Global Epidemiological Impact of PNPLA3 I148M on Liver Disease

Abstract

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased exponentially over the past three decades, in parallel with the global rise in obesity and type 2 diabetes. It is currently the most common cause of liver-related morbidity and mortality. Although obesity has been identified as a key factor in the increased prevalence of MASLD, individual differences in susceptibility are significantly influenced by genetic factors. PNPLA3 I148M (rs738409 C>G) is the variant with the greatest impact on the risk of developing progressive MASLD and likely other forms of steatotic liver disease. This variant is prevalent across the globe, with the risk allele (G) frequency exhibiting considerable variation. Here, we review the contribution of PNPLA3 I148M to global burden and regional differences in MASLD prevalence, focusing on recent evidence emerging from population-based sequencing studies and prevalence assessments. We calculated the population attributable fraction (PAF) as a means of quantifying the impact of the variant on MASLD. Furthermore, we employ quantitative trait locus (QTL) analysis to ascertain the associations between rs738409 and a range of phenotypic traits. This analysis suggests that these QTLs may underpin pleiotropic effects on extrahepatic traits. Finally, we outline potential avenues for further research and identify key areas for investigation in future studies.

Keywords: PNPLA3; HSD17B13; MASH; MASLD; genetics; rs6006460; rs738409.

FIGURE 1

Worldwide allele frequency distribution of PNPLA3 rs738409 I148M. Allele frequencies are based on data from the 1000 Genomes Project and gnomAD database, downloaded from NCBI dbSNP: https://www.ncbi.nlm.nih.gov/snp/rs738409/. Estimates of SLD prevalence derived from recent meta‐analyses and population‐based studies [1, 22, 23, 24, 25, 26, 27, 28].

FIGURE 2

cis‐eQTLs associated with variant: rs738409 (22:43928847_C/G) and various phenotypic traits. This analysis employed a range of resources, including FIVEx [54], and the QTLbase.