Genetic Variation in NR1H4 Encoding the Bile Acid Receptor FXR Determines Fasting Glucose and Free Fatty Acid Levels in Humans

Context: Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models. Objective: To understand the role of FXR in human metabolism, we investigated associations of common single-nucleotide polymorphisms (SNPs) in the FXR-encoding gene NR1H4 with glucose and lipid metabolism, body fat mass, and liver fat content. Design: We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of common genetic variation (minor allele frequency > 10%). Outcome Measures: Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by H-1-magnetic resonance spectroscopy were performed. Results: SNP rs4764980 was significantly associated with fasting glycemia (P = .0043) and nominally associated with fasting and postglucose load free fatty acid (FFA) levels (P = .01). Upon interrogation of publicly available Meta-Analyses of Glucose and Insulin-related traits Consortium data, the association of rs4764980 with fasting glycemia was replicated (Meta-Analyses of Glucose and Insulin-related traits Consortium, P = .005). Additionally, SNP rs11110390 showed significant associations with fasting (P = .0054) and postload (P = .0051) FFA levels. For none of the investigated SNPs, associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected. Conclusions: We conclude that FXR contributes to fasting glucose and FFA levels in humans independent of unhealthy body fat accumulation. The receptor represents an interesting target to influence lipid and glucose metabolism.