The FOXC2 -512C>T variant is associated with hypertriglyceridaemia and increased serum C-peptide in Danish Caucasian glucose-tolerant subjects

Abstract

Aims/hypothesis. The transcription factor FOXC2 plays a key role in adipocyte differentiation and the FOXC2 gene is a candidate gene for Type 2 diabetes, obesity and dyslipidaemia. We investigated whether the FOXC2 -512C>T promoter variant is associated with Type 2 diabetes or its intermediary phenotypes in glucose tolerant subjects. Methods. The variant was genotyped using PCR-RFLP in 705 unrelated Type 2 diabetic patients, 505 unrelated glucose-tolerant control subjects and 219 glucose-tolerant offspring of Type 2 diabetic probands.Results. The frequency of the T-allele was 58% (95% CI 56-61%) and 59% (56-62%) among the Type 2 diabetic patients and the unrelated glucose-tolerant control subjects, respectively (p=0.6). Among the glucose-tolerant subjects, the T-allele carriers had higher fasting serum triglyceride (p=0.03), fasting serum C-peptide concentrations (p=0.009) and insulinogenic index (p=0.04). Furthermore, in glucose-tolerant women, the waist-to-hip ratio was significantly higher in carriers of the T-allele. Conclusion/interpretation. Our data suggest that the FOXC2 -512C>T variant is not associated with Type 2 diabetes. However, among glucose-tolerant subjects the variant is associated with hypertriglyceridaemia and increased fasting serum C-peptide. [Diabetologia (2003) Short CommunicationThe FOXC2 -512C>T variant is associated with hypertriglyceridaemia and increased serum C-peptide in Danish Caucasian glucose-tolerant subjects Transgenic mice over-expressing FOXC2 in adipose tissue were leaner and had reduced concentrations of serum triglyceride, plasma glucose and insulin and were more insulin sensitive on standard and highfat diets than their wild-type littermates [4].In a recent study FOXC2 mRNA levels were increased in visceral fat compared with subcutaneous fat from human obese subjects and there was a correlaThe forkhead box C2 (FOXC2) is a member of the Fox transcription factor family and is expressed in white and brown adipose tissue [1]. Recently, the understanding of the molecular basis of adipose tissue

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

“…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. 10 Insulin resistance and additional features of the metabolic, or rather dysmetabolic, syndrome including abdominal obesity, hypertension and dyslipidemia are under strong genetic influence and cluster in families and they are the hallmark feature of 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. 10 Insulin resistance and additional features of the metabolic, or rather dysmetabolic, syndrome including abdominal obesity, hypertension and dyslipidemia are under strong genetic influence and cluster in families and they are the hallmark feature of type 2 diabetes. 11 A concomitant diagnosis of dysmetabolic syndrome is present in up to 80% of type 2 diabetic patients and is associated with a doubling of the risk for cardiovascular morbidity and mortality.…”

“…Although the C-allele has originally been described as the wild-type allele for this single-nucleotide polymorphism (GenBank Accession no. NM_005251), the more common allele in Scandinavian populations is T. 7,10 Differences in type 2 diabetes-related phenotypes between genotype carriers are presented in Table 3. Unintentionally, there were significantly more females than males homozygous for the T-allele among the control subjects (47.6 vs 35.5% for female and male control subjects, respectively, P ¼ 0.04).…”

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

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Letters 757Lack of association between metabolic traits and the −512 polymorphism in FOXC2 in German people with normal glucose toleranceTo the Editor: A recent paper reported an association between the −512C>T promoter polymorphism in the forkhead box C2 (FOXC2) gene and increased serum C-peptide and hypertriglyceridaemia in normal-glucose-tolerant subjects from Denmark [1]. An association with Type 2 diabetes was not observed in this population.

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“…For example, in comparison with the Danish report [1], we studied younger subjects with a higher proportion of positive family history of Type 2 diabetes. The Danish study reported marginally higher fasting insulin and significantly higher fasting C-peptide in carriers of the T-allele.…”