PNPLA3 as a Genetic Determinant of Risk for Progression and Outcomes in Non-Alcoholic Fatty Liver Disease and Alcoholic Liver Disease

Introduction: Patatin-like phospholipase domain protein 3 (PNPLA3) polymorphisms (rs738409 C>G) are associated with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). There are no data on association of PNPLA3 polymorphisms with progression and outcomes in NAFLD or ALD. Methods: Blood samples were collected for DNA analysis from NAFLD or ALD patients after informed consent in a prospective study at our center. Diagnosis of NAFLD was based on excluding other causes of liver disease and presence of steatosis on ultrasound or liver biopsy. Diagnosis of ALD was based on excluding other causes of liver disease and documenting history of alcohol use of >30 g/d for females and >50 g/d for males for >5 years. Extracted DNA was tested for presence of PNPLA3 polymorphisms. Over a maximum follow-up period of 3 years, PNPLA3 polymorphisms were examined for association with disease progression (increase in ≥3 MELD points for cirrhosis or ALT ≥30 for patients without cirrhosis) based on risk factor control (decrease in HbA1c to < 7% or weight loss >7% for NAFLD, or abstinence from alcohol >6 months for ALD). Association was determined for occurrence of alcoholic hepatitis (AH) among ALD patients. Results: Of the 90 NAFLD patients (median age 58 yrs., 46% males, 82% white), proportion of PNPLA3 genotypes (CC: CG: GG) comparing 55 patients with cirrhosis (median MELD 9, 50% decompensated) vs. 35 patients without cirrhosis (median ALT 62) were 14: 25: 61 vs. 22: 49: 29, p=0.0097. Of the 83 ALD patients (median age 53 yrs., 69% males, 83% white) PNPLA3 polymorphism frequencies among 29 AH patients vs. 54 non-AH patients were 1: 3: 15 vs. 9: 20: 25 respectively (P=0.21). Distribution of PNPLA3 polymorphisms based on the progression of disease and risk factor control are shown in Table 1 among NAFLD and ALD patients with cirrhosis and in Table 2 among NAFLD patients without cirrhosis.Table: Table. Distribution of PNPLA3 polymorphisms based on progression of disease and risk factor control in NAFLD and ALD with cirrhosisTable: Distribution of PNPLA3 polymorphisms based on progression of disease and risk factor control among NAFLD without cirrhosisConclusion: PNPLA3 CG and GG polymorphisms in ALD tended to be overrepresented among AH compared to non-AH patients. This could be a genetic marker predisposing for AH among chronic drinkers at risk for ALD, however, it requires confirmation in a larger sample. Association of PNPLA3 polymorphisms with disease progression based on risk factor control were not seen in this small cohort with relatively short follow-up. Larger multicenter studies with longer follow-up are suggested among NAFLD or ALD patients to examine the association of disease progression with PNPLA3 polymorphisms.