A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease

Abstract

The adiponutrin (PNPLA3) rs738409 polymorphism has been found to be associated with susceptibility to non-alcoholic fatty liver disease (NAFLD) in various cohorts. We further investigated the association of this polymorphism with non-alcoholic steatohepatitis (NASH) severity and with histological features of NAFLD. A total of 144 biopsy-proven NAFLD patients and 198 controls were genotyped for PNPLA3 gene polymorphism (rs738409 C>G). The biopsy specimens were histologically graded by a qualified pathologist. We observed an association of G allele with susceptibility to NAFLD in the pooled subjects (OR 2.34, 95% CI 1.69–3.24, p < 0.0001), and following stratification, in each of the three ethnic subgroups, namely Chinese, Indian and Malay (OR 1.94, 95% CI 1.12–3.37, p = 0.018; OR 3.51, 95% CI 1.69–7.26, p = 0.001 and OR 2.05, 95% CI 1.25–3.35, p = 0.005, respectively). The G allele is associated with susceptibility to NASH (OR 2.64, 95% CI 1.85–3.75, p < 0.0001), with NASH severity (OR 1.85, 95% CI 1.05–3.26, p = 0.035) and with presence of fibrosis (OR 1.95, 95% CI 1.17–3.26, p = 0.013) but not with simple steatosis nor with other histological parameters. Although the serum triglyceride level is significantly higher in NAFLD patients compared to controls, the G allele is associated with decreased level of triglycerides (p = 0.029) in the NAFLD patients. Overall, the rs738409 G allele is associated with severity of NASH and occurence of fibrosis in patients with NAFLD.

PNPLA3 and TNF-&lt;i&gt;α&lt;/i&gt; G238A Genetic Polymorphisms in Egyptian Patients with Different Grades of Severity of NAFLD

“…Zain and Mohamed, demonstrated a significant association between the GG genotype and the fibrosis stage (p = 0.038); patients with GG genotype had a greater mean score of 2.03 compared to those with the CC genotype who had a mean score of 1.52. This association between the risk allele G of the rs738409 and the fibrosis stage, however, could not be assessed in the present study because only 3 patients with NASH had fibrosis [36].…”

“…This finding does not agree with the findings of Speliotes et al and Hotta et al who reported that the G allele of the rs738409 was significantly associated with decreased triglycerides levels in NAFLD patients but not in the control subjects and that this may be explained by decreased production of triglycerides due to the severity of NASH fibrosis [37] [41]. Moreover, in a study by Zain and Mohammed, the triglycerides levels and the G allele frequency were found to be higher in NASH patients without significant fibrosis compared to NASH patients with significant fibrosis [36]. The variation in our study can thus be explained by the fact that only 3 out of 46 patients with NASH had significant fibrosis and therefore strongly supports the suggestion by Jou et al that the triglycerides level drops with the extent of hepatocellular injury [42].…”

CYP3A Activity and Expression in Nonalcoholic Fatty Liver Disease

“…1C). PNPLA3 genotypes are associated with histologic severity of NAFLD (Sookoian and Pirola, 2011) and susceptibility to NASH (Zain et al, 2012). In the NAFLD cohort, carriers of the risk PNPLA3 (rs738409) G allele tended to have lower 4b-OHC concentrations, although the association was not statistically significant (Supplemental Fig.…”

Composite prognostic models across the non-alcoholic fatty liver disease spectrum: Clinical application in developing countries

“…The rs738409 variant similarly confers risk for increased histological severity dissociated from its effects on central obesity and IR [157,158] . Its pathogenic role in impaired lipid homeostasis as evidenced by a peripheral decrease in serum triglyceride, total and high-density lipoprotein cholesterol [159,160] is furthermore unmasked in the presence of increased visceral adiposity [161] and impaired glucose tolerance [162] , in addition to being modulated by lifestyle and dietary habits [161,163] . It has further been proposed that lipotoxicity and inflammatory stress resulting from impaired intra-hepatic lipid metabolism and free cholesterol deposition associated with PNPLA3 rs738409 activates dormant hepatic stellate cells (HSCs), leading to increased fibrogenesis.…”