Integrating PNPLA3 into clinical risk prediction

Abstract

The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.

Keywords: APRI; FIB‐4; VCTE; genetics; non‐invasive test; precision medicine.

FIGURE 1

The role of the PNPLA3 risk variant in clinical risk prediction. Schematic of the role of PNPLA3 genotype in risk prediction. The top left shows PNPLA3 as well as other key liver steatosis/fibrosis‐associated variants (TM6SF2, MBOAT7, GCKR, HSD17B13). The bottom left illustrates reported potential uses of the PNPLA3 genotype in diagnosis, including in combination with routine clinical predictors. The right side illustrates reported potential uses of the PNPLA3 genotype in characterizing the disease trajectory of liver disease, especially metabolic dysfunction‐associated steatotic liver disease, from early‐stage (no/minimal fibrosis) to significant fibrosis to cirrhosis then hepatic decompensation and hepatocellular carcinoma (HCC). For the transition from significant fibrosis to cirrhosis, PNPLA3 genotype utility has especially been reported when considered in conjunction with clinical risk factors such as cardiometabolic comorbidities (insulin resistance, diabetes, and/or obesity) and/or Fibrosis‐4 score. Additional, PNPLA3 has been reported to have utility in predicting decompensation and hepatocellular carcinoma in patients with established cirrhosis, including in conjunction with HCC risk scores.