Supplementary Material for: 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

<b><i>Background:</i></b> The adiponutrin <i>(PNPLA3)</i> p.I148M and transmembrane 6 superfamily member 2 <i>(TM6SF2)</i> 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 <i>PNPLA3</i> and <i>TM6SF2</i> genotypes. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> Both <i>PNPLA3</i> (p = 0.002) and <i>TM6SF2</i> (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 <i>PNPLA3</i> or <i>TM6SF2</i> risk genotype. The improvement of phenotypic traits, apart from WHR (p = 0.02), was not modified by the presence of <i>PNPLA3</i> or <i>TM6SF2</i> variants. <b><i>Conclusions:</i></b> The <i>PNPLA3</i> and <i>TM6SF2</i> polymorphisms are associated with NAFLD assessed by the Hamaguchi score. Neither <i>PNPLA3</i> nor <i>TM6SF2</i> risk alleles impair the response to dietetic intervention in NAFLD.

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