Effects of PNPLA3, TM6SF2 and SAMM50 on the development and severity of non‐alcoholic fatty liver disease in children

Abstract

Summary Background Although genetic variants of PNPLA3, TM6SF2 and SAMM50 have been reported to increase the risk of non‐alcoholic fatty liver disease (NAFLD), no pediatric studies have evaluated the association between SAMM50 and NAFLD. Objective This study aimed to investigate the risk factors, including genetic variants, of pediatric NAFLD. Methods NAFLD was defined as the presence of hepatic steatosis on ultrasound. We included 228 patients with NAFLD (body mass index‐Z [BMI‐Z] = 2.51 ± 1.01) and 225 controls (BMI‐Z = 0.22 ± 1.48). We genotyped four variants of PNPLA3 (rs738409), TM6SF2 (rs58542926) and SAMM50 (rs2073080 and rs3761472) by TaqMan allelic discrimination. The pediatric NAFLD fibrosis score, aspartate transaminase (AST)/platelet ratio index and fibrosis‐4 score were used to evaluate the degree of fibrosis. We calculated the genetic risk score for additive effects according to the sum of risk alleles. Results The mean age was 12.6 ± 3.5 years. The four genetic variants, male sex and BMI‐Z, independently increased susceptibility to NAFLD. These four variants, in addition to fasting insulin and triglycerides, remained significant risk factors with higher odds ratios in children with overweight. These variants increased the alanine aminotransferase (ALT) level and three fibrosis scores independently. As the genetic risk score increased, AST, ALT and the fibrosis scores increased independently. Conclusion PNPLA3, TM6SF2 and SAMM50 are associated with the development and severity of pediatric NAFLD. The impact of genetic variants is greater in children with overweight. The four genetic variants have synergetic effects on the severity of pediatric NAFLD.

Metabolic dysfunction-associated fatty liver disease in obese youth with insulin resistance and type 2 diabetes

“…A recent Korean study has examined SAMM50 variant which is previously studied only in adult patients. According to this study, SAMM50 did not correlate with normal weight pediatric patients with NAFLD [24]. SAMM50 encodes Sam50, which is important for the proper assembling and functions of mitochondria [35].…”

“…Some genetic variants predispose to the development of NAFLD in childhood [24,25]. NAFLDrelated genes are implicated in a large spectrum of pathogenic mechanisms, such as lipid metabolism, IR, oxidative stress, inflammation and fibrogenesis which are the main processes characterizing the pathogenesis and the progression of the NAFLD [3].…”

An adult‐based genetic risk score for liver fat associates with liver and plasma lipid traits in children and adolescents

“…6,9,12,39,40 However, few studies have comprehensively evaluated the metabolic effects of well-established and novel susceptibility variants in children. [41][42][43] It therefore remains unclear to what extent genetic predisposition for hepatic steatosis contributes to liver and cardiometabolic traits in children.…”

The body mass index increases the genetic risk scores' ability to predict risk of hepatic damage in European adolescents: The HELENA study

“…Thus, the PNPLA3 rs738409 was also part of the ALT‐GRS developed within the studied cohort. Moreover, the susceptibility of PNPLA3 rs738409 to increased hepatic fat content in youth can be observed across different ethnic populations 5,34 …”