Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial

J Hepatol. 2015 Dec;63(6):1476-83. doi: 10.1016/j.jhep.2015.07.036. Epub 2015 Aug 10.


Background & aims: Genetic variation in both patatin-like phospholipase domain-containing protein-3 (PNPLA3) (I148M) and the transmembrane 6 superfamily member 2 protein (TM6SF2) (E167K) influences severity of liver disease, and serum triglyceride concentrations in non-alcoholic fatty liver disease (NAFLD), but whether either genotype influences the responses to treatments is uncertain.

Methods: One hundred three patients with NAFLD were randomised to omega-3 fatty acids (DHA+EPA) or placebo for 15-18months in a double blind placebo controlled trial. Erythrocyte enrichment with DHA and EPA was measured by gas chromatography. PNPLA3 and TM6SF2 genotypes were measured by PCR technologies. Multivariable linear regression and analysis of covariance were undertaken to test the effect of genotypes on omega-3 fatty acid enrichment, end of study liver fat percentage and serum triglyceride concentrations. All models were adjusted for baseline measurements of each respective outcome.

Results: Fifty-five men and 40 women (Genotypes PNPLA3 I148M, 148I/I=41, 148I/M=43, 148M/M=11; TM6SF2 E167K 167E/E=78, 167E/K+167K/K=17 participants) (mean ± SD age, 51 ± 11 years) completed the trial. Adjusting for baseline measurement, measured covariates and confounders, PNPLA3 148M/M variant was independently associated with percentage of DHA enrichment (B coefficient -1.02 (95% CI -1.97, -0.07), p=0.036) but not percentage of EPA enrichment (B coefficient -0.31 (95% CI -1.38, 0.75), p=0.56). This genotype was also independently associated with end of study liver fat percentage (B coefficient 9.5 (95% CI 2.53, 16.39), p=0.008), but not end of study triglyceride concentration (B coefficient -0.11 (95% CI -0.64, 0.42), p=0.68).

Conclusions: PNPLA3 148M/M variant influences the changes in liver fat and DHA tissue enrichment during the trial but not the change in serum triglyceride concentration.

Trial registration: NCT00760513.

Keywords: Docosahexaenoic acid; Eicosapentaenoic acid; Liver fat; NAFLD; Omega-3 fatty acid; PNPLA3; Triglyceride; WELCOME, Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD with OMacor thErapy.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Dietary Supplements
  • Docosahexaenoic Acids / therapeutic use*
  • Double-Blind Method
  • Drug Combinations
  • Eicosapentaenoic Acid / therapeutic use*
  • Female
  • Genetic Variation
  • Genotype
  • Humans
  • Lipase / genetics*
  • Lipid Metabolism / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / diet therapy*
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Polymorphism, Single Nucleotide
  • Triglycerides / blood


  • Drug Combinations
  • Membrane Proteins
  • TM6SF2 protein, human
  • Triglycerides
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • Omacor
  • Lipase
  • adiponutrin, human

Associated data