Reduction of Caloric Intake Might Override the Prosteatotic Effects of the <b><i>PNPLA3</i></b> p.I148M and <b><i>TM6SF2</i></b> p.E167K Variants in Patients with Fatty Liver: Ultrasound-Based Prospective Study

Abstract

Background: The adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent risk factors for non-alcoholic fatty liver disease (NAFLD). In this study, we assessed the effects of caloric restriction on liver phenotypes in NAFLD patients in relation to the PNPLA3 and TM6SF2 genotypes. Methods: We genotyped both variants in 143 individuals with NAFLD (55 females, age 18-74 years) and 180 controls (85 females, age 33-66 years). Liver steatosis was assessed using the ultrasound-based Hamaguchi score. A 4-month dietetic intervention, consisting of restriction of daily caloric intake without changes in physical activity, was performed. Results: Both PNPLA3 (p = 0.002) and TM6SF2 (p = 0.041) variants were associated with NAFLD before intervention. Overall, 88 patients completed the intervention, which led to a significant decrease of steatosis, ALT activities, body mass index, hip and waist circumferences, and waist-hip ratio (all p < 0.0001). Hepatic steatosis and anthropometric traits improved significantly (p < 0.05) in carriers of either PNPLA3 or TM6SF2 risk genotype. The improvement of phenotypic traits, apart from WHR (p = 0.02), was not modified by the presence of PNPLA3 or TM6SF2 variants. Conclusions: The PNPLA3 and TM6SF2 polymorphisms are associated with NAFLD assessed by the Hamaguchi score. Neither PNPLA3 nor TM6SF2 risk alleles impair the response to dietetic intervention in NAFLD.

Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes

“…1 . Characteristics of studies included in the meta-analysis of liver enzymes in NAFLD 12 16 19 20 21 22 23 24 25 26 27 ( n = 11) are shown in Table 1 , while those included in the meta-analysis of patients with viral hepatitis 15 16 17 18 ( n = 4) are summarized in Table 2 .…”

“…Eleven studies included in the meta-analysis were hospital-based 15 16 17 18 19 20 21 22 23 24 27 , while the other three were population-based 12 25 26 studies; three studies included pediatric population 20 21 25 .…”

“…Genotyping for rs58542926 was carried out using a Taqman assay 15 17 18 19 21 22 23 24 26 27 , Sequenom MassARRAY system and iPLEX Gold chemistry 16 , automated sequencing 20 , Exome BeadChip 25 , and specific Illumina arrays (Illumina, CA, USA) 12 .…”

Nutrition and Genetics in NAFLD: The Perfect Binomium

“…However, Krawczyk et al reported that TM6SF2 variant as well as PNPLA3 variation did not impair the response to low-calorie four-month dietetic intervention in 143 NAFLD patients [71]. Indeed, the dietary interventions improved phenotypic traits, steatosis and ALT concentrations independently of the presence of these two variants [71]. Finally, Dongiovanni et al revealed that the rs58542926 TM6SF2 variant did not impact on the beneficial effect of statins administration in NAFLD patients [72], opening the possibility to treat T allele carriers with statins to ameliorate liver damage, even if the lipid profile of these patients does not encourage this therapeutic strategy [67].…”

“…However, Krawczyk et al reported that TM6SF2 variant as well as PNPLA3 variation did not impair the response to low-calorie four-month dietetic intervention in 143 NAFLD patients [71]. Indeed, the dietary interventions improved phenotypic traits, steatosis and ALT concentrations independently of the presence of these two variants [71].…”