MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08–2.55; n = 765), particularly in those without advanced fibrosis (p < 0.001). The risk T allele was linked to 3’-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. 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. When combining data from an independent UK NAFLD cohort, in the overall cohort of non-cirrhotic patients (n = 913, 41 with HCC) the T allele remained associated with HCC (OR 2.10, 1.33–3.31). Finally, in a combined cohort of non-cirrhotic patients with chronic hepatitis C or alcoholic liver disease (n = 1121), the T allele was independently associated with HCC risk (OR 1.93, 1.07–3.58). In conclusion, the MBOAT7 rs641738 T allele is associated with reduced MBOAT7 expression and may predispose to HCC in patients without cirrhosis, suggesting it should be evaluated in future prospective studies aimed at stratifying NAFLD-HCC risk.

PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases

“…We also observed a higher rate of the at‐risk G allele of PNPLA3 rs738409 in patients with HCC develop on nonfibrotic liver. This association was firstly suggested in a case/control study including 25 HCC developed on noncirrhotic liver (F0‐F2) in patients with HCV infection or alcoholic liver disease . Now, we confirmed this association in a larger series of 212 patients with HCC developed on nonfibrotic liver (F0‐F1) and mostly without any etiologies of liver diseases and using two different control populations composed of a total of 2,484 healthy subjects.…”

Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease

“…Despite previous contrasting evidence,8, 9, 10, 11, 12, 13 these novel data lend strong support to the hypothesis that the PPP1R3B variation does protect against hepatic fat accumulation, at least in at‐risk individuals. Furthermore, they support the notion that steatosis is a major driver of liver disease progression to fibrosis7 and HCC18 in individuals with NAFLD.…”

“…Part of the NAFLD‐hepatocellular carcinoma (NAFLD‐HCC) cohort of the exome sequencing for the identification of inherited variants associated with hepatocellular carcinoma in NAFLD (EPIDEMIC‐NAFLD) study has been described 18, 19. Briefly, this is a case‐control study in which we genotyped Italian patients with NAFLD‐HCC and compared the frequency of risk variants with healthy individuals and with controls with advanced fibrosis due to NAFLD.…”

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

“…A subsequent exome-wide A recent candidate gene association study from Italy and the UK investigated the association between variants within MBOAT7 and HCC in a mixed cohort of patients with NAFLD, chronic hepatitis C and alcohol-related liver disease the majority of whom did not have cirrhosis [21].…”

“…For preparation of genotyping, DNA samples were evaluated by gel electrophoresis and adjusted to [20][21][22][23][24][25][26][27][28][29][30] ng/µl DNA content using the Picogreen fluorescent dye (Molecular Probes -Invitrogen, Carlsbad, Ca, USA) on a robotic platform using TECAN liquid handling equipment. One microliter of genomic DNA was amplified with the GenomiPhi (Amersham, Uppsala, Sweden) whole genome amplification kit and fragmented at 99°C for three minutes.…”