Global epidemiology and implications of PNPLA3 I148M variant in MASLD: a systematic review and meta-analysis

Background and Aims: PNPLA3 rs738409 variant is a risk factor for onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess its global prevalence, clinical and histological characteristics, and long-term outcomes in patients with MASLD. Methods PubMed and Embase were searched until December 2023 for observational studies on PNPLA3 genotyped adults with MASLD. Proportions were pooled using a generalised linear mixed model with Clopper-Pearson intervals. Continuous and dichotomous variables were analysed using the DerSimonian-Laird method. Subgroup, meta-regression and sensitivity analyses were also performed. PROSPERO registration number: CRD42023449838. Results We identified 109 studies (118,302 MASLD individuals) with an overall minor allele frequency of the G allele at PNPLA3 [MAF(G)] of 0.45 (95%CI 0.43; 0.48, I²=98%), adjusted to 0.39 (95%CI 0.36; 0.43, I²=98%) due to publication bias. The highest MAF(G) was found in Latin America and the lowest in Europe. No African countries were identified. Carriers of the PNPLA3 variant had reduced adiposity, altered fat metabolism and worse liver damage/histology than non-carriers. Additionally, only the PNPLA3 GG genotype was associated with mortality and liver-related events. Meta-regressions showed the influence of adiposity, age, diabetes mellitus and glucose on PNPLA3 expression. Conclusions This study reveals the global pattern of PNPLA3 and its clinical, histological and outcomes implications in MASLD. Our findings underscore the importance of PNPLA3 genotyping in clinical trials and advocate for personalized medicine approaches. Further research is needed on the genetic epidemiology of underrepresented populations, challenges of incorporating genotyping into clinical practice and gene-environment interactions.