Abstract
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.
Original language | English |
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Pages (from-to) | E1496-501 |
Journal | Journal of Clinical Endocrinology & Metabolism |
Volume | 96 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sept 2011 |
Externally published | Yes |
Keywords
- Animals
- Cholesterol/blood
- Cholesterol, LDL/blood
- European Continental Ancestry Group/genetics
- Female
- Genetic Association Studies
- Genetic Variation
- Genotype
- Humans
- Liver/metabolism
- Male
- Mice
- Mice, Transgenic
- Polymorphism, Single Nucleotide
- STAT5 Transcription Factor/genetics