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PNPLA3 gene predicts clinical recovery after sustained virological response in decompensated hepatitis C cirrhosis
  1. Winston Dunn1,
  2. Anusha Vittal1,2,
  3. Jie Zhao1,
  4. Jianghua He3,
  5. Shweta Chakraborty4,
  6. Melissa Whitener1,
  7. Sara Fohn4,
  8. Ryan Ash5,
  9. Ryan M Taylor1,
  10. Mojtaba Olyaee1,
  11. Jody C Olson1,
  12. Nancy Todd4,
  13. Beth N Floyd1,
  14. Prashant Pandya1,6,
  15. Melissa Laycock4,
  16. Timothy Schmitt7,
  17. Steven A Weinman1
  1. 1 Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Missouri, USA
  2. 2 NIH/NIDDK, Bethesda, MD, United States
  3. 3 Department of Biostatistics, University of Kansas Medical Center, Kansas City, Missouri, USA
  4. 4 Liver Transplant Center, University of Kansas Medical Center, Kansas City, Missouri, USA
  5. 5 Department of Diagnostic Radiology, University of Kansas Medical Center, Kansas City, Missouri, USA
  6. 6 Department of Internal Medicine, Kansas City VA Medical Center, Kansas City, Missouri, USA
  7. 7 Department of Surgery, University of Kansas Medical Center, Kansas City, Missouri, USA
  1. Correspondence to Dr Winston Dunn; winstondunnmd{at}gmail.com

Abstract

Background Patients with decompensated hepatitis C virus (HCV) cirrhosis experience various outcomes after sustained virological response (SVR), ranging from clinical recovery to further deterioration. We hypothesised that the genetic risk for steatosis, namely the polymorphisms rs738409 of Patatin-like Phospholipase Domain-Containing 3 (PNPLA3), rs58542926 of Transmembrane-6-Superfamily-2 (TM6SF2), and rs641738 of Membrane-bound O-acyltransferase Domain-Containing 7 (MBOAT7), is predictive of recovery.

Methods We prospectively enrolled 56 patients with Child-Pugh (CPT) B/C cirrhosis who underwent antiviral therapy. The primary outcome was change in CPT score at 12, 24, and 48 weeks after SVR. We used a linear mixed-effects model for analysis.

Results Forty-five patients (PNPLA3: 21 CC, 19 CG, 5 GG) survived to the first endpoint without liver transplantation. The mean change in CPT score at 12, 24, and 48 weeks was −1.57 (SE=0.30), –1.76 (SE=0.32), and −2.0 (SE=0.36), respectively, among the patients with the PNPLA3 CC genotype and −0.50 (SE=0.20), –0.41 (SE=0.25), and −0.24 (SE=0.27), respectively, among the other 24 patients. After adjustment for baseline characteristics, the PNPLA3 CG/GG genotypes were associated with a 1.29 (SE=0.30, p<0.0001) point higher CPT score. Most of the difference came from differences in hepatic encephalopathy and bilirubin. The results for rs58542926 and rs641738 were not significant.

Conclusion The PNPLA3 CG/GG genotypes could identify a subgroup of patients with decompensated HCV cirrhosis that had suboptimal clinical recovery despite SVR. An understanding of the genetic factors that influence clinical outcomes will help target patients for liver transplant based on individual genetic risk factors and provide insight leading to new therapeutic approaches.

  • decompensated cirrhosis
  • hepatitis C
  • PNPLA3
  • recovery

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Footnotes

  • Contributors Study concept and design, critical revision of the manuscript, obtained funding: WD, SAW. Analysis and interpretation of data: WD, Brooke Fridley, JH. Drafting of the manuscript: WD. Facilitation of access to patients: RMT, JCO, MSO, NT, BNF, PKP, ML, TMS. Acquisition of data: AV, Brian Bridges, JZ, Cindy Garcia, MW, RA, CG, SF, Hillary Smith.

  • Funding This study was supported in part by an NIH Clinical and Translational Science Award grant (UL1 TR000001, formerly UL1RR033179), awarded to the University of Kansas Medical Center and NIH_NOA_1K23DK109294-01A1 awarded to WD. The study is also supported by the University of Kansas Medical Center Liver Center.

  • Competing interests WD reports speaking and consultation fees from Gilead and Merck. RT reports speaking fees from Bristol-Myers Squibb, Gilead, Intercept, Merck and Salix/Valeant, and consultation fees from Bayer and Gilead. PKP reports speaking fees from AbbVie and Gilead.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the KUMC Human Research Protection Program (STUDY00002047).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

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