Higher Risk of Liver Disease Progression Seen Among Patients With PNPLA3 I148M Variant


Individuals who were homozygous carriers of the PNPLA3 I148M genetic variant and reported excessive drinking and obesity had a 17.5 to 30.1 higher risk of progression to liver disease complications.

The genetic variant I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene was found to have synergistic interplay with alcohol consumption and obesity that is associated with increase risk of developing cirrhosis, hepatocellular carcinoma (HCC), and death attributed to liver disease in older individuals.

These findings were published in JAMA Network Open.

The study authors sought to understand whether the genetic variant could play a role in stratifying the risk of individuals with alcohol consumption and obesity. They explained these 2 factors are associated with increased risk of cirrhosis and HCC, but the risk is not uniform.

The prospective cohort study included 414,209 individuals enrolled in the UK Biobank study between March 2006 and December 2010. These participants had received no previous diagnosis of cirrhosis or HCC and were followed through March 2021.

The mean (SD) age was 56.3 (8.09) years, 52.8% were women, and 94% were of White race and ethnicity.

Alcohol consumption was self-reported, and the mean number of alcohol units was calculated assuming 2 units of pure alcohol in a pint of beer, 1.5 units in a 125-mL serving of wine, and 1 unit in a 25-mL serving of liquor. Consumption was categorized as excessive, defined as at least 36 units for men and at least 25 units for women, or nonexcessive. Of the entire group, 10.8% of participants reported excessive alcohol consumption.

Obesity was defined as a body mass index of 30 kg/m2 or higher, with 23.8% of participants reporting obesity.

Participants were also categorized as a noncarrier, heterozygous carrier, or homozygous carrier of the PNPLA3 I148M variant. The variant was genotyped using either the UK BiLEVE Axiom Array or the UK Biobank Axiom Array. Genotyping information was coded as 0 for noncarriers who had the CC genotype, 1 for heterozygous carriers who had the GC genotype, and 2 for homozygous carriers who had the GG genotype of the minor allele, the G allele.

Of 414,209 individuals, 4.8% were homozygous carriers of the PNPLA3 I148M variant, and 21.6% had a G allele genotype. Among participants who reported both excessive drinking and obesity, 4.7% were homozygous carriers.

Other covariables were also noted, including current smoking, hypertension, dyslipidemia, and diabetes.

Individuals who were homozygous carriers of the PNPLA3 I148M variant and reported excessive drinking and obesity had a 17.5 to 30.1 higher risk of progression to liver disease complications, including cirrhosis, HCC, and liver disease–related death.

In multivariable-adjusted Cox proportional hazards regression models containing different combinations of the 3 risk factors, the authors observed synergistic interactions between the risk factors and the risk of the listed complications. For example, individuals who were homozygous variant carriers with nonexcessive drinking and without obesity still had a higher risk of cirrhosis compared with noncarriers. Additionally, a person with any single risk factor had a higher risk of cirrhosis vs someone without any of the 3 risk factors.

Similar trends were also observed for HCC and mortality.

The synergistic interplay was not observed in overall and cardiovascular disease-related mortality.

“The results suggest that screening for obesity, heavy alcohol drinking, and a single genetic variant could distinguish people at risk for progressive liver disease with nonviral etiologies from people at low risk, particularly in the context of population screening programs,” the authors said. “In addition, these 3 factors may be important to examine in prevention trials targeting individuals at high risk for progression to decompensated cirrhosis or HCC.”


Kim HS, Xiao X, Byun J, et al. Synergistic associations of PNPLA3 I148M variant, alcohol intake, and obesity with risk of cirrhosis, hepatocellular carcinoma, and mortality. JAMA Netw Open. 2022;5(10):e2234221. doi:10.1001/jamanetworkopen.2022.34221

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