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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Primary Biliary Cirrhosis Fund for the Cure Postdoctoral Research Fellowship
Mayo Clinic, Rochester
Project Title: Dissecting the genetic predispostion to response of ursodeoxycholic acid therapy in PBC
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease caused by immune mediated destruction of intrahepatic bile ducts and presents with elevated alkaline phosphatase (AP). With the advent of genome-wide technology, several risk loci have been identified, which collectively support an important role for both innate and adaptive immunity in development of disease. The only available medical therapy for PBC is ursodeoxycholic acid (UDCA), which improves biochemical profile of cholestasis, slows the histological progression of the disease in the majority of patients, and prolongs survival. Nevertheless, about 40% of PBC patients do not respond (i.e., Non-Responders) favorably to UDCA therapy. To date, although criteria for biochemical response to UDCA therapy have been established, the etiology of suboptimal response to UDCA among PBC patients is lacking. Such a discovery could also shed light on predictive factors of poor outcomes in PBC. In the present study, Dr. Lammert proposes to continue to dissect the genetic susceptibility to biochemical response of UDCA in PBC using a translational approach given that UDCA has likely anti-inflammatory as well as immuno-modulating effects. He would like to test the hypothesis that biochemical response to UDCA is mediated through immune/inflammatory genes and pathways. Utilizing the Illumina Immunochip, he has identified a single nucleotide polymorphism, with the accession number rs467868 on the short arm of chromosome 3, is significantly associated with lack of UDCA response in PBC. Dr. Lammert’s primary aim is to perform replication and fine mapping of the genetic variants associated with response to UDCA treatment in the Mayo Clinic PBC cohort (442 patients) by using an independent cohort of UDCA treated PBC patients from Canada (390 patients). His second aim is to carry out association analysis of immuneinflammatory genes with survival of PBC patients. Dr. Lammert’s anticipated results of this combined cohort approach will assist in strengthening the previously associated signal at 3p22.3 and possibly identify new statistically significant UDCA treatment response associated alleles. Evaluation of genetic variant associations with overall and transplant-free survival could lead to the development of an individualized therapeutic profile for PBC patients.