Elsevier

Metabolism

Volume 56, Issue 9, September 2007, Pages 1174-1178
Metabolism

The rs12255372(G/T) and rs7903146(C/T) polymorphisms of the TCF7L2 gene are associated with type 2 diabetes mellitus in Asian Indians

https://doi.org/10.1016/j.metabol.2007.04.012Get rights and content

Abstract

One thousand thirty-eight normal glucose-tolerant and 1031 type 2 diabetic subjects selected from the Chennai Urban Rural Epidemiology Study were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay to investigate the association of rs12255372(G/T) and rs7903146(C/T) polymorphisms of the transcription factor 7–like 2 (TCF7L2) gene with type 2 diabetes mellitus in Asian Indians. The frequency of the “T” allele of both rs12255372(G/T) and rs7903146(C/T) polymorphisms was significantly higher in diabetic subjects (23% and 33%) compared to that in normal glucose-tolerant subjects (19% and 28%; P = .001 and P = .0001, respectively). Logistic regression analysis of the rs12255372(G/T) polymorphism showed that the odds ratio (adjusted for age, sex, and body mass index) was 1.56 (95% confidence interval [CI], 1.03-2.37; P = .034) for the TT genotype and 1.29 (95% CI, 1.06-1.58; P = .011) for the TG genotype when compared with the GG genotype. Adjusted odds ratios for the TT and TC genotypes of the rs7903146(C/T) polymorphism were found to be 1.50 (95% CI, 1.08-2.08; P = .013) and 1.44 (95% CI, 1.18-1.76; P = .0003), respectively, compared with the CC genotype. Normal glucose-tolerant subjects with the TT genotype of rs12255372(G/T) had significantly higher 2-hour plasma glucose levels (mean ± SD, 6.1 ± 1.4 mmol/L) than those with the GG genotype (5.6 ± 1.0 mmol/L, P = .011). Normal glucose-tolerant subjects with the TT genotype of rs7903146(C/T) polymorphism had significantly higher 2-hour plasma glucose levels (mean ± SD, 6.0 ± 1.3 mmol/L) than those with the CC genotype (5.6 ± 1.0 mmol/L, P = .004). In conclusion, the T allele of the rs12255372(G/T) and rs7903146(C/T) polymorphisms of TCF7L2 gene confer susceptibility to type 2 diabetes mellitus in Asian Indians.

Introduction

Although type 2 diabetes mellitus has a strong genetic basis, until recently, most candidate genes for type 2 diabetes mellitus have shown only modest effects and the associations have been inconsistent [1], [2]. Reproducible associations have been documented for the Pro12Ala polymorphism in the peroxisome proliferator–activated receptor (PPARG) gene and the E23K polymorphism in the KCNJ11 gene [3], [4]. Recently, Grant et al [5] reported that the transcription factor 7–like 2 (TCF7L2) gene was strongly associated with type 2 diabetes mellitus in Icelandic subjects. TCF7L2 encodes a transcription factor that plays a role in the Wnt signaling pathway, a key cell developmental and growth regulatory mechanism. Florez et al [6] reported that polymorphisms rs12255372 and rs7903146 in the TCF7L2 gene were associated with an increased risk of developing type 2 diabetes mellitus. Subsequent studies confirmed association of these polymorphisms with type 2 diabetes mellitus in British [7], US [8], Finnish [9], Amish [10], Scandinavian, Polish [11], French [12], Dutch Breda [13], European whites, migrant Asian Indian, Afro-Caribbean [14], northern Swedish [15], and German [16] populations. The rs7903146 polymorphism alone was found to be associated with type 2 diabetes mellitus in Japanese population [17]. India has the largest number of people with diabetes mellitus in the world [18]. Although the association of variants of the TCF7L2 gene and type 2 diabetes mellitus has been investigated in several studies among white populations, there is only one study from the western part of India [19]. Hence, we examined the association of the 2 most strongly associated single nucleotide polymorphisms (SNPs) of the TCF7L2 gene in almost all populations reported so far, the rs12255372 and rs7903146 polymorphisms, with type 2 diabetes mellitus in an Asian Indian population in southern India.

Section snippets

Study subjects

A total of 2069 subjects, 1031 type 2 diabetic subjects and 1038 normal glucose tolerant (NGT) subjects, were selected from phase 2 and phase 3 of the Chennai Urban Rural Epidemiology Study (CURES), respectively. The methodology of the study has been published elsewhere [20]. Briefly, 26 001 adult subjects (>20 years of age) were recruited in phase 1 of the CURES using a systematic random sampling method covering the whole Chennai city. This included 1529 “self-reported” diabetic subjects. In

Clinical and biochemical characteristics of the study subjects

Table 1 shows the clinical and biochemical characteristics of the study subjects. The diabetic subjects were older compared with the NGT subjects (49 ± 10 and 41 ± 11 years, respectively; P < .0001). A comparison between diabetic subjects and NGT subjects showed that the age- and sex-adjusted mean ± SD of BMI (P < .0001), waist circumference (P < .0001), total cholesterol (P < .0001), serum triglycerides (P < .0001), and low-density lipoprotein cholesterol (P = .001) were significantly higher

Discussion

The important finding of this study is that the rs12255372 and rs7903146 SNPs are associated with type 2 diabetes mellitus in this Asian Indian population studied in southern India. The SNPs rs12255372 and rs7903146 showed the strongest association with type 2 diabetes mellitus in an Icelandic sample, and this association was confirmed in white samples from Denmark and the United States in the study by Grant et al [5]. All subsequent studies conducted on various other populations [7], [8], [9],

Acknowledgments

The study was supported by a grant from the Department of Biotechnology, New Delhi, India.

We express our gratitude to the Indian Council for Medical Research for nominating MDRF as an ICMR-Advanced Centre for Genomics of type 2 diabetes mellitus. We thank the Chennai Wellingdon Corporate Foundation for their support for the CURES field studies (CURES-42).

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