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 fullblooded 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 52:1292-1295, 2003 T he forkhead box C2 (FOXC2; also known as homologue-like 14 or mesenchyme forkhead 1) is a winged helix transcription factor whose clinical relevance was first recognized in the context of hereditary lymphedema. Several loss-of-function mutations were initially identified in families with lymphedema distichiasis (1), a condition characterized not only by lymphedema of the limbs but also by double rows of eyelashes (distichiasis), cardiac defects, cleft palate, extradural cysts, and photophobia, illustrating the developmental pleiotropy of this transcription factor.The role of FOXC2 as a key regulator of adipocyte metabolism has recently been described (2). In mice overexpressing FOXC2 in adipocytes, the intra-abdominal white adipose tissue depot was reduced and had acquired a histology similar to brown adipose tissue, whereas interscapular brown adipose tissue was hypertrophic. Increased adipocyte FOXC2 expression had a pleiotropic effect on the expression of genes influencing cellular differentiation and metabolism, insulin action, ␤-adrenergic sensitivity, and intracellular signaling. The net effect of these FOXC2-related alterations was consistent with protection against obesity. Furthermore, increased FOXC2 expression induced by a high-fat diet seemed to counteract most of the symptoms associated with obesity, including hypertriglyceridemia and diet-induced insulin resistance, suggesting a protective effect also against type 2 diabetes. These findings in mice suggest that FOXC2 is a plausible candidate gene for obesity, insulin resistance, and type 2 diabetes in humans.The prevalence of obesity and type 2 diabetes...

Role of the FOXC2 –512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome

“…7 The T/T genotype of a common polymorphism in the 5 0 untranslated region (5 0 UTR) of the gene (À512C4T) has been associated with increased mRNA expression in visceral compared to subcutaneous fat, and the T-allele with higher insulin sensitivity and lower triglyceride levels. 7,8 Although these data identified FOXC2 as a candidate gene for insulin resistance and/or type 2 diabetes, three recent reports in Japanese, Pima Indians and Danish Caucasians have failed to identify an association between FOXC2 and type 2 diabetes. [8][9][10] In addition, contrasting with previous data, the Tallele was weakly associated with increased waist-to-hip ratio (WHR), plasma triglycerides and measures of insulin resistance in the Danish study.…”

Lack of association between metabolic traits and the -512 polymorphism in FOXC2 in German people with normal glucose tolerance

“…It is worth noting, however, that in this paper the carriers of the T-allele had a somewhat higher WHR and this variable was not included in the multivariate regression analysis. Although the WHR difference was not quite significant, it may have contributed to the borderline In addition, it should be mentioned that other studies have found just the opposite, namely an association of the T-allele with enhanced insulin sensitivity [3] and lower plasma triglycerides [2,3]. To detect a 10% difference between genotypes, the statistical power of our data set was more than 80% for the relevant parameters tested.…”

“…Since a previous study [2] found a sex-specific effect on triglycerides, we performed the analysis in men and women separately, but also found no significant association with the −512 genotype. In particular, no associations with plasma insulin, C-peptide or serum triglycerides were observed.…”

“…An association with Type 2 diabetes was not observed in this population. Previous papers had found conflicting data on this common polymorphism regarding an association with obesity and diabetes-related traits [2,3].…”

“…An association with Type 2 diabetes was not observed in this population. Previous papers had found conflicting data on this common polymorphism regarding an association with obesity and diabetes-related traits [2,3].We genotyped this polymorphism in 732 subjects (264 male, 468 female; aged 36±12 years [SD]) with normal glucose tolerance according to WHO criteria, and studied any associations with metabolic traits. The subjects were participants of the ongoing Tübingen family study of Type 2 diabetes in the south-west of Germany.…”