FOXC2 mRNA Expression and a 5' untranslated region polymorphism of the gene are associated with insulin resistance.

University of Gothenburg, Goeteborg, Västra Götaland, Sweden
Diabetes (Impact Factor: 8.47). 01/2003; 51(12):3554-60. DOI: 10.2337/diabetes.51.12.3554
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We give a short variant of the classical proofs for the generation of the symplectic group Spn(Z) over Z by the standard matrices.
    Linear Algebra and its Applications 03/1997; 253(1):363-367. DOI:10.1016/0024-3795(95)00708-3 · 0.98 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    ABSTRACT: FOXC2 is a winged helix gene that has been shown to counteract obesity, hypertriglyceridemia, and diet-induced insulin resistance in rodents. Therefore, FOXC2 was analyzed as a candidate gene for susceptibility to type 2 diabetes in Pima Indians. Four variants were identified by sequencing the coding region, as well as 638 bp of the 5' region and 300 bp of the 3' region of the gene. Two single nucleotide polymorphisms (SNPs) were found in the putative promoter region, a C-512T transition and a G-350T. In addition, two SNPs were found in the 3' region, a C1548T and a C1702T. The G-350T and the C1702T variants were in complete linkage disequilibrium, and the C1548T variant was relatively rare; therefore, only the C-512T and G-350T variants were additionally genotyped in 937 full-blooded Pima Indians. Neither of these polymorphisms were associated with type 2 diabetes; however, the C-512T variant was associated with BMI (P = 0.03) and percentage of body fat (P = 0.02) in male and female Pima subjects, as well as with basal glucose turnover and fasting plasma triglycerides in women. Our data indicate that variation in FOXC2 may have a minor role in body weight control and seems to be involved in the regulation of basal glucose turnover and plasma triglyceride levels in women, but this gene does not significantly contribute to the etiology of type 2 diabetes in Pima Indians.
    Diabetes 06/2003; 52(5):1292-5. DOI:10.2337/diabetes.52.5.1292 · 8.47 Impact Factor