The IBDGC encourages applications for ancillary studies that complement its ongoing activities. Both IBDGC investigators and those not previously associated with the Consortium are welcome to apply. Proposed studies may use existing Consortium data and biospecimens, and may also propose to collect new data from existing study participants. Ancillary studies may also utilize the central resources of the Consortium (e.g., NIDDK Central Repository, Data Coordinating Center), provided that such use is approved in advance and is supported by funding from the proposed study.
Those wishing to apply for an ancillary study must have a Consortium liaison who can serve as the main point of contact between the applicant and the Consortium. Any IBDGC investigator (including co-investigators) may serve as a liaison; the liaison may be involved in the study but that is not required. If you need help in identifying someone who can serve as a liaison, please contact Yashoda Sharma.
Before an application for an ancillary study may be submitted to NIDDK, the proposal must be reviewed by the Consortium's Ancillary Studies Committee. This review evaluates the proposed study according to the following criteria:
- Is the proposed study relevant to the Consortium's overall goals?
- Does the study have scientific merit?
- Is the investigator well-qualified to carry out the proposed research?
- Is the study design appropriate?
- Does the proposed study require Consortium resources or involvement? (it must to qualify)
- Is there potential for interference with other Consortium activities?
Applicants will receive feedback from this review which will help them prepare their proposal for the NIH review process.
Materials for preparing an application for submission to the Consortium's Ancillary Studies Committee are available below:
Please note that applicants wishing to submit a proposal for the March 20, 2018 NIH deadline must submit a proposal (using the form above) to Yashoda Sharma by midnight ET February 15th, 2018. You will receive a decision from the NIDDK IBDGC Steering Committee no later than midnight ET March 6th, 2018.
Ancillary Studies to the NIDDK Inflammatory Bowel Disease Genetics Consortium (R21 - Clinical Trial Optional)
Gene Discoveries in Subjects with Crohn's Diseases of African Descent
Subra Kugathasan, PI, Emory University (5R01DK087694-07, 2017-2021)
Crohn’s disease (CD) is heritable. Most genetic discovery to date has been performed in Caucasians of European descent. African Americans (AAs) endure a similar disease burden as Caucasians, yet less than 1% of research, publications, or clinical trials have focused on AA with CD. It remains to be seen whether these genetic markers will have prognostic utility in admixed individuals, such as AAs. Furthermore, AAs are at higher risk for disease complications and often have worse disease outcomes, suggesting that the underlying biology of CD in AAs may be different than Caucasians. The genome of AAs is admixed (~80% West African and 20% Caucasian), with greater diversity and shorter linkage disequilibrium (LD) blocks. Higher levels of diversity can make genetic / post-GWAS studies more challenging, but identifying causal variants in AA may prove easier because of shorter physical LD region. We have successfully completed a well-powered GWAS for gene discoveries in AA. While common susceptibility variants discovered in Caucasians are also generally found in AAs with IBD, new AA-specific variants/loci in IBD, UC and human leukocyte antigen (HLA) region along with several new regions of significant admixture linkage disequilibrium and multiple new signaling pathways. Following these exciting results and discoveries, we propose a post GWAS studies to comprehensively identify rare, causal and population specific variants in African Americans with CD.
Functional Outcomes of Inflammatory Bowel Disease Associated Variants
Clara Abraham, PI, Yale University (5R01DK099097-02, 2013-2018)
The interplay between microbial and genetic susceptibility factors is central to the development of IBD. Innate mechanisms, in particular through pattern recognition receptor (PRR) pathways, are the initiating drivers of host responses to microbes. A central outcome of PRR activation by bacterial and viral products is induction of cytokine secretion. To a large extent, IBD is characterized by dysregulated cytokines, and modulation of cytokines plays a primary role in IBD treatment. We hypothesize that polymorphisms in multiple IBD-associated genes contribute to inter-individual variation in PRR-induced cytokine secretion. We will utilize a large, well- powered cohort to screen for IBD-associated polymorphisms contributing to the variation in PRR-initiated cytokine secretion across individuals, and then define the molecular mechanisms wherein the implicated IBD-associated genes, as well as the identified polymorphisms, regulate PRR-induced cytokine secretion.
