© Kamla-Raj 2008 Int J Hum Genet, 8(1-2): 199-215 (2008) Emergence of TCF7L2 as a Most Promising Gene in Predisposition of Diabetes Type II Vipin Gupta *# , Rajesh Khadgawat ** , K. N. Saraswathy *## , M. P. Sachdeva *+ and A. K. Kalla *++ *Biochemical and Molecular Anthropology Laboratory, Department of Anthropology, University of Delhi, Delhi 110 007, India # Telephone: 9899346222, E-mail: # <udaiig@gmail.com>, <knsaraswathy@yahoo.com> ## , + < mpsachdeva@rediffmail.com>, ++ < alokekalla@rediffmail.com> **Deptartment of Endocrinology & Metabolism, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India Telephone: +91 11 26588641 ext. 3237 (O), 4760 (W), Fax: +91 11 26589386, E-mail: rajeshkhadgawat@hotmail.com “Subject never gives you anything, you have to extract from it, and thus making it alive again.” Udai G KEYWORDS T2D (type 2 diabetes); BMI (body mass index; LD (linkage disequilibrium); SNP (single nucleotide polymorphism); WNT pathway ABSTRACT The genetics of the complex disorder like Diabetes Type II, which is clinically diagnosed as disease of insulin resistance and impaired insulin secretion leading to impaired glucose homeostasis in body, remains a nightmare for geneticists. But the recent progress in identification of a most promising marker in predisposition of diabetes Type II, namely, TCF7L2 with its large effect size and its global presence in various ethnically and geographically different populations offers some hope as the robust genetic approach like genome-wide association studies seem to corroborate the evidence in favour of association of this gene with predisposition to the disease. This paper presents a comprehensive review of studies on the association of this gene with type II diabetes. INTRODUCTION Diabetes type II (T2D) is a non-autoimmune, complex, heterogeneous and polygenic meta- bolic disease condition in which body fails to produce enough insulin. Diabetes type II is characterized by abnormal glucose homeostasis, and its pathogenesis appears to involve complex interactions between genetic and environmental factors. There are two hypotheses regarding the pathophysiology of T2D. According to one hypothesis the primary defect is represented by insulin resistance, which is already present at very early stage of the prediabetic state. While initially the beta cells are able to compensate for this resistance, overt diabetes occurs when the beta cells become exhausted. The alternative hypothesis proposes that the primary defect in T2D is due to mild dysregulation in insulin secretory mechanisms that leads to overt diabetes following the secondary superimposi- tion of insulin resistance (Korc 2003). Therefore, T2D (formerly known as adult onset diabetes) occurs when impaired insulin effectiveness (insulin resistance) is accompanied by the failure to produce sufficient β cell insulin. The burden of diabetes is to a large extent the consequence of macrovascular and microvascular complica- tions of the disease (Permutt et al. 2005). The peripheral symptoms of diabetes type 2 include variable inability of the liver to properly suppress hepatic glucose release and, production of adipose tissue derived hormones and cytokines that antagonize insulin action. GENETICS OF DIABETES TYPE II The genetic status of T2D is appreciated by twin, family and admixture studies, which suggest that the risk varies widely across populations, from 5% or less in White and Asian populations to 50% or more among Pima Indians and South sea Island populations (Elbein et al. 2002). The genetic differences in disease predisposition in different ethnic groups have also been demon- strated by some studies in admixed populations (Barroso 2005). Lifetime concordance rates among identical twins approach 100%. Concor- dance rate is found to increase with the duration of follow up. Most conservative estimates place long term concordance at about 60%, which is at least double to that of dizygotic twins. Such