PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non‐obese subjects with hepatitis C

Abstract

SummaryBackgroundThe PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non‐alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC).AimTo test in genotype 1(G1)‐CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis.MethodsFour hundred and thirty‐four consecutively biopsied Caucasian G1‐CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients.ResultsThe prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype (P = 0.02). By multiple logistic regression, PNPLA3 genotype (OR 1.54, 95% CI 1.03–2.30, P = 0.03), together with age (OR 1.03, 95% CI 1.00–1.05, P = 0.02), BMI ≥ 30 (OR 2.06, 95% CI 1.04–4.10, P = 0.03) and homoeostasis model assessment (HOMA, OR 1.18, 95% CI 1.04–1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non‐obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders (OR 2.06, 95% CI 1.26–3.36, P = 0.004). We showed an independent association between steatohepatitis (OR 2.05, 95% CI 1.05–4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA (P = 0.002).ConclusionIn patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non‐obese subjects.

The PNPLA3 Genetic Variant rs738409 Influences the Progression to Cirrhosis in HIV/Hepatitis C Virus Coinfected Patients

“…Although Signelli et al found a relation of this SNP with steatosis in a small population [10], our finding has been replicated by others [8, 9]. This was a relatively surprising result since this genetic variant has been extensively related to non-alcoholic FLD in general population [23–25] and in HCV-monoinfected patients [18, 20, 26, 27]. The relation of this genetic variant to cirrhosis without a clear association with FLD in the HIV/HCV-coinfected population could be pointing out to the existence of other factors that modulate the effect of this variant on the liver [22].…”

PNPLA3polymorphism increases risk for and severity of chronic hepatitis C liver disease

“…The data was heterogeneous ( I 2 = 65.9%, P = 0.081), with evidence of publication bias as assessed by Begg-Mazumdar test ( P = 0.036) and tendency for publication bias as assessed by Egger test ( P = 0.059). Sensitivity analysis after excluding studies with lowest[14] and highest[49] OR revealed similar effect size: 1.82 (95%CI: 1.41-2.34) with I 2 = 18.8%, P = 0.30. Additionally, when Dual and Tweedie trim and fall test was used to assess publication bias, 3 studies were trimmed with no change in effect size (OR = 1.39, 95%CI: 1.01-1.92).…”

“…The 95%CI not crossing 1 indicates a significant association. Valenti 2012 a in panel (A) refers to reference[43], and in panel (B) refers to reference[14]. …”

“…In contrary to the previous meta-analysis on PNPLA3 polymorphisms in alcoholic and non-alcoholic liver diseases that compared different genotypes[5-8], our current analysis used the recessive model when comparing GG genotype vs CC and CG genotypes, and the dominant model when comparing GG and CG genotypes related to the CC genotype. Finally, no pooled data were provided on steatohepatitis in chronic HCV patients as only one study had reported such an association[14], while the studies by Ezzikouri et al[44] and Yasui et al[48] either did not have biopsies performed or reported “necroinflammatory changes”. Lack of standard definition amongst these studies prevented pooling them together.…”

“…Given that the association between PNPLA3 polymorphism and liver disease spectrum in chronic hepatitis C (CHC) patients has not been consistent, especially for HCC[12,13] and cirrhosis[14,15], we performed this meta-analysis to further examine the association of PNPLA3 polymorphisms with the predisposition to the entire spectrum of liver disease among patients with CHC.…”