TCF7L2 genetic variants and progression to diabetes in the Chinese population: pleiotropic effects on insulin secretion and insulin resistance
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TCF7L2 genetic variants were associated with progression to type 2 diabetes in Europeans. However, the role of TCF7L2 in type 2 diabetes remained uncertain in Chinese. Seventeen tag single nucleotide polymorphisms were genotyped in 1,094 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance family study. At baseline, the rs7903146 T allele in the exon 4 linkage disequilibrium (LD) block were associated with lower insulinogenic index at 60 min (P = 0.01), while the rs290481 G allele near the 3′ end was associated with higher 2-h post-challenge glucose (P = 0.003) and insulin concentration (P = 0.02), elevated systolic (P = 0.01) and diastolic blood pressure (P = 0.006), lower waist circumference (P = 0.01), and increased steady-state plasma glucose (SSPG) concentration measured with modified insulin suppression test (P = 0.02). Over an average follow-up period of 5.43 years, participants with the rs7903146 T allele or variants in the same LD block, but not those with the rs290481 G allele, were more likely to progress to diabetes (hazard ratio = 2.61, 95% confidence interval, 1.27–5.39, P = 0.009) than were non-carriers. TCF7L2 gene expression was inversely associated with SSPG in human visceral (r = −0.73, P = 0.006) and subcutaneous adipose tissue (r = −0.62, P = 0.03). TCF7L2 may exert pleiotropic effects on insulin secretion or insulin resistance. However, only variants associated with impaired β-cell function predict progression to diabetes in Chinese.
KeywordsTCF7L2 Insulin resistance Single nucleotide polymorphisms Chinese
The authors express their sincere gratitude to all of the SAPPHIRe participants. The authors thank Dr. Andrian Vella and Dr. Robert A. Rizza (Mayo Clinic, Rochester, MN, USA) for their critical reading of the manuscript. We also thank Ms. Su-Mei Wang for her computing assistance and Ms. Shan-Shan Kuo and Ms. Kuan-Ching Lee for their technical support. The genotyping support from the Genome Center of the National Taiwan University Hospital is also acknowledged. This work is supported in part by the National Science Council of Taiwan (NSC 95-3112-B002-002; NSC 96-3112-B002-002) and a NTUH-TVGH Joint Research Program (96VN03) from the National Taiwan University Hospital and Taipei Veterans General Hospital, Taiwan, and in part by the grants PH-098-pp-03 and PH-095-pp-04 from the National Health Research Institutes, Taiwan. All authors declared no potential conflict of interest.
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