BA and fibroblast growth factor 19 (FGF19) levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and non-lean NAFLD were investigated in a cohort of Caucasian patients with biopsy-proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models.
A genome-wide exome association study has identified the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 variant encoding an E167K substitution as a genetic determinant of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD).
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.
The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: A meta-analysis.
We first demonstrated in childhood obesity the role of the MBOAT7 rs641738 variant on serum ALT and the combined effect of the MBOAT7, PNPLA3, and TM6SF2 variants on NAFLD risk.
Importantly, our data indicates that the genetic variant TM6SF2E167K, previously associated with increased risk for NAFLD, induces increased hepatocyte fat content by reducing APOB particle secretion.
<i>TM6SF2, GCKR</i><i>,</i> and <i>MBOAT7</i> risk alleles did not show any impact on kidney function, while the <i>PNPLA3</i> G allele was associated with lower eGFR, but only in children with NAFLD (<i>p</i> = 0.003).
An I148 M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3) and an E167K variant in transmembrane 6 superfamily 2 (TM6SF2) are major genetic risk factors for the development and progression of NAFLD.
The rs58542926 SNP in the TM6SF2 gene is associated with pediatric nonalcoholic fatty liver disease but may confer protection against cardiovascular risk.
Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL).
And, our data suggested a strong link between the TM6SF2E167K variant and the risk of NAFLD in a dominant model (CT + TT, OR = 2.327, 95% CI: 1.542-3.513, P = 0.000).
Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms.
However, recent progress on the genotype/phenotype relationships in NAFLD patients indicates the development of NAFLD with a relative conservation of glucose metabolism in individuals with specific gene variants, such as the patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 protein (TM6SF2) variants.
We first review the association of TM6SF2 variant with plasma lipid traits, cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD).
Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2rs58542926 and MBOAT7 rs641738 on overall and cardiovascular disease (CVD) specific mortality among subjects with or without NAFLD.
These results suggested that TM6SF2rs58542926 could be used to identify individuals at higher susceptibility to chronic liver disease, especially for HCC, cirrhosis, ALD, and NAFLD.
The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical factors (p < 0.001), but did not significantly improve their predictive accuracy.