Inflammatory bowel disease (IBD) is a common, chronic disorder of the gastrointestinal tract characterized by abdominal pain, diarrhea, growth disturbances, and general discomfort. Administration of glucocorticoids is one of the mainstays of treatment. However, the efficacy of glucocorticoids is highly variable, and adverse effects are common in affected individuals whose disease is glucocorticoid-dependent. The overall goal of this project is to determine whether variants in genes encoding mediators of immune response pathways directly affected by glucocorticoids influence susceptibility to IBD, as well as an affected individual's response to treatment with glucocorticoids. This goal will be accomplished by (1) characterizing the pattern of population genetic variation in each of 16 candidate genes encoding members of the NF-icB, MAPK/JNK/AP-1, and JAK/STAT signaling networks, and the human glucocorticoid receptor; and (2) testing for association between variants in these candidate genes and susceptibility to IBD and therapeutic response to glucocorticoids. Association studies will be performed in 2 different cohorts: (1) 552 affected-IBD cases of all ages including approximately 230 affected sib-pairs; and (2) 315 pediatric IBD trios (affected child plus parents). A five year mentored program is proposed that will incorporate both didactic and research training and will be guided by a well-established investigator at the University of Utah. Through an NIH-funded K30 award, the University of Utah's General Clinical Research Center provides a unique training program in clinical research focused on the inherited basis of human disease. This program incorporates access to resources-such as multiuser core facilities, large research centers at the University, and a designated clinical research unit in the University Hospital- with a specific mentored intensive research experience for maturing clinical investigators. The candidate will enroll in the K30 program. Thus the University of Utah provides an ideal environment for maximizing the potential of this study and the candidate.
| Huff, Chad D; Witherspoon, David J; Zhang, Yuhua et al. (2012) Crohn's disease and genetic hitchhiking at IBD5. Mol Biol Evol 29:101-11 |
| Willson, Tara A; Kuhn, Benjamin R; Jurickova, Ingrid et al. (2012) STAT3 genotypic variation and cellular STAT3 activation and colon leukocyte recruitment in pediatric Crohn disease. J Pediatr Gastroenterol Nutr 55:32-43 |
| Huff, Chad D; Witherspoon, David J; Simonson, Tatum S et al. (2011) Maximum-likelihood estimation of recent shared ancestry (ERSA). Genome Res 21:768-74 |
| Guthery, Stephen L; Mineau, Geraldine; Pimentel, Richard et al. (2011) Inflammatory bowel disease aggregation in Utah kindreds. Inflamm Bowel Dis 17:823-30 |
| Anderson, Carl A; Boucher, Gabrielle; Lees, Charlie W et al. (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43:246-52 |
| Wang, Kai; Baldassano, Robert; Zhang, Haitao et al. (2010) Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. Hum Mol Genet 19:2059-67 |
| Simonson, Tatum S; Yang, Yingzhong; Huff, Chad D et al. (2010) Genetic evidence for high-altitude adaptation in Tibet. Science 329:72-5 |
| Huff, Chad D; Harpending, Henry C; Rogers, Alan R (2010) Detecting positive selection from genome scans of linkage disequilibrium. BMC Genomics 11:8 |
| Huff, Chad D; Xing, Jinchuan; Rogers, Alan R et al. (2010) Mobile elements reveal small population size in the ancient ancestors of Homo sapiens. Proc Natl Acad Sci U S A 107:2147-52 |
| Franke, Andre; McGovern, Dermot P B; Barrett, Jeffrey C et al. (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42:1118-25 |
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