The Proportion of PNPLA3 rs738409 GG Homozygous in Different Populations and Its Impact on Fibrosis Progression in Biopsy-Proven NAFLD Patients: Meta-Analysis and Systematic Review

Abstract

Context: Some studies have reported that the phospholipase domain-containing protein 3 (PNPLA3) rs738409 GG homozygous genotype is associated with increased risk of liver disease severity in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). Given the increasing global prevalence of NAFLD and the lack of definitive treatment for non-alcoholic steatohepatitis (NASH) or a first-line therapy for NAFLD, many researchers are seeking a cure for NASH in individuals with NAFLD who have the rs738409 GG homozygous genotype. Objectives: We conducted a systematic review and meta-analysis to assess the proportion of PNPLA3 rs738409 GG homozygous individuals in different populations and its impact on fibrosis progression in biopsy-proven NAFLD patients, to support data basis for Precision Gene Therapy of NAFLD. Methods: PubMed, Cochrane Library, and Embase Database were searched for case-control studies from inception to July 3, 2024. The following keywords were used: Fatty liver, PNPLA3, and rs738409 gene or variants or polymorphism or alleles. A meta-analysis and systematic review were conducted utilizing the articles retrieved. Results: A total of 13 eligible studies and 3823 people were included in this study. The pooled PNPLA3 rs738409 GG homozygous proportion of NAFLD was estimated to be 30% (95% CI: 0.22 - 0.37) in adults, 24% (95% CI: 0.15 - 0.33) in adolescents, 33% (95% CI: 0.26 - 0.39) in the Asian population, 39% (95% CI: 0.32 - 0.47) in Japanese, and 25% (95% CI: 0.22 - 0.28) in Chinese. Advanced fibrosis (≥ 2) was estimated to be 11% (95% CI: 0.07 - 0.16) in adults, 11% (95% CI: 0.06 - 0.16) in the Asian population, and 15% (95% CI: 0.07 - 0.23) in Japanese. Two articles from the Chinese population showed that advanced fibrosis (≥ 2) was estimated to be 5.9% and 4.8%. Our results showed that the incidence of GG homozygous in patients with advanced fibrosis (≥ 2) had a 1.27-fold and 1.24-fold greater proportion compared with low-level fibrosis (< 2) in adult and Asian populations, respectively. Conclusions: The rs738409 GG homozygous proportion in biopsy-proven NAFLD varies due to geographic and population heterogeneity. Our results showed that rs738409 GG homozygous exerts a strong influence on developing fibrosis.