Systematic Search for Single Nucleotide Polymorphisms in the FOXC2 Gene

Osawa, Haruhiko; Onuma, Hiroshi; Murakami, Akiko; Ochi, Masayuki; Nishimiya, Tatsuya; Kato, Koichi; Shimizu, Ikki; Fujii, Yasuhisa; Ohashi, Jun; Makino, Hideichi

doi:10.2337/diabetes.52.2.562

Cited by 19 publications

(18 citation statements)

References 14 publications

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“…Our findings show that the FOXC2 -512C>T substitution is not a major cause of Type 2 diabetes in the Danish Caucasian population. This is consistent with previous reports in Japanese subjects [8] and Pima Indian subjects [9].…”

Section: Discussionsupporting

confidence: 94%

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

et al. 2003

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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

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Section: Discussionsupporting

confidence: 94%

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

et al. 2003

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“…In agreement with our data, none of these studies performed in Japanese, 9 Pima Indians 8 and Danish Caucasians, 10 respectively, could show an association between FOXC2 and type 2 diabetes. However, also in agreement with our present data, a significant association between the À512C4T variant and BMI (P ¼ 0.03) and measures of body composition (percent body fat; P ¼ 0.02) was noted in Pima Indians.…”

Section: Discussionsupporting

confidence: 90%

“…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.…”

Section: Introductioncontrasting

confidence: 91%

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

2004

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OBJECTIVE: Overexpression of the human transcription factor FOXC2 gene (FOXC2) protects against insulin resistance in mice and a common FOXC2 polymorphism (À512C4T) has been suggested to be associated with insulin resistance in humans. Here, we addressed the potential role for FOXC2 as a candidate gene for type 2 diabetes and associated phenotypes. MATERIALS AND METHODS: A case-control study was performed in 390 type 2 diabetic patients and 307 control subjects. The number of patients was increased to a total of 768 subjects for further study of phenotypic differences relating to the dysmetabolic syndrome relative to genetic variation. The FOXC2 -512C4T polymorphism was genotyped by a restriction fragment length polymorphism PCR assay. RESULTS: FOXC2 À512C4T allele and genotype distribution did not differ between patients with type 2 diabetes and control subjects, but the C/C genotype was associated with increased body mass index (BMI, kg/m 2 ) (P a ¼ 0.03) among type 2 diabetic patients. The FOXC2 -512C4T polymorphism was a significant independent predictor of BMI (P ¼ 0.001) in a multiple regression model including age, gender and affection status. We found no significant association with type 2 diabetes-related metabolic parameters but that the C-allele (P ¼ 0.01) and C/C and C/T genotypes (P ¼ 0.03) were significantly over-represented in type 2 diabetic males with a concomitant diagnosis of dysmetabolic syndrome. CONCLUSION: We conclude that FOXC2 is associated with obesity and metabolic deterioration but does not contribute to an increased risk for type 2 diabetes.

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“…The genotype distributions for all SNPs were consistent with Hardy-Weinberg equilibrium (P Ͼ 0.13 vs. expected frequency, 2 test). There was no association of either the C-512T or the G-350T with type 2 diabetes in 937 full-blooded Pima Indians (611 diabetic and 326 nondiabetic subjects), which is consistent with a recent Japanese study (4). However, the C-512T SNP was associated with BMI in 644 Pimas with normal glucose tolerance who were at least 18 years of age.…”

supporting

confidence: 75%

Genetic Variation in the Human Winged Helix/Forkhead Transcription Factor Gene FOXC2 in Pima Indians

Kovacs

Lehn-Stefan²,

Stümvoll³

et al. 2003

Diabetes

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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...

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Systematic Search for Single Nucleotide Polymorphisms in the FOXC2 Gene

Cited by 19 publications

References 14 publications

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

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

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

Genetic Variation in the Human Winged Helix/Forkhead Transcription Factor Gene FOXC2 in Pima Indians

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