The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant, obesity, and excessive alcohol use are all linked to an increased risk of cirrhosis, hepatocellular carcinoma (HCC), and liver disease-related mortality.

A team, led by Hyun-seok Kim, MD, MPH, PhD, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, investigated the joint associations of the PNPLA3 1148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease-related mortality.

Excessive Drinking and Obesity

Both alcohol use and obesity are linked to an increased risk of cirrhosis and HCC. However, this risk was not uniform among patients with these risk factors.

Genetic variants could play an important role modulating the risk of cirrhosis and HCC.

In the prospective cohort study, the investigators identified 414,209 patients enrolled in the UK Biobank study between March 2006 and December 2010.

The mean age was 56.3 years.

Each participant had no previous diagnosis of cirrhosis and HCC and was followed-up with through March 2021.

Each patient underwent an initial assessment for self-reported alcohol intake, obesity, and PNPLA3 I148M variant status.

The investigators sought main outcomes of incident cirrhosis and HCC cases and liver disease-related death. This was identified from inpatient hospitalization records and death registry and the risks were calculated with Cox proportional hazards regression models.

Evaluating the Risk of Disease

The results show 0.6% (n = 2398) of patients developed cirrhosis (5.07 cases per 100 person-years; 95% CI, 4.87-5.28), 0.1% (n = 323) developed HCC (0.68 cases per 100 person-years; 95% CI, 0.61-0.76), and 0.2% (n = 878) died from a liver disease-related cause (1.76 cases per 100 person-years; 95% CI, 1.64-1.88) during a median follow-up of 10.9 years.

The investigators found the synergistic interactions between the variant, obesity, and alcohol intake were linked to the risk of cirrhosis, HCC, and liver disease-related mortality, while the risk of cirrhosis increased supramultiplicatively (aHR, 17.52; 95% CI, 12.84-23.90) in patients with obesity, with excessive drinking, and who were homozygous carriers compared to patients with no obesity, with nonexcessive drinking, and who were noncarriers.

Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease–related mortality (aHR, 21.82; 95% CI, 13.78-34.56).

Overall, the PNPLA3 I148M variant status significantly differentiated the individual risk of cirrhosis, HCC, and liver disease-related mortality for individuals with both excessive drinking and obesity.

“This study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease–related death in the general population,” the authors wrote.

The study, “Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality,” was published online in JAMA Network Open.