Journal
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
Volume 33, Issue 6, Pages 1277-1285Publisher
WILEY
DOI: 10.1111/jgh.14056
Keywords
insulin resistance; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; PNPLA3; TM6SF2
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Funding
- National Research Foundation of Korea grant - Korea government (MEST) [2016R1D1A1B04934590]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute - Ministry of Health & Welfare, Republic of Korea [H I17C0912]
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Background and AimWe investigated the effects of PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7-TMC4 rs641738 variants on metabolic phenotypes and their combined effects on the histological severity of non-alcoholic fatty liver disease (NAFLD). MethodsWe genotyped rs738409, rs58542926, and rs641738 in biopsy-proven NAFLD patients (n=416) and healthy controls (n=109). Homeostasis model assessment of insulin resistance and adipose tissue insulin resistance were calculated. ResultsThe rs738409 and rs58542926 variants, but not rs641738, were associated not only with non-alcoholic steatohepatitis (NASH) (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.46-2.73 and OR, 1.91; 95% CI, 1.04-3.51) but also with significant fibrosis (F2) (OR, 1.53; 95% CI, 1.11-2.11 and OR, 1.88; 95% CI, 1.02-3.46) in NAFLD, even after adjustment for metabolic risk factors. Of both variants, only rs738409 was associated with homeostasis model assessment of insulin resistance and adipose tissue insulin resistance even in healthy controls (P=0.046 and 0.002, respectively) as well as in the entire study cohort (P=0.016 and 0.048, respectively). PNPLA3 and TM6SF2 risk variants additively increased the risk of NASH and significant fibrosis (OR per risk allele, 2.03; 95% CI, 1.50-2.73 and 1.61; 95% CI, 1.19-2.17). Even in subjects with low insulin resistance, the risk of NASH or significant fibrosis increased as the number of risk alleles increased (P=0.008 and 0.020, respectively). ConclusionsPNPLA3 and TM6SF2 determine the risk of NASH and significant fibrosis, even after adjustment for insulin resistance, and exert an additive effect on NASH and significant fibrosis.
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