Fish intake interacts with TM6SF2 gene variant to affect NAFLD risk: results of a case–control study
Non-alcoholic fatty liver disease (NAFLD) is a complex disease, resulting from a variety of genetic and environmental factors. The aim of this case–control study was to evaluate the effect of selected genetic polymorphisms, nutrition aspects and their interaction on the risk of NAFLD.
The sample consisted of 134 patients with NAFLD and 217 controls. Disease was diagnosed by liver ultrasound and volunteers were clinically and nutritionally assessed. Food groups were extracted from a 172 food-item FFQ questionnaire. Three genetic polymorphisms were assessed: PNPLA3 rs738409, TM6SF2 rs58542926 and GCKR rs780094.
We replicated the effect of previously reported risk factors for NAFLD, such as elevated liver enzymes, obesity and metabolic syndrome. Food groups rich in simple sugars, fat and especially saturated fat were positively associated with NAFLD risk, whereas food groups rich in polyunsaturated fatty acids were reversely associated with the possibility of developing the disease (p < 0.05). Only the PNPLA3 genetic variant was statistically significantly associated with the disease (padditive = 0.015). However, it was found that a one-portion increase in fish intake increased the risk of NAFLD in carriers of the risk allele of TM6SF2 rs58542926 polymorphism compared to non-carriers, after adjusting for age, gender, energy intake, pack-years, PAL, TM6SF2 genotype and fish consumption (ORdominant = 1.503, 95% CI 1.094–2.064).
Fish intake exerts an additive effect on NAFLD risk for carriers of the TM6SF2 polymorphism. This novel finding provides further rationale on the need for personalized nutritional advice, based on the genetic background of NAFLD patients.
KeywordsNAFLD Gene–diet interactions Fatty liver Genes Nutrition
Athens physical activity questionnaire
Body mass index
Diastolic blood pressure
Gastroesophageal reflux disease
Genetic risk score
Homeostatic model assessment
Impaired fasting glucose
Monounsaturated fatty acids
Non-alcoholic fatty liver disease
NAFLD fibrosis score
Polyunsaturated fatty acids
Systolic blood pressure
Single nucleotide polymorphisms
Type 2 diabetes mellitus
White blood cells
This study was funded by the project “Obesity and metabolic syndrome: dietary intervention with Greek raisins in NAFLD/NASH. Investigation of molecular mechanisms” reviewed and approved by the Greek Secretariat for Research and Technology (Cooperation 890/2009).
Compliance with ethical standards
Conflict of interest
No potential conflicts of interest relevant to this article were reported.
- 7.Tan HL, Zain SM, Mohamed R, Rampal S, Chin KF, Basu RC, Cheah PL, Mahadeva S, Mohamed Z (2014) Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene. J Gastroenterol 49:1056–1064CrossRefGoogle Scholar
- 11.Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502Google Scholar
- 13.Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr et al (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645CrossRefGoogle Scholar
- 24.Wang X, Liu Z, Wang K, Wang Z, Sun X, Zhong L, Deng G, Song G, Sun B, Peng Z et al (2016) Additive effects of the risk alleles of PNPLA3 and TM6SF2 on non-alcoholic fatty liver disease (NAFLD) in a Chinese population. Front Genet 7:140Google Scholar
- 25.Krawczyk M, Rau M, Schattenberg JM, Bantel H, Pathil A, Demir M, Kluwe J, Boettler T, Lammert F, Geier A; NAFLD Clinical Study Group (2017) Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study. J Lipid Res 58:247–255CrossRefGoogle Scholar