Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians
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.
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ABSTRACT: Obesity, which is assuming alarming proportions, has been attributed to genetic factors, hypothalamic dysfunction, and intestinal gut bacteria and an increase in the consumption of energy-dense food. Obesity predisposes to the development of type 2 diabetes mellitus, hypertension, coronary heart disease, and certain forms of cancer. Recent studies have shown that the intestinal bacteria in obese humans and mice differ from those in lean that could trigger a low-grade systemic inflammation. Consumption of a calorie-dense diet that initiates and perpetuates obesity could be due to failure of homeostatic mechanisms that regulate appetite, food consumption, and energy balance. Hypothalamic factors that regulate energy needs of the body, control appetite and satiety, and gut bacteria that participate in food digestion play a critical role in the onset of obesity. Incretins, cholecystokinin, brain-derived neurotrophic factor, leptin, long-chain fatty acid coenzyme A, endocannabinoids and vagal neurotransmitter acetylcholine play a role in the regulation of energy intake, glucose homeostasis, insulin secretion, and pathobiology of obesity and type 2 diabetes mellitus. Thus, there is a cross-talk among the gut, liver, pancreas, adipose tissue, and hypothalamus. Based on these evidences, it is clear that management of obesity needs a multifactorial approach.Nutrition 12/2009; 26(5):459-73. DOI:10.1016/j.nut.2009.09.020 · 3.05 Impact Factor
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ABSTRACT: Varicose veins (VV) and hemorrhoids (H) are common vascular abnormalities worldwide. Several factors contribute to the development of these vascular abnormalities including; age, diet, occupation and genetic factors. FOXC2 gene encodes a 2.2 kb transcript with a 1.5 kb single exon and is expressed in the developing cardiovascular system. FOXC2 is the first gene in which mutations have been implicated in primary venous valve failure. This study aimed at detecting FOXC2 gene alterations in familial VV and H patients to look for genetic variations that might be implicated in the development of VV and H. Three SNPs were identified in the proximal upstream region of FOXC2 gene among patients, but not in control subjects, recruited in this study. The first SNP (-91 C G) found in 5 subjects (~20.8 %) with severe H. The second SNP (-41G A) was detected in 2 subjects (~ 8 %) and, a third SNP (-41 G T) was identified only in one VV patient (~ 4.1%). These SNPs might be implicated in the regulation of FOXC2 gene and, therefore; contribute to the development of VV or H. Moreover, the clinical profile of the families recruited in this study along with the consistent SNP (-91 C G), show that VV and H are closely related vascular abnormalities, implying that they might have a common genetic etiology.