The rs11705701 G>A Polymorphism of IGF2BP2 is Associated With IGF2BP2 mRNA and Protein Levels in the Visceral Adipose Tissue - A Link to Type 2 Diabetes Susceptibility

Abstract

■ AbstractBACKGROUND: Insulin-like growth factor 2 mRNAbinding protein 2 (IGF2BP2) regulates translation of IGF2, a growth factor that plays a key role in controlling fetal growth and organogenesis including adipogenesis and pancreatic development. In Caucasians, the rs4402960 G>T polymorphism of IGF2BP2 has been shown to predispose to type 2 diabetes (T2D) in multiple populations. In this study, we tested whether rs4402960 G>T and rs11705701 G>A contribute to the development of T2D in a Russian population. METHODS: Both markers were genotyped in Russian diabetic (n = 1,470) and non-diabetic patients (n = 1,447) using a Taqman allele discrimination assay. The odds ratio (OR) for the risk of developing T2D was calculated using logistic regression assuming an additive genetic model adjusted for age, sex, HbA1c, hypertension, obesity, and body mass index (BMI). Multivariate linear regression analyses were used to test genotype-phenotype correlations, and adjusted for age, sex, hypertension, obesity, and BMI. Expression of IGF2BP2 in the visceral adipose tissue was quantified using real-time PCR. The content of IGF2BP2 protein and both its isoforms (p58 and p66) in the adipose tissue was measured using Western blot analysis. RESULTS: There was no significant association between rs4402960 and T2D. Whereas, allele A of rs11705701 was associated with higher T2D risk (OR = 1.19, p < 0.001). Diabetic and non-diabetic carriers of genotype TT (rs4402960) had significantly increased HOMA-IR (p = 0.033 and p = 0.031, respectively). Nondiabetic patients homozygous for AA (rs11705701) had higher HOMA-IR (p = 0.04), lower HOMA-β (p = 0.012), and reduced 2-h insulin levels (p = 0.016). Non-obese individuals (diabetic and non-diabetic) homozygous for either AA (rs11705701) or TT (rs4402960) had higher levels of IGF2BP2 mRNA in the adipose tissue than other IGF2BP2 variants. Also, allele A of rs11705701 was associated with reduced amounts of the short isoform (p58) and increased levels of the long isoform (p66) of the IGF2BP2 protein in adipose tissue of non-obese diabetic and non-diabetic subjects. CONCLUSIONS: IGF2BP2 genetic variants contribute to insulin resistance in Russian T2D patients. The short protein isoform p58 of IGF2BP2 is likely to play an antidiabetogenic role in non-obese individuals.

Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population 在突尼斯人群中，CDKAL1 rs7756992与IGF2BP2 rs4402960的多态性对2型糖尿病、糖尿病并发症、肥胖风险以及高血压的影响

“…Furthermore, the IGF2BP2 rs4402960 was not found to be associated with hypertension status, diabetic nephropathy and cardiovascular risk. This is in agreement with previous studies that have described the lack of association of rs4402960 with hypertension, diabetic nephropathy and cardiovascular risk . Otherwise, our study failed to replicate the association of rs7756992 of CDKAL1 with T2DM in the Tunisian population.…”

IGF2BP2 Polymorphisms Are Associated with Clinical Characteristics and Development of Oral Cancer

“…Rao et al [10] and Wu et al [11] demonstrated that the IGF2BP2 polymorphism is associated with type 2 diabetes (T2D) and obesity. Chistiakov et al demonstrated that the IGF2BP2 rs11705701 A allele is associated with higher T2D risk [12]. Chen et al suggested that the IGF2BP2 rs4402960 polymorphism T allele may be a protective factor for decreased susceptibility to NSCLC among women [13].…”

<p>Type 2 Diabetes-Associated Genetic Polymorphisms as Potential Disease Predictors</p>

“…This is also known as the interplay between IGF2BP2 and obesity with T2DM. 126 In keeping with this hypothesis, Chistiakov and co-workers, 127 reported that patients with T2DM have a more than twofold increase in IGF2BP2 expression levels in adipose tissue compared with healthy individuals. Associations between IGF2BP2 and visceral/abdominal total fat were also demonstrated in Mexican Americans and Canadian Caucasians, proposing a possible role of IGF2BP2 in insulin resistance.…”