AncestryAsian AncestryNot genotyped or too little data
Representative AA admixture at NOD2 loci
http://blog.openhelix.eu/?p=6906
Adeyanju et al. Inflamm Bowel Dis. 2012 Dec;18(12):2357-9
Cases (n=220)
Controls (n=210)
Cases (n=40)
Controls (n=500)
Cases (n=210)
Controls (n=111)
Caucasians Africans African Americans-0.05
-4.16333634234434E-17
0.05
0.1
0.15
0.2
0.25
0.30.3
0.17
0.0025 0.0025
0.09
0.04
Alle
le F
requ
enci
es
100% European Ancestry
100% African
Ancestry80%
African Ancestry
20% European Ancestry
Adeyanju et al. Inflamm Bowel Dis. 2012 Dec;18(12):2357-9
Common NOD2 risk variants in AA with CD are due to recent Caucasian admixture
Carrier of NOD2 variants (1000fs, R702W, G908R)
First Collaborative AA Immunochip2,236 AA IBD 192,402 SNPs
1770 AA IBD 136,497 SNPs
QC filtering
Cases + Controls
Healthy Controls
All IBD Cases
CD Cases
UC Cases
Total 1770701
(39.6%)1069
(60.4%)767
(43.3%)251
(14.2%)
Global YRI (%) 83.0 ± 8.3 82.9 ± 8.4 83.1 ± 8.2 83.2 ± 8.0 82.9 ± 8.5
Allele frequencies of Yoruba's (YRI) and Caucasians (CEU) HapMap used to estimate ancestry. Joint admixture/association tests (logistic regressions) were implemented:
1. Estimate test burdens for admixture and association mapping 2. Genotypic association stratified by local ancestry3. Combined regression coefficient in each strata and calculated pooled p-values4. Converted pooled p-values into posterior probability (pp) by using pp from admixture
mapping as prior and test burden from association mapping.
Removed SNPs with low genotyping quality or errors in duplicates/parent-offspring trios
Cedars Sinai
Emory University
John Hopkins
Second Collaborative AA Immunochip
Cedars Sinai Emory University John Hopkins TOTAL
Cases 281 746 998 2025Controls 49 283 1691 2023
TOTAL 330 1029 2689 4048
CD UC IBD-U Affected
(no disease record)
Control non-IBD
TOTAL 1472 460 80 13 1994 29
2025 Cases 2023 Controls
~ 500 pediatric cases (2 to 17 years); include ~200 early onset (2 to 10 years)
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.
Minor Allele Frequencies of Selected SNPsLoci
Risk Allele Frequency (RAF)Caucasians African Americans
SNP* Gene* Cases* Controls (Hapmap CEU) Cases Controls
rs5743289 NOD2 0.024 0.226 0.056 0.033
rs12994997 ATG16L1 0.523 0.575 0.352 0.311
rs11209026 IL23R 0.933 0.959 0.989 0.986
rs12942547 STAT3 0.580 0.545 0.597 0.582
rs516246 FUT2 0.483 0.531 0.517 0.495
rs4246905 TNFSF15 0.709 0.676 0.928 0.932
rs17293632 SMAD3 0.235 0.230 0.077 0.068
rs3024505 IL10 0.160 0.181 0.065 0.048
rs10781499 CARD9 0.412 0.487 0.319 0.284
rs4728142 IRF5 0.444 0.398 0.288 0.287
rs6871626 IL12B 0.337 0.367 0.232 0.191
rs10758669 JAK2 0.349 0.366 0.23 0.206
rs3197999 MST1 0.296 0.259 0.25 0.241
*Jostins L et al. Nature. 2012 Nov 1;491(7422):119-24
Exome Sequencing –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)
• 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.
Conclusions & Future directions
Acknowledgements to our partnersNIH/NIDDK Genetic consortium