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

Jan-Wilhelm Kornfeld, Aaron Isaacs, Veronique Vitart, J Andrew Pospisilik, Thomas Meitinger, Ulf Gyllensten, James F Wilson, Igor Rudan, Harry Campbell, Josef M Penninger, Veronika Sexl, Richard Moriggl, Cornelia van Duijn, Peter P Pramstaller, Andrew A Hicks

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)E1496-501
JournalJournal of Clinical Endocrinology & Metabolism
Volume96
Issue number9
DOIs
Publication statusPublished - Sep 2011
Externally publishedYes

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

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