Familial clustering of nonalcoholic fatty liver disease in first‐degree relatives of adults with lean nonalcoholic fatty liver disease

Abstract Background and Aims The heritability of nonalcoholic fatty liver disease (NAFLD) in lean individuals is undetermined. This familial aggregation study aimed to evaluate familial linkage for NAFLD and the risk of NAFLD among first‐degree relatives of probands with lean NAFLD. Methods This study prospectively recruited cohorts of probands with lean NAFLD, probands with obese NAFLD, and lean probands with non‐NAFLD and their respective first‐degree relatives. A total of 257 participants were evaluated for liver steatosis, defined by the controlled attenuation parameter ≥288 dB/m 2 , metabolic characteristics, and the PNPLA3, TM6SF2, and MBOAT7 polymorphisms. Results The prevalence of NAFLD in first‐degree relatives of lean NAFLD probands (39.9%) was similar to that in the obese NAFLD group (36.9%) and was significantly higher than in lean persons without NAFLD (19.1%). First‐degree relatives of probands with NAFLD who were male, and had central obesity, hypertriglyceridaemia, insulin resistance, and the PNPLA3 rs738409C>G allele had a significantly higher prevalence of NAFLD. After multivariable adjustment for gender, metabolic characteristics, and the PNPLA3 rs738409C>G allele, first‐degree relatives of probands with lean NAFLD (odds ratio [OR], 5.13; 95% CI, 1.77–14.86) and obese NAFLD (OR, 3.20; 95% CI, 1.14–8.99) exhibited an increased risk of NAFLD compared with those of lean controls without NAFLD. Conclusions Our well‐phenotype cohorts revealed familial clustering of NAFLD and higher risks of NAFLD in first‐degree relatives of probands with lean or obese NAFLD. The findings encourage clinicians caring for NAFLD patients to be more vigilant for NAFLD in their family members.