Associations of TM6SF2 167K allele with liver enzymes and lipid profile in children: the PANIC Study

Abstract

Background: The 167K allele in the TM6SF2 gene has been suggested to protect against cardiovascular disease at the cost of developing nonalcoholic fatty liver disease in adults. Methods: We performed a cross-sectional study in a population sample of 462 Caucasian children aged 6-9 y, genotyped the polymorphism using HumanCoreExome BeadChip, and assessed several cardiometabolic risk factors. results: The 51 (11%) carriers of the 167K allele had higher plasma alanine aminotransferase (ALT) (20.8 vs. 18.4 U/l, P = 0.011) but lower plasma triglycerides (0.54 vs. 0.61 mmol/l, P = 0.024), total cholesterol (4.08 vs. 4.30 mmol/l, P = 0.016), and low-density lipoprotein (LDL) cholesterol (2.22 vs. 2.38 mmol/l, P = 0.012) than the 411 noncarriers. In factor analysis, the first factor was heavily loaded by plasma ALT (factor loading 0.63), triglycerides (−0.82), LDL cholesterol (−0.71), and waist circumference (0.61) in the carriers but not in the noncarriers. conclusions: The carriers of the 167K allele have higher plasma ALT but lower plasma triglycerides and total and LDL cholesterol than the noncarriers already in childhood. n onalcoholic fatty liver disease (NAFLD), recognized as the hepatic manifestation of the metabolic syndrome (1), is the most common liver disease not only in adults (2) but also in children (3). Increased liver fat content is typically associated with the overproduction of triglyceride-rich very-lowdensity lipoprotein particles from the liver due to the reduced insulin-induced suppression of very-low-density lipoprotein production that leads to hypertriglyceridemia and decreased plasma levels of high-density lipoprotein (HDL) cholesterol (1). NAFLD has been related to increased cardiovascular morbidity and mortality that has been suggested to be partly explained by hypertriglyceridemia and decreased plasma HDL cholesterol levels (2).A recent exome-wide association study showed that adults with a cytosine-to-thymine substitution which replaces glutamate with lysine at residue 167 (E167K polymorphism) in the TM6SF2 gene had increased hepatic triglyceride content and increased plasma levels of alanine aminotransferase (ALT) but decreased plasma levels of triglycerides and low-density lipoprotein (LDL) cholesterol (4). The carriers of the 167K allele were found to have a loss of function of the TM6SF2 that reduces the ability of the liver to export triglycerides in verylow-density lipoprotein particles to circulation that explains the increased liver fat content and the decreased plasma levels of triglycerides among the carriers (5). Consistent with these findings, other studies in adults have shown that the carriers of the 167K allele are more susceptible to NAFLD and liver fibrosis (6-9) but have a lower risk of developing cardiovascular disease that is partly explained by lower plasma total cholesterol levels among the carriers (7,10).A recent study in obese children provided further evidence for the finding in adults that the carriers of the 167K allele in the TM6SF2 gene have a higher liver fat ...

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 .…”

Association of MBOAT7 gene variant with plasma ALT levels in children: the PANIC study

“…The I148M variant of the patatin-like phospholipase domain containing 3 (PNPLA3) gene has been associated with increased risk of NAFLD in adults (3) and also with increased liver fat content in children (6,7). The E167K variant of the transmembrane 6 superfamily member 2 (TM6SF2) gene has been related to increased liver fat content but with decreased plasma levels of triglycerides and total and low-density lipoprotein cholesterol in adults (4,8) and in children (9,10).…”

“…There is accumulating evidence that certain gene variants predispose to the development of NAFLD in adults (3)(4)(5) and in children (6,7,9,10) and that genetic risk scores may improve risk prediction for NAFLD beyond single risk variants in adults (13). There are no previous studies on the MBOAT7 variant and its associations with liver fat content and other cardiometabolic risk factors among children.…”