Crohn's disease (CD) is a highly heritable disorder. Genome wide association studies (GWAS) have proved to be highly successful at identifying susceptibility loci, many of which define previously unsuspected pathways as playing an important role in pathogenesis. Nearly all genetic studies focused exclusively on Caucasians of European descent who represents only ~70% of the US population. Thus, it remains to be seen whether these genetic markers will have prognostic utility in admixed individuals, such as African Americans (AAs) who constitute about 15% of the US population and in whom each chromosome is likely to be a mosaic of blocks of DNA from different ancestral populations. Furthermore, variation data from the HapMap and other disease studies suggest the possibility that the allelic architecture of CD in AA populations may significantly differ from that in Caucasians. African American populations remain dramatically understudied. There is a great need to extend these gene discovery studies in AA with CD by recruiting a large numbers of AA to increase the sample size and to enhance the power of discovery. In this ancillary R01 proposal to NIDDK IBDGC, we aim to recruit additional 1485 AA CD subjects that can be used to augment the discovery cohort and for the replication studies to the IBDGC efforts.
Our aims will be;
Aim 1 : Detailed phenotypic characterization of CD with African descent (AA). A minimum of 1000 AA subjects with CD will be recruited in 3 year period:
Aim 2 : Perform Genome Wide Association Study (GWAS) jointly with IBDGC to discover CD (IBD) genes / loci in CD with African descent (AA) using case control analysis, pathway analysis and CNV (copy number variation) analysis:
Aim 3 : Refine genome-wide association peaks by conducting targeted sequencing for population specific SNP discovery followed by Illumina genotyping of common SNPs in AA cases and controls. Genome-wide association scans in CD with European ancestry found more than 40 confirmed variants affecting the risk of developing CD. Open question, however, is how relevant the variants discovered in Europeans, are to AA population? Together, our well powered studies with high-throughput genotyping, state of the art analysis and sequencing in AA population with CD will discover, compare and contrast the already gained knowledge in Europeans in CD.

Public Health Relevance

Genome-wide association scans in CD with European ancestry found more than 40 confirmed variants affecting the risk of developing Crohn's disease (CD). An open question, however, is how relevant the variants discovered in Europeans are to African American (AA) population? Together, our well powered studies with high-throughput genotyping, state of the art analysis and sequencing in African American (AA) population with CD will discover, compare and contrast the already gained knowledge in Europeans in CD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK087694-02
Application #
8228123
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O4))
Program Officer
Karp, Robert W
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$781,214
Indirect Cost
$186,241
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Okou, David T; Mondal, Kajari; Faubion, William A et al. (2014) Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 58:561-8
Okou, David T; Kugathasan, Subra (2014) Role of genetics in pediatric inflammatory bowel disease. Inflamm Bowel Dis 20:1878-84
Middleton, Jeremy P; Bhagavathula, Anita P; Gaye, Bilkisu et al. (2013) Vitamin D status and bone mineral density in African American children with Crohn disease. J Pediatr Gastroenterol Nutr 57:587-93