Should PNPLA3 polymorphism be performed in clinical practice in patients with NAFLD to predict the risk of disease progression?

Genomewide association studies (GWAS) have found strong and reproducible associations between NAFLD and the patatinlike phospholipase domaincontaining 3 (PNPLA3) polymorphism (rs738409 C>G) encoding the 148M protein sequence variant worldwide. Recently, a study using a multiethnic biobank demonstrated that the coding variant of the “G” risk allele has a frequency of 23.1% in the general population (n = 125,568), with a higher frequency in Hispanic/Latino populations (47.2%) than in EuropeanAmerican (22.8%) and AfricanAmerican (13.7%)[1] Although the prevalence is lower in European Americans than in Hispanic/Latino populations, a European GWAS study involving 1483 European NAFLD cases and 17,781 genetically matched controls confirmed PNPLA3 as a risk factor for the entire histologic spectrum of NAFLD at GWAS significance levels.[2] Nevertheless, it is still unclear whether the PNPLA3 polymorphism is responsible for the increased risk of disease progression due to increased steatosis, hepatocellular ballooning, lobular and portal inflammation, or whether it has a direct impact on hepatic fibrogenesis pathways. In this issue, VilarGomez et al. use causal mediation analysis, a method that hypothesizes that part or all of the effect of an exposure on an outcome acts through a mediator. They interestingly demonstrated in 1153 liver biopsies from the NASH Clinical Research Network that the presence of the G allele in nearly 50% of patients with NAFLD in this U.S. cohort had a direct impact on the severity of fibrosis, independent of histologic variables, suggesting that PNPLA3 rs738409 may promote fibrosis development through activation of specific fibrogenic signaling pathways.[3] The authors demonstrated that PNPLA3 rs738409 has a direct effect in 47% of nonHispanic Whites and in 62% of other racial/ethnic groups that do not operate through histologic scores. Based on these recent studies, is it not time to introduce PNPLA3 rs738409 mutation into clinical practice in all patients with NAFLD, to predict prognosis and risk of more advanced disease? On the other hand, can PNPLA3 rs738409 be used as a potential therapeutic approach beyond its prognostic value? Lindén et al.[4] have shown in an elegant experimental study that knockdown of PNPLA3 with antisense oligonucleotides in the presence of the PNPLA3 148M mutation has a positive, direct effect on the development of fibrosis, accumulation of liver fat, and inflammation. VillarGomes et al.[3] drew attention to the fact that PNPLA3 may play a role in fibrosis directly and independently of histological scores. On the other hand, they suggested that PNPLA3, in addition to having a direct effect on fibrosis severity, also has an indirect effect on histologic scores that may worsen fibrosis severity. They found that portal inflammation was the most important histologic feature for predicting fibrosis severity in 89% of Whites and 63% of other racial/ethnic groups. These results are very interesting and suggest that the PNPLA3 rs738409 mutation may promote disease progression in two ways: by direct activation of fibrosis pathways or by inflammation. Regarding the latter pathway, in another robust experimental study examining the metabolic, transcriptomic, and molecular signature in a mouse model of NASH on a Western diet, Banini et al.[5] showed that overexpression of human PNPLA3I148M accelerates the development of NASH with fibrosis and exacerbates disease severity. This occurs through metabolic reprogramming with increased triglycerides, diglycerides and ceramides, and the resulting signal transducer and activator of transcription phosphorylation and downstream activation of the inflammatory process, leading to increased fibrogenic activity of stellate cells.[5] Is it time to introduce PNPLA3 rs738409 genotyping to predict genetic phenotype to aid in the followup and treatment of these patients? This could be done in all racial/ethnic groups. In Latin America, PNPLA3 may be an important genetic factor to consider in the development of NAFLD due to the higher proportion of Hispanic ancestry. In Chile, a preliminary study demonstrated the frequency of the G allele in 59% of the general Received: 31 March 2022 | Accepted: 31 March 2022