Impact of patatin‐like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension

Abstract

SummaryBackgroundThe rs738409 C>G p.I148M variant in the patatin‐like phospholipase domain containing 3 (PNPLA3)‐gene promotes triglyceride accumulation in hepatocytes and hepatic stellate cell activation and has previously been linked to hepatic steatosis/liver fibrosis.AimTo investigate its impact on hepatic decompensation and (liver‐related) mortality in patients who had already developed portal hypertension. Moreover, we assessed its link with hepatic steatosis as evaluated by controlled attenuation parameter.MethodsWe performed a retrospective analysis in prospectively characterised patients with viral hepatitis/fatty liver disease‐induced portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) diagnosed at the Medical University of Vienna who underwent HVPG measurement (until 2013; n = 372; longitudinal study) or simultaneous HVPG and controlled attenuation parameter measurement (2014‐2017; n = 153; cross‐sectional study).ResultsWhile survival was similar between PNPLA3‐C/C and ‐C/G patients, we observed substantially increased mortality in PNPLA3‐G/G patients. PNPLA3‐G/G had no impact on mortality in the subgroup of patients with viral hepatitis; however, we observed a strong independent association between PNPLA3‐G/G and hepatic decompensation (adjusted subdistribution hazard ratio [aSHR]: 2.1, 95% confidence interval [95% CI]: 1.1‐4; P = 0.024) as well as mortality (overall: aSHR: 2.2, 95% CI: 1.22‐3.98; P = 0.009; liver‐related: aSHR: 2.2, 95% CI: 1.08‐4.46; P = 0.029) in patients with fatty liver disease. Interestingly, even in the subgroup of patients who had already progressed to clinically significant portal hypertension (HVPG ≥ 10 mm Hg), PNPLA3‐G/G substantially increased mortality (aSHR: 2.33, 95% CI: 1.27‐4.29; P = 0.006). PNPLA3‐genotype had no influence on controlled attenuation parameter or the prevalence of values ≥248 dB/m.Conclusion PNPLA3‐G/G‐genotype seems to double the risks of hepatic decompensation and (liver‐related) mortality in patients with portal hypertension due to fatty liver disease. Further studies are warranted to investigate potential underlying pathophysiological mechanisms unrelated to hepatic steatosis.

Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

“…This is consistent with published reports that 148M was not associated with metabolic changes in a study of over 100 metabolic measures . In another study of patients at high risk for cardiovascular events, 148M was inversely associated with total and low‐density lipoprotein cholesterol …”

“…(35) In another study of patients at high risk for cardiovascular events, 148M was inversely associated with total and low-density lipoprotein cholesterol. (36) Multiple studies found relationships of PNPLA3 I148M with NAFLD, but reported associations with mortality from liver disease or all causes are limited. In the Study of Health in Pomerania in North-Eastern Germany, 148M was associated with a 4-fold increase in the liver disease mortality hazard for men only, most likely attributable to small sample size, shorter followup time, and fewer events in women.…”

Editorial: surviving your genes—the role of PNPLA3 variation in end‐stage liver disease

“…In a recent issue of AP&T , Mandorfer and colleagues retrospectively evaluated the impact of the missense PNPLA3 ‐rs738409 C>G variant on liver‐related mortality in a cohort of patients with different underlying diseases and portal hypertension at the time of diagnosis . The authors observed that homozygous status of the risk G‐allele (rs738409‐GG) substantially increased mortality rates among patients with NAFLD/ALD two‐fold without influencing survival rates in patients with viral hepatitis.…”

Editorial: surviving your genes—the role of PNPLA3 variation in end‐stage liver disease. Authors’ reply

“…We thank Drs. Pirola and Sookoian for reviewing the role of the rs738409 C>G p.I148M variant in the patatin‐like phospholipase domain containing 3 ( PNPLA3 ) gene and its interaction with other genetic and nongenetic factors in modulating the course of (non‐alcoholic) fatty liver disease as well as for their insightful comments on our manuscript …”

“…Importantly, all patients included in our study had portal hypertension, indicating ACLD . Moreover, we accounted for potential differences in the severity of liver disease at baseline by adjusting all our survival analyses for HVPG.…”