FOXC2 mRNA Expression and a 5' untranslated region polymorphism of the gene are associated with insulin resistance.
ABSTRACT The human transcription factor FOXC2 has recently been shown to protect against diet-induced insulin resistance in transgenic mice. We investigated the expression of FOXC2 in fat and muscle and performed a genetic analysis in human subjects. FOXC2 mRNA levels were increased in visceral compared with subcutaneous fat from obese subjects (12 +/- 4-fold; P = 0.0001), and there was a correlation between whole-body insulin sensitivity and FOXC2 mRNA levels in visceral fat (fS-insulin R = -0.64, P = 0.01, and homeostasis model assessment of insulin resistance [HOMA-IR] R = -0.68, P = 0.007) and skeletal muscle (fS-insulin R = -0.57, P = 0.03, and HOMA-IR R = -0.55, P = 0.04). Mutation screening of the FOXC2 gene identified a common polymorphism in the 5' untranslated region (C-512T). The T allele was associated with enhanced insulin sensitivity (HOMA-IR P = 0.007) and lower plasma triglyceride levels in females (P = 0.007). Also, the higher expression of FOXC2 in visceral than in subcutaneous fat was restricted to subjects homozygous for the T allele (P = 0.03 vs. P = 0.7). Our data suggest that increased FOXC2 expression may protect against insulin resistance in human subjects and that genetic variability in the gene may influence features associated with the metabolic syndrome.
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ABSTRACT: The hereditary lymphedemas provide an opportunity to identify genes involved in normal and deranged lymphatic development. Genetic analysis of families with Milroy's disease identified mutations in VEGFR3 as a cause of congenital lymphedema, confirming the importance of VEGFC/VEGFR3 signaling in lymphatic development. These observations led to the identification of a mouse model for primary lymphedema, and subsequent analysis of this mouse model, using transgenic and gene transfer techniques, has provided initial clues to the development of a biologically based therapy for primary lymphedema. Of more importance from a public health perspective is the fact that manipulation of this pathway may lead to effective therapies for the more prevalent forms of secondary lymphedema. Identification of FOXC2 as the gene mutated in the lymphedema-distichiasis syndrome has revealed new molecular insight into lymphatic development. Molecular analysis of the FOXC2 pathway may provide clues to developmental pathways shared by the lymphatic system and the other developmental abnormalities associated with this complex syndrome. With improving knowledge of the human genome, genetic analysis of families with lymphedema continues to offer one of the most promising approaches to identifying genes influencing lymphatic development.Annals of the New York Academy of Sciences 01/2003; 979:39-51; discussion 76-9. DOI:10.1111/j.1749-6632.2002.tb04866.x · 4.31 Impact Factor
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