Saturday, April 20, 2024
4/20/2024
PROJECT SUMMARY Crohn’s disease (CD) is a devastating inflammatory disorder of the gastrointestinal tract that affects over 1 million Americans, yet disproportionately affects African Americans (AA) for unknown reasons. Although AAs constitute ~15% of the US population, they have disparate levels of severe disease progression, non-responsiveness to anti-TNF treatment, which we have shown is likely to at least in part have a genetic basis. Our research group is an ancillary member of the NIDDK IBD-genetics consortium (NIDDK IBD-GC) and we have been successful in addressing many African American-specific issues. Our RO1 award funding through an ancillary award from the NIDDK IBD Genetics Consortium enabled us to complete the first GWAS and whole genome sequencing based study in AAs with IBD. We have discovered the first genome-wide significant, multi-study replicated, locus in AA IBD, and demonstrated enhanced effect sizes at that locus (5p13.1 near the PTGER4 gene encoding the Prostaglandin E2 Receptor) and LACC1 for Crohn’s disease in African ancestry populations relative to European derived populations. We have also identified novel loci with smaller effect sizes in need of replication, and demonstrated that African-specific effect estimates substantively improve the performance of polygenic risk assessment in African derived populations. The strongest associations in 5p13.1 are approximately 250kb from PTGER4 and contain a 22 SNP block which appears to explain approximately ~3.5% of the variance in CD in the African American population, an approximately 1.4-fold effect size increase over European populations. This motivates the current grant’s attempt to understand this region at the genetic, molecular, and functional levels, while studying this locus’ specific effects within the context of broader signatures associated with treatment failure in AA patients. Moving forward with our progress and momentum through established collaborations, patient recruitment sites, sample collection pipelines and state-of-the-art epigenome and transcriptome analysis, we propose herein to complete the following Aims that will test our hypothesis that patients who are at risk for disease progression and poor response to anti-TNF therapy are identifiable via molecular signatures, driven in part by ancestry-specific allelic effects at the single cell level. Since CD progression disproportionately affects AA and can be prevented, it is a high priority to understand the impact of biologic therapy in the gut and to use this information to inform intervention strategies. Thus, in Aim1, we will establish cell-type specific transcription profiles that predict CD progression in AAs. In Aim 2, we will determine the molecular mechanisms responsible for enhanced risk in AA at 5p13.1/PTGER4 and LACC1. Finally, in Aim3, we will be working with NIDDK IBD-GC to substantially increase the AA IBD cohort size by innovative engagement and recruitment methods, while collaborating with NIDDK GC to fulfil their mission. The outcomes of these studies are important to the NIH and NIDDK as it fulfills many of the unmet needs in missing molecular profiles from these under studied patient populations.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
