Despite serious efforts to identify genetic variants that predispose to common forms of type 2 diabetes, till now only a few genes, such as KCNJ11, PPARG and HNF4A have been reproducibly associated with this complex disease in a variety of large-scale studies performed in the different populations [16
]. Replication studies show that the TCF7L2 gene is an important candidate gene contributing to susceptibility to type 2 diabetes. Since the most strongly associated SNP is within an intron of the TCF7L2 gene, this SNP is not likely to be the true disease variant. However, the intronic variants may influence the risk of T2D through altering gene expression in human islets or possibly transcription regulation. TCF7L2 SNP rs7903146 is the strongest variant polymorphism
associated with T2DM [18
] and has been confirmed in numerous populations throughout the world [18
,20,21]. In this study, we aimed to investigate the association between the TCF7L2 rs7903146 (C/T) variant and T2DM among study groups. Our case-control study, along with the previous reports from different region of the world prove that the rs7903146 (C/T) variant of the TCF7L2 gene is associated with T2DM. The T allele of TCF7L2 rs7903146 (C/T) was observed to be significantly associated with T2D risk in our studied diabetic patients (p<0.001, OR=6.74, 95% CI: (2.63-15.91).
This finding is consistent with the previous reports from other populations, except for Arab population of Persian Gulf [22
]. This reflects the role of other genetic factors that influence the disease risk among these populations [22
T allele frequency for rs7903146 was 32.5% in the control subjects and 68.5% in T2DM subjects of this study. The frequency of the minor T allele in the control subjects was consistent with that of rs7903146 T in the populations of Icelandic, Palestinian, Danish, Asian-Indian, Dutch, (UK-resident South Asians and Emirati populations (30.4, 29.3, 29, 26.1, 28, 29 and 37.2%, respectively) [18
] but strikingly different from that reported in the Japanese (4.2%) and Chinese (~2%) populations [6
].The frequency of the minor T allele in the diabetic subjects was consistent with that of rs7903146 T among broad ethnic backgrounds, including for example populations of UK [27
], Dutch [25
], Amish [28
], Finnish [29
], Swedish [30
], French [31
], and US [31
], Indian [33
], and Japanese [26
] origin but strikingly different from that reported in Pima Indians and Chinese diabetics [6
]. The variability in the allele frequency, which probably reflects different ethnic backgrounds, would partly account for the discrepancies found in the results among different studies. Other factors include small sample size, age of subjects [26
] and effects of environmental factors, such as life-style.
Haplotype analysis involving rs7903146 (IVS3C/T) of TCF7L2 in our study participants revealed a significant association of the T-allele and T2DM, compared to obese (χ 2
=16.07 with p value<0.001). Obese group showed no significant p-value for TT genotype.
Reinehr et al. 2004 found that reduction of overweight improves glucose metabolism in overweight children [35
]. However, not all children reducing overweight demonstrated an improvement of glucose metabolism suggesting further influencing factors such as genetic markers [36
]. The SNP rs7903146 in TCF7L2 is associated with an increased risk of type 2 diabetes mellitus [2
]. The TT haplotype increases the risk of T2D in diabetic group. As well, we analyzed the association of metabolic measurements and genotype of the locus. For TCF7L2 rs7903146, mean FBG significantly increased with the number of T-allelels; CC 103.0 mg/dl ,C/T 108.41, TT 117.67 (p value=0.001). In this study, our results showed that over expression HOMA β significantly and inversely associated with T2D risk. Functional studies demonstrated that TCF7L2 specifically risk allele (T) of rs7903146 polymorphism was associated with impaired pancreatic β cell function through regulation of insulin production and secretion pathways [40
]. However, the exact molecular genetic mechanisms need yet to be determined. The rs7903146 variant showed an association with T2D, but no statistically significant interactions was observed between the genotype and BMI, HDL, LDL or TG levels. Studies have reported modulating factors on the effect of TCF7L2 variant such as lipid profile, nutrition and obesity status [41
]. Similarly, Hansson et al. found that allele- specific over expression of TCF7L2 in human pancreatic islets that may cause impaired insulin secretion was not altered by either insulin sensitivity or BMI [42
Interestingly, the TCF7L2 rs7903146 variant has been associated with decreased BMI and this variant polymorphism is thought to exert a greater effect on T2D risk in lean individuals compared to obese as speculated by Van Vlit-Ostaptchouk [25
]. Also, Hegalson et al. [24
] reported that the rs7903146 T allele, probably an ancestral and not causative variant, tags an unidentified functional variant lying outside the studied locus. It is challenging to study gene-environmental interaction effect on β cell function and genetic variant risk for T2D. Moreover, our group will conduct knowledge to confirm the association of this SNP with T2D in Egypt.