IGF1 and PPARG polymorphisms are associated with reduced estimated glomerular filtration rate in a cohort of children and adolescents with type 1 diabetes.

INTRODUCTION: Several genetic loci have been associated with diabetic nephropathy; however, the underlying genetic mechanisms are still poorly understood, with no robust candidate genes identified yet. AIM: We aimed to determine whether two polymorphisms, previously associated with renal decline, influence kidney impairment evaluating their association with markers of renal function in a pediatric population with type 1 diabetes (T1D). MATERIAL AND METHODS: Renal function was evaluated by glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) in a cohort of pediatric subjects with T1D (n = 278). Risk factors for diabetes complications (diabetes duration, blood pressure, HbA1c) were assessed. The IGF1 rs35767 and PPARG rs1801282 SNPs were genotyped by TaqMan RT-PCR system. An additive genetic interaction was calculated. Association analysis between markers of renal function and both SNPs or their additive interaction were performed. RESULTS: Both SNPs showed a significant association with eGFR: the A allele of rs35767 or the C allele of rs1801282 were associated to reduced eGFR compared to G alleles. Multivariate regression analysis adjusted for age, sex, z-BMI, T1D duration, blood pressure and Hba1c values showed that the additive genetic interaction was independently associated with lower eGFR (ß = -3.59 [-6.52 to -0.66], p = 0.017). No associations were detected between SNPs, their additive interaction and ACR. CONCLUSIONS: These results provide new insight into the genetic predisposition to renal dysfunction, showing that two polymorphisms in IGF1 and PPARG genes can lead to a reduction in renal filtration rate leading these patients to be exposed to a higher risk of early renal complications.

Cardiovascular Risk Factors in Children and Adolescents with Type 1 Diabetes Mellitus: The Role of Insulin Resistance and Associated Genetic Variants.

INTRODUCTION: Type 1 diabetes (T1D) is associated with an increased risk of cardiovascular disease. Insulin resistance is an important cardiovascular risk factor (CVRF), also in subjects with T1D, but the influence of the genetic predisposition of insulin resistance on cardiovascular risk is still unknown in T1D. We aimed to determine whether a genetic score composed of six variants, previously associated with insulin resistance and type 2 diabetes (T2D) risk, associates with insulin sensitivity and known CVRFs in children and adolescents with T1D. MATERIALS AND METHODS: 330 children and adolescents (174 males; mean age 15.7 ± 3.5 years) with T1D were genotyped for the following genetic variants: rs1801278 (IRS1), rs1044498 (ENPP1), rs2295490 (TRIB3), rs1801282 (PPARG), rs780094 (GCKR), and rs35767 (IGF1). An additive genetic risk score (GRS) and cardiovascular risk score (CVRS) were calculated. Anthropometric, glycemic control, insulin sensitivity, blood pressure, and biochemical parameters were assessed. Multivariate regression between evaluated phenotypes and GRS was performed. RESULTS: We found a significant association between the GRS and estimated insulin sensitivity (ß = -0.027 [-0.040 to -0.013], R2 = 0.86, p≤ 0.001), diastolic blood pressure (ß = 0.68 [0.08-1.27], R2 = 0.20, p = 0.026), triglycerides (ß = 4.26 [1.74-6.77], R2 = 0.13, p = 0.001), waist to height ratio (ß = 0.003 [0.001-0.006], R2 = 0.75, p = 0.010), non-HDL-cholesterol (ß = 3.63 [1.39-5.87], R2 = 0.12, p = 0.002), and CVRS (ß = 0.063 [0.008-0.118], R2 = 0.19, p = 0.025), independent of age, sex, BMI, pubertal stage, diabetes duration, glycated hemoglobin, type of treatment, and total insulin requirement. The addition of the GRS to established clinical risk factors significantly improved the discriminatory capability of the regression model for predicting subjects with more CVRFs (C-statistic 0.89 [95% CI: 0.84-0.95] versus 0.83 (0.73-0.93); p = 0.037). CONCLUSIONS: Insulin resistance and T2D risk-associated genetic variants influence insulin sensitivity and known CVRFs in children and adolescents with T1D.