Association Between Patatin-Like Phospholipase Domain Containing 3 Gene (PNPLA3) Polymorphisms and Nonalcoholic Fatty Liver Disease: A HuGE Review and Meta-Analysis

Abstract

We conducted a meta-analysis to assess the association between patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism and nonalcoholic fatty liver disease (NAFLD) and its subtypes simple steatosis(SS) and nonalcoholic steatohepatitis (NASH). The study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models, with assessment for heterogeneity and publication bias. Twenty-three case-control studies involving 6071 NAFLD patients and 10366 controls were identified. The combined results showed a significant association between NAFLD risk and the rs738409 polymorphism in all genetic models (additive model: OR = 3.41, 95% CI = 2.57–4.52; P < 0.00001). In addition, evidence indicated that the rs738409 polymorphism was significantly associated with NASH in all genetic models (additive model: OR = 4.44, 95% CI = 3.39–5.82; P < 0.00001). The subgroup and sensitivity analyses showed that these changes were not influenced by the ethnicities and ages of subjects or by the source of controls. The rs738409 polymorphism was only significantly associated with risk of simple steatosis in the allele contrast and had no effect in the other genetic models. These findings suggest that the rs738409 polymorphism in PNPLA3 gene confers high cross-ethnicity risk for NAFLD and NASH development.

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

“…This is in accordance with the results of many trials which showed an association between the rs738409 polymorphism and the risk of NAFLD [32]- [34]. The exact mechanisms by which the I148M polymorphism increases the susceptibility to NAFLD and its influence on the histological severity of NAFLD still remains to be fully elucidated [35]. The homozygous GG genotype was most frequent among the patients with NASH (26%) when compared to subjects with borderline NASH (20.5%) and those with simple steatosis (20%).…”

“…This was concordant to the results of the meta-analysis by Sookoian and Pirola which showed that the rs738409 exerts a strong influence on the susceptibility to a more aggressive disease with greater hepatic injury, as the GG homozygous subjects had a 3.24-fold more risk of higher necro-inflammatory scores when compared with those who had the CC genotype [8]. Also a meta-analysis by Xu et al reported that the rs738409 polymorphism was more likely to increase the risk of NASH instead of simple steatosis [35]. 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.…”

PNPLA3 gene in liver diseases

“…Other authors reported similar results and further highlighted the fact that rs738409 [G] was not merely associated with steatosis but also with severe liver damage throughout the NAFLD spectrum [12][13][14]. These findings have been summarized in several meta-analyses [15][16][17][18][19] (Table 1). Since the physiopathology of NAFLD is tightly related to the metabolic syndrome, a link between rs738409[G] and the parameters that define the metabolic syndrome was a likely hypothesis.…”

Is nonalcoholic fatty liver disease an endogenous alcoholic fatty liver disease? – A mechanistic hypothesis

“…The disease has two very distinct clinical presentations: the primary form or diet-induced NAFLD and secondary forms, which occur in patients with various apparently unrelated diseases [2]. It is known that NAFLD and alcoholic fatty liver disease (AFLD) share similar histopathological and molecular biological features, as well as identical polymorphism in the patatin-like phospholipase domain-containing 3 gene (PNPLA3) [3][4][5]. Besides, the finding that patients with nonalcoholic steatohepatitis (NASH) produce more endogenous ethanol (EE) than control subjects further strengthens this connection [6][7][8][9].…”