Familial Aggregation of Insulin Resistance in First-Degree Relatives of Patients With Nonalcoholic Fatty Liver Disease

Background & Aims: An association between nonalcoholic fatty liver disease (NAFLD) and the insulin resistance (IR) syndrome exists. Familial clustering of IR may support a genetic predisposition to NAFLD or cryptogenic cirrhosis (CC). Methods: Patients with NAFLD (n = 20) and healthy controls (n = 20) matched for age, sex, and body mass index with at least 4 living relatives and 2 generations of lineage participated in a familial aggregation study. A medical history was obtained from each subject and confirmed with first-degree family members. Results: NAFLD patients were more likely to have cirrhosis (odds ratio [OR] = 12.0), cardiac disease (OR, 3.0), hyperlipidemia (OR, 12.1), diabetes mellitus (DM) (OR, 9.1), renal stones (OR, 4.1), and arthritis (OR, 6.1). IR ( P = .042) (the primary dependent variable) and DM ( P = .013) were noted in their first-degree relatives. A trend for familial clustering of NAFLD or CC ( P = .059) with a maternal linkage for disease expression also may exist. Cholelithiasis ( P = .047), presumed NAFLD and/or CC ( P = .049), and a trend toward IR ( P = .07) were noted in the mothers, but not the fathers, of patients with NAFLD. An increased risk of DM (OR, 4.2; 95% confidence interval, 1.26–18.7; P = .013), IR (OR, 2.86; 95% confidence interval, 1.02–9.38; P = .042), and smoking (OR, 3.41; 95% confidence interval, 1.43–9.07; P = .003) was observed in first-degree relatives of NAFLD patients. No significant survival difference was observed between family cohorts. Conclusions: Familial clustering and a potential maternal linkage for IR support a genetic predisposition for NAFLD. Alternatively, the presence of suppressor genes modifying the expression of IR in paternal lineage warrants further investigation.