Defining the Genetic Architecture of IBD in Ashkenazi Jewish Populations
Judy Cho, PI, Icahn School of Medicine at Mount Sinai (5R01DK092235-04, 2012-2017)
A central feature of IBD epidemiology is the 4.3-7.7 fold increased prevalence of disease in Ashkenazi Jewish populations. It is unknown at present what factors account for this higher disease prevalence. This proposal will address this gap through testing two hypotheses. A complete exploration of the underlying etiology for the markedly increased IBD prevalence in the Ashkenazim will be achieved through the interrogation of uncommon SNPs in the exome and throughout the genome through case control studies. Important in this regard will be the ascertainment of large case-control cohorts, for which additional recruitment is proposed. New and existing IBDGC resources will be utilized to ascertain larger subject groups and to collaborate on genotyping studies.
Autophagy Genes and the Microbiome in Crohn’s Disease
Ramnik Xavier, PI, Broad Institute, Inc. (5R01DK092405-03, 2012-2015)
This study proposes to advance understanding of CD by determining how the interactions and influences of host genetics, the microbiome and the immune response contribute to Crohn's disease. The proposal will assess how genetic variants associated with IBD shape the microbiota and the functional consequences that alter host responses and culminate pathologic inflammation. We focus on autophagy-linked genetic variants to determine whether genetic subsets of Crohn's disease (CD) are associated with specific changes in the luminal microbiome. We will leverage the extensive resources and detailed phenotypic information of the IBDGC as well as several other IBD registries to enroll subjects with ATG16L1, IRGM, and NOD2 disease-associated variants, as well as healthy individuals with and without these risk alleles.
Gene Discoveries in Subjects with Crohn's Diseases of African Descent
Subra Kugathasan, PI, Emory University (5R01DK087694-04, 2011-2016)
We will collaborate with Subra Kugathasan to perform genetic studies, including a genome-wide association study (GWAS) in African-Americans (AA) with Crohn’s disease. Because such approaches have been particularly fruitful in CD case-control cohorts of European ancestry (EA), we anticipate that similar studies in African-Americans will provide important, comparative insight into the pathogenesis of this important disease. The AA population may be important in identifying novel genomic loci not currently implicated in EA cohorts. In addition, genetic features of the AA population, including European admixture, increased allelic diversity and shorter regions of linkage disequilibrium pose both challenges and opportunities in developing an integrated understanding of the overall genetic architecture contributing to CD.
PSC Resource of Genetics Risk, Environment and Synergy Studies
Kostas Lazaridis, PI, Mayo Clinic, Rochester (5R01DK084960-05, 2010-2015)
In our combined clinical and research experiences with IBD we’ve become increasingly more aware of the critical relationship that exists between IBD and PSC. Therefore this study will be a great addition to the IBDGC’s mission to understand the genetic mechanisms underlying IBD in general and ulcerative colitis, specifically. In addition to the IBDGC resources available to Dr. Lazaridis each GRC is collaborating with their respective liver clinics to recruit PSC patients with and without IBD.
Identifying Disease Variants for Family Crohn's Disease
Steve Brant, PI, Johns Hopkins University (5R01DK083553-02, 2009-2011)
This project used existing IBDGC resources and also developed additional resources to enable the identification of disease alleles for the significant chromosomes 1p, 3q and 13q CD genetic loci discovered in the IBDGC genome wide SNP linkage. The identification of these loci was a major effort by the IBDGC to identify loci for familial CD and complements our efforts to identify genes by genome wide association mapping. It is important that we follow up the successes in familial locus identification and take the next step to actually identify the genetic variants responsible for these loci. Dr. Brant’s application put forth a solid plan to do just that.