Primary sclerosing cholangitis (PSC) is a progressive liver disease strongly associated with inflammatory bowel disease (IBD). About 75% of PSC patients are diagnosed with IBD, most commonly ulcerative colitis (UC) and conversely, 5-7% of IBD patients develop PSC. Life expectancy of PSC patients is reduced due to lack of medical therapy, advancement to end-stage liver disease and an increased risk of colon cancer and cholangiocarcinoma (CCA). Thus, while rare in the population, PSC is a notable threat to patients with IBD. Like IBD, PSC is thought to arise as the result of interacting genetic and environmental risk factors. Taken further, the IBD-PSC relationship may be one of overlapping risk capable of prompting both liver and gut involvement, with distinct mechanisms further influencing organ specific disease development. Yet, comprehensive studies focused on the dissection of the genetic and environmental risks in PSC, and its relationship with UC, have not been performed. To this end, we created the PSC Resource of Genetic Risk, Environment and Synergy Studies (PROGRESS). This resource currently comprises 618 PSC patients and 779 primary clinic-based controls;the largest of its kind in North America. Moreover, we have established collaborations between PROGRESS and the Norwegian PSC Research Center (NOPSC), UK PSC Consortium (UKPSC) and IBD Genetics Consortium (IBDGC) to share resources in pursuit of our common goals. In this application, we propose to test the hypothesis that genetic variants and/or environmental mediators contribute to PSC susceptibility and its association with UC. To achieve this, we propose three Specific Aims.
In Aim 1, we will expand PROGRESS through continued recruitment of PSC patients at Mayo Clinic and seven other participating medical centers across North America.
In Aim 2, we will perform 2 genome wide association studies (GWAS) to identify genetic variants for: (a) susceptibility to PSC- discovery study: 2000 PSC patients and 5000 controls;replication study: 1900 PSC patients and 3000 controls;and, (b) susceptibility to PSC in UC- discovery study: 1400 PSC patients with UC and 1000 UC patients without PSC;replication group: 1330 PSC patients with UC and 1000 UC patients without PSC.
In Aim 3, we will determine environmental risk factors for PSC using validated, self-administered questionnaires collected from PROGRESS participants (1000 PSC patients and 1000 controls). This study will begin to identify the genetic variants and environmental factors associated with PSC and its relationship with UC. These findings will serve as foundation for future risk assessment and disease prevention strategies as well as for basic research studies looking for implicated mechanisms and potentially leading to novel therapies for PSC.
The goals of this study are to identify genetic susceptibility to and environmental risks for Primary Sclerosing Cholangitis (PSC) and to embark on dissecting its strong association with inflammatory bowel disease (IBD). To achieve these objectives, we established the PSC Resource Of Genetic Risk, Environment and Synergy Studies (PROGRESS) and formed collaborations with national and international consortia of IBD and PSC. If successfully performed, this study will improve our knowledge of PSC and IBD pathogenesis, which could advance the prognosis and therapy of these disorders.
|Alberts, Rudi; de Vries, Elisabeth M G; Goode, Elizabeth C et al. (2018) Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis. Gut 67:1517-1524|
|Eaton, John E; Vesterhus, Mette; McCauley, Bryan M et al. (2018) Primary Sclerosing Cholangitis Risk Estimate Tool (PREsTo) Predicts Outcomes of the Disease: A Derivation and Validation Study Using Machine Learning. Hepatology :|
|Cheung, Angela C; LaRusso, Nicholas F; Gores, Gregory J et al. (2017) Epigenetics in the Primary Biliary Cholangitis and Primary Sclerosing Cholangitis. Semin Liver Dis 37:159-174|
|Eaton, John E; McCauley, Bryan M; Atkinson, Elizabeth J et al. (2017) Variations in primary sclerosing cholangitis across the age spectrum. J Gastroenterol Hepatol 32:1763-1768|
|Cheung, Angela C; Lazaridis, Konstantinos N; LaRusso, Nicholas F et al. (2017) Emerging pharmacologic therapies for primary sclerosing cholangitis. Curr Opin Gastroenterol 33:149-157|
|Ji, Sun-Gou; Juran, Brian D; Mucha, Sören et al. (2017) Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet 49:269-273|
|Henriksen, E K K; Viken, M K; Wittig, M et al. (2017) HLA haplotypes in primary sclerosing cholangitis patients of admixed and non-European ancestry. HLA 90:228-233|
|Cheung, Angela C; Juran, Brian D; Moore, Raymond M et al. (2017) Doublecortin domain containing protein 2 (DCDC2) genetic variants in primary sclerosing cholangitis. J Hepatol 67:651-652|
|Weismüller, Tobias J; Trivedi, Palak J; Bergquist, Annika et al. (2017) Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis. Gastroenterology 152:1975-1984.e8|
|Eaton, John E; Dzyubak, Bogdan; Venkatesh, Sudhakar K et al. (2016) Performance of magnetic resonance elastography in primary sclerosing cholangitis. J Gastroenterol Hepatol 31:1184-90|
Showing the most recent 10 out of 25 publications