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Genetic Variants of TCF7L2 Are Associated with Insulin Resistance and Related Metabolic Phenotypes in Taiwanese Adolescents and Caucasian Young Adults

Research Center for Genes, Environment, and Human Health (P.-H.L., W.J.C.), and Institute of Epidemiology (P.-H.L., W.J.C.), College of Public Health, National Taiwan University, Taipei 100, Taiwan; Department of Internal Medicine (Y.-C.C.), National Taiwan University Hospital, Yunlin Branch, Yunlin 640, Taiwan; Department of Internal Medicine (Y.-D.J., T.-J.C., S.-S.K., K.-C.L., L.-M.C.), National Taiwan University Hospital, Taipei 100, Taiwan; Genetic Epidemiology Core Laboratory (W.J.C., P.-C.H.), Research Center for Medical Excellence, National Taiwan University, Taipei 100, Taiwan; Department of Diabetes, Endocrinology, and Metabolism (K.C.C.), City of Hope National Medical Center, Duarte, California 91010; Division of Endocrinology, Metabolism, and Nutrition (K.C.C.), Department of Internal Medicine, Harbor-University of California-Los Angeles, Los Angeles County Medical Center, Torrance, California 90502; and Institute of Clinical Medicine (L.-M.C.), College of Medicine, National Taiwan University, Taipei 100, Taiwan

Address all correspondence and requests for reprints to: Lee-Ming Chuang, M.D., Ph.D., Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. E-mail: leeming{at}ntu.edu.tw.

Objectives: The effect of TCF7L2 rs7903146 on glucose homeostasis is considered primarily due to impaired insulin secretion in European populations. Because we previously demonstrated that TCF7L2 rs290487 near the 3' end of TCF7L2 was significantly associated with type 2 diabetes (T2D) in Taiwanese subjects, we aimed to investigate potential mechanisms underlying the associations of rs290487 with T2D.

Methods: Eighteen single nucleotide polymorphisms (SNPs) were tested for association with glucose/insulin homeostasis as well as other quantitative metabolic phenotypes using the quantitative transmission disequilibrium test in 525 Taiwanese adolescent twin-pairs and siblings. The results were further replicated in 116 nondiabetic normotensive Caucasian young adults.

Results: Among the 18 SNPs, rs290487 C allele was significantly associated with higher 60-, 90-, and 120-min glucose concentrations (P = 0.001, 0.01, and 0.02, respectively); higher 60- and 90-min insulin concentrations (P = 0.01 and 0.01, respectively); and a lower insulin sensitivity index (P = 0.04). No association was found for rs290487 with measures of insulin secretion. The rs290487 C allele was also associated with HOMA-IR (P = 0.005) and insulin sensitivity index (P = 0.01) in Caucasian young adults. Another SNP, rs10749127 C allele located in intron 4, was also associated with features of the metabolic syndrome, including elevated systolic (P = 0.02) and diastolic (P = 2.0 x 10^–4) blood pressure, triglycerides (P = 7.0 x 10^–4), and uric acid (P = 0.03). In a meta-analysis, the rs290487 C allele was confirmed to be associated with an increased risk of T2D (odds ratio, 1.11; 95% confidence interval, 1.03–1.19; P = 0.005) across East Asian populations.

Conclusions: These findings support an important role for T2D risk-conferring gene TCF7L2 in insulin resistance in both Taiwanese and Caucasian youth and underscore the emerging role of Wnt signaling in insulin resistance.