Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C

Winston Dunn, Maura O'Neil, Jie Zhao, Chuang Hong Wu, Benjamin Roberts, Shweta Chakraborty, Craig Sherman, Brandy Weaver, Ryan Taylor, Jody Olson, Mojtaba Olyaee, Richard Gilroy, Timothy Schmitt, Yu-Jui Yvonne Wan, Steven A. Weinman

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalHepatology
Volume59
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

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Hepatitis C
Liver Transplantation
Fibrosis
Genotype
Tissue Donors
Transplants
Mortality
Confidence Intervals
Donor Selection
Warm Ischemia
Phospholipases
Liver
Viral Load
Genetic Markers
Proportional Hazards Models
Adipocytes
Antiviral Agents
Single Nucleotide Polymorphism
Liver Diseases
Cohort Studies

ASJC Scopus subject areas

  • Hepatology

Cite this

Dunn, W., O'Neil, M., Zhao, J., Wu, C. H., Roberts, B., Chakraborty, S., ... Weinman, S. A. (2014). Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C. Hepatology, 59(2), 453-460. https://doi.org/10.1002/hep.26758

Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C. / Dunn, Winston; O'Neil, Maura; Zhao, Jie; Wu, Chuang Hong; Roberts, Benjamin; Chakraborty, Shweta; Sherman, Craig; Weaver, Brandy; Taylor, Ryan; Olson, Jody; Olyaee, Mojtaba; Gilroy, Richard; Schmitt, Timothy; Wan, Yu-Jui Yvonne; Weinman, Steven A.

In: Hepatology, Vol. 59, No. 2, 02.2014, p. 453-460.

Research output: Contribution to journalArticle

Dunn, W, O'Neil, M, Zhao, J, Wu, CH, Roberts, B, Chakraborty, S, Sherman, C, Weaver, B, Taylor, R, Olson, J, Olyaee, M, Gilroy, R, Schmitt, T, Wan, Y-JY & Weinman, SA 2014, 'Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C', Hepatology, vol. 59, no. 2, pp. 453-460. https://doi.org/10.1002/hep.26758
Dunn, Winston ; O'Neil, Maura ; Zhao, Jie ; Wu, Chuang Hong ; Roberts, Benjamin ; Chakraborty, Shweta ; Sherman, Craig ; Weaver, Brandy ; Taylor, Ryan ; Olson, Jody ; Olyaee, Mojtaba ; Gilroy, Richard ; Schmitt, Timothy ; Wan, Yu-Jui Yvonne ; Weinman, Steven A. / Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C. In: Hepatology. 2014 ; Vol. 59, No. 2. pp. 453-460.
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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.",
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AU - Dunn, Winston

AU - O'Neil, Maura

AU - Zhao, Jie

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AU - Roberts, Benjamin

AU - Chakraborty, Shweta

AU - Sherman, Craig

AU - Weaver, Brandy

AU - Taylor, Ryan

AU - Olson, Jody

AU - Olyaee, Mojtaba

AU - Gilroy, Richard

AU - Schmitt, Timothy

AU - Wan, Yu-Jui Yvonne

AU - Weinman, Steven A.

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AB - 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.

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