Waist circumference mediates the association between rs1260326 in GCKR gene and the odds of lean NAFLD.

While non-alcoholic fatty liver disease (NAFLD) has been widely studied, the pathophysiology of lean NAFLD, the critical NAFLD subgroup, remains elusive. This study aimed to clarify the association between polymorphisms of GCKR, waist circumference, and the odds of lean NAFLD in the elderly Chinese Han population who live in the Zhangjiang community center of Shanghai, China. Three single nucleotide polymorphisms (SNPs), including rs1260326, rs780093, and rs780094, were genotyped in MassARRAY Analyzer. The association between SNPs with waist circumference in five genetic models was analyzed and rechecked by the logistic regression analysis. Mediation models were established to evaluate whether the waist circumstance can mediate the association between SNPs and lean NAFLD. In this study, the frequency of the C allele of rs1260326, rs780093, and rs780094 was significantly lower in lean NAFLD individuals than in lean non-NAFLD ones. The association between rs1260326 in GCKR and the odds of lean NAFLD was mediated via waist circumference after adjusting gender and age in the elderly Chinese Han population (β = 1.196, R2 = 0.043, p = 0.020). For the first time, this study examined the mediating effect of waist circumference on the association between rs1260326 in GCKR and the odds of lean NAFLD (β = 0.0515, 95% CI 0.0107-0.0900, p = 0.004). It may contribute to illustrating the pathogenesis of lean NAFLD and indicate that waist circumference management might improve lean NAFLD control.