title: Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C.
abstract: The rs738409 G>C single nucleotide polymorphism occurring in the patatin-like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV-related mortality/graft loss was analyzed by the Cox model adjusting for HCV-Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow-up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV-related mortality/graft loss, the time to which differed by donor (P = 0.019) but not recipient (P = 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25-5.02, P = 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all-cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11-3.53).
  
  
  CONCLUSIONS
  The rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment.
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.
authors.forename: Winston
authors.initials: W
authors.lastname: Dunn
authors.forename: Maura
authors.initials: M
authors.lastname: O'Neil
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Chuang Hong
authors.initials: CH
authors.lastname: Wu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Roberts
authors.forename: Shweta
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Craig
authors.initials: C
authors.lastname: Sherman
authors.forename: Brandy
authors.initials: B
authors.lastname: Weaver
authors.forename: Ryan
authors.initials: R
authors.lastname: Taylor
authors.forename: Jody
authors.initials: J
authors.lastname: Olson
authors.forename: Mojtaba
authors.initials: M
authors.lastname: Olyaee
authors.forename: Richard
authors.initials: R
authors.lastname: Gilroy
authors.forename: Timothy
authors.initials: T
authors.lastname: Schmitt
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
authors.forename: Steven A
authors.initials: SA
authors.lastname: Weinman
mesh_terms: D001706:Biopsy; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006526:Hepatitis C / Q000601:surgery*; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D016031:Liver Transplantation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D014019:Tissue Donors; D014180:Transplantation; D016896:Treatment Outcome; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent