Variants in STAT5B associate with serum TC and LDL-C levels.

CONTEXT Known genetic variants influencing serum lipid levels do not adequately account for the observed population variability of these phenotypes. The GH/signal transducers and activators of transcription (STAT) signaling pathway is an evolutionary conserved system that exerts strong effects on metabolism, including that of lipids. RESEARCH DESIGN AND METHODS We analyzed the association of 11 single-nucleotide polymorphisms (SNP) spanning the STAT5B/STAT5A/STAT3 locus with serum lipid levels in six European populations (n = 5162 nondiabetic individuals). RESULTS After adjustment for age, sex, alcohol use, smoking, and body mass index, we identified STAT5B variants (rs8082391 and rs8064638) in novel association with total cholesterol (TC; P = 0.001 and P = 0.002) and low-density lipoprotein cholesterol (P = 0.002 and P = 0.004) levels. The minor alleles of these single-nucleotide polymorphisms were significantly enriched in hyperlipidemic individuals across the six discovery populations (P = 0.004 and P = 0.006). In transgenic mice deficient for hepatic STAT5A and STAT5B, reduced serum TC levels coincided with reduced hepatic cholesterol biosynthesis as demonstrated using gene expression profiling and pathway enrichment analysis. CONCLUSIONS Genetic variants in STAT5B are associated with TC and low-density lipoprotein cholesterol levels among six populations. Mechanistically, STAT5B transcriptionally regulates hepatic cholesterol homeostasis.