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Impact of Genetic Factors on the Age of Onset for Type 2 Diabetes Mellitus in Addition to the Conventional Risk Factors.

ABSTRACT: It is generally accepted that the early detection of type 2 diabetes mellitus (T2DM) is important to prevent the development of complications and comorbidities, as well as premature death. The onset of type 2 diabetes mellitus results from a complex interplay between genetic, environmental, and lifestyle risk factors. Our study aims to evaluate the joint effect of T2DM associated single nucleotide polymorphisms (SNPs) on the age of onset for T2DM in combination with conventional risk factors (such as sex, body mass index (BMI), and TG/HDL-C ratio) in the Hungarian population. This study includes 881 T2DM patients (Case population) and 1415 samples from the Hungarian general population (HG). Twenty-three SNPs were tested on how they are associated with the age of onset for T2DM in the Case population and 12 of them with a certified effect on the age of T2DM onset were chosen for an optimized genetic risk score (GRS) analysis. Testing the validity of the GRS model developed was carried out on the HG population. The GRS showed a significant association with the age of onset for T2DM (? = -0.454, p = 0.001) in the Case population, as well as among T2DM patients in the HG one (? = -0.999, p = 0.003) in the replication study. The higher the GRS, the earlier was the T2DM onset. Individuals with more than eight risk alleles will presumably be diabetic six and a half years earlier than those with less than four risk alleles. Our results suggest that there is a considerable genetic predisposition for the early onset of T2DM; therefore, in addition to conventional risk factors, GRS can be used as a tool for estimating the risk of the earlier onset of T2DM and stratifying populations at risk in order to define preventive interventions.

SUBMITTER: Piko P

PROVIDER: S-EPMC7822179 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Impact of Genetic Factors on the Age of Onset for Type 2 Diabetes Mellitus in Addition to the Conventional Risk Factors.

Piko Peter P Werissa Nardos Abebe NA Fiatal Szilvia S Sandor Janos J Adany Roza R

Journal of personalized medicine 20201222 1

It is generally accepted that the early detection of type 2 diabetes mellitus (T2DM) is important to prevent the development of complications and comorbidities, as well as premature death. The onset of type 2 diabetes mellitus results from a complex interplay between genetic, environmental, and lifestyle risk factors. Our study aims to evaluate the joint effect of T2DM associated single nucleotide polymorphisms (SNPs) on the age of onset for T2DM in combination with conventional risk factors (su ...[more]

PMID: 33375163

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Project description:PurposeNew-onset diabetes after transplantation (NODAT) is a major complication after kidney transplantation. The risk factors for NODAT include the use of calcineurin inhibitors as part of the immunosuppressive regimen, among which tacrolimus has the most pronounced diabetogenic effect. Both NODAT and type 2 diabetes mellitus (T2DM) share several risk factors. Recent studies have identified a number of common genetic variants associated with increased risk of T2DM. Here we report the results of our study on the potential effect of single nucleotide polymorphisms (SNPs) previously associated with T2DM on the risk of NODAT in kidney transplant patients medicated with tacrolimus.MethodsSeven SNPs in six genes known to increase the risk of T2DM in Caucasians were genotyped by means of TaqMan assays in 235 kidney transplant patients medicated with tacrolimus: rs4402960 and rs1470579 in IGF2BP2; rs1111875 in HHEX; rs10811661 upstream of CDKN2A/B; rs13266634 in SLC30A8; rs1801282 in PPARG; rs5215 in KCNJ11. The TCF7L2 rs7903146 SNP was also included in the multivariate analysis.ResultsNone of the analyzed SNPs was significantly associated with the risk of NODAT. However, the IGF2BP2 rs4402960 T allele was present significantly more frequently among patients diagnosed with NODAT more than 2 weeks after transplantation (p?=?0.048). Mean (± standard deviation) number of the analyzed alleles tended to be lower in patients without NODAT (6.19?±?1.71) than in NODAT patients (6.58?±?1.1.95; p?=?0.09) and significantly lower compared to late-onset NODAT patients (7.03?±?1.88; p?=?0.018). Multivariate analysis confirmed the significance of 'diabetogenic' allele number in late-onset NODAT development [odds ratio (OR) 1.37, 95 % confidence interval (CI) 1.05-1.78; p?=?0.017]. Additionally, individuals carrying >7 of the analyzed 'diabetogenic' alleles were at a significantly higher risk of NODAT (OR 2.17, 95 % CI 1.18-3.99; p?=?0.015).ConclusionsComplex analysis of genotypes increasing the risk of diabetes may lead to the identification of NODAT susceptibility predictors.

Project description:BackgroundAlthough cumulating evidence has suggested that early-onset type 2 diabetes mellitus (T2DM) conferred on patients a broader tendency for complications beyond vascular ones, a comprehensive analysis of patterns of complications across all relevant systems is currently lacking.MethodWe prospectively studied 1 777 early-onset (age at diagnosis ≤ 45 years) and 35 889 late-onset (>45 years) T2DM patients with matched unexposed individuals from the UK Biobank. Diabetes-specific and -related complications were examined using phenome-wide association analysis, with patterns identified by comorbidity network analysis. We also evaluated the effect of lifestyle modifications and glycemic control on complication development.ResultsThe median follow-up times for early-onset and late-onset T2DM patients were 17.83 and 9.39 years, respectively. Compared to late-onset T2DM patients, patients with early-onset T2DM faced a significantly higher relative risk of developing subsequent complications that primarily affected sense organs [hazard ratio (HR) 3.46 vs. 1.72], the endocrine/metabolic system (HR 3.08 vs. 2.01), and the neurological system (HR 2.70 vs. 1.81). Despite large similarities in comorbidity patterns, a more complex and well-connected network was observed for early-onset T2DM. Furthermore, while patients with early-onset T2DM got fewer benefits (12.67% reduction in pooled HR for all studied complications) through fair glycemic control (median HbA1c ≤ 53 mmol/mol) compared to late-onset T2DM patients (18.01% reduction), they seemed to benefit more from favorable lifestyles, including weight control, healthy diet, and adequate physical activity.ConclusionsOur analyses reveal that early-onset T2DM is an aggressive disease resulting in more complex complication networks than late-onset T2DM. Aggressive glucose-lowering intervention, complemented by lifestyle modifications, are feasible strategies for controlling early-onset T2DM-related complications.

Dataset Information

Impact of Genetic Factors on the Age of Onset for Type 2 Diabetes Mellitus in Addition to the Conventional Risk Factors.

Publications

Impact of Genetic Factors on the Age of Onset for Type 2 Diabetes Mellitus in Addition to the Conventional Risk Factors.

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