There was a significant difference in the distribution of genotype and allele of TM6SF2rs58542926 in NAFLD and NAFLD&CRA patients compared to controls.
In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%).
We conclude that the E167K variant in TM6SF2 is associated with a distinct subtype of NAFLD, characterized by preserved insulin sensitivity with regard to lipolysis, hepatic glucose production and lack of hypertriglyceridemia despite a clearly increased LFAT content.
Here, we accessed the seven polymorphisms of rs1260326, rs780094 in GCKR, rs2954021 near TRIB1, rs2228603 in NCAN, rs58542926 in TM6SF2, rs12137855 near LYPLAL1, and rs10883437 near CPN1 on NAFLD susceptibility in the Uygur population.
As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials.
Among individual variants, rs1260326 in GCKR and rs641738 in MBOAT7 (recessive), rs58542926 in TM6SF2 and rs738409 in PNPLA3 (dominant) emerged as associated to NAFLD, with PNPLA3 rs738409 being the strongest predictor (OR 3.12, 95% CI, 1.8-5.5, P < 0.001).
This study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals.
Here we show that adiposity significantly amplifies the effect of three sequence variants (encoding PNPLA3 p.I148M, TM6SF2p.E167K, and GCKR p.P446L) associated with nonalcoholic fatty liver disease (NAFLD).
Because PNPLA3 rs738409, GCKR rs780094 and TM6SF2rs58542926 variants are known to confer susceptibility to NAFLD, we assessed the influence of MBOAT7 rs641738 on hepatic steatosis, and serum levels of CK-18 fragment (a biomarker of hepatocellular injury and apoptosis for NAFLD) after adjusting the effects of PNPLA3, GCKR and TM6SF2 polymorphisms.
The TM6SF2E167K variant was genotyped by TaqMan assays, steatosis graded according to the nonalcoholic fatty liver disease activity score, and necroinflammation and fibrosis graded and staged according to Ishak in Italian, and to Metavir in Swiss/German patients.
Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD.
Genetic variation in both patatin-like phospholipase domain-containing protein-3 (PNPLA3) (I148M) and the transmembrane 6 superfamily member 2 protein (TM6SF2) (E167K) influences severity of liver disease, and serum triglyceride concentrations in non-alcoholic fatty liver disease (NAFLD), but whether either genotype influences the responses to treatments is uncertain.
This implies that NAFLD is heterogeneous and that "Obese/Metabolic NAFLD" but not NAFLD due to the PNPLA3 or TM6SF2 genetic variants predisposes to type 2 diabetes and cardiovascular disease.
Nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) share risk factors, and recent meta-analysis confirmed that NAFLD is an independent risk factor for incident CKD.<sup>1</sup> Genetic variants associated with NAFLD, such as patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409<sup>2</sup> and transmembrane 6 superfamily member 2 (TM6SF2) rs5854292,<sup>2</sup> have been reported to be associated with renal function in NAFLD subjects.
Among the 9342 participants with available genetic and aminotransferase data, the PNPLA3 G allele (odds ratio [OR], 1.53; 95% CI, 1.41-1.66), TM6SF2 T allele (OR, 1.41; 95% CI, 1.20-1.67), and PPP1R3B G allele (OR, 1.16; 95% CI, 1.06-1.28) were associated with suspected NAFLD.
Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3 and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease.