A Genetic Risk Score Improves the Prediction of Type 2 Diabetes Mellitus in Mexican Youths but Has Lower Predictive Utility Compared With Non-Genetic Factors

Abstract

BackgroundType 2 diabetes (T2D) is a multifactorial disease caused by a complex interplay between environmental risk factors and genetic predisposition. To date, a total of 10 single nucleotide polymorphism (SNPs) have been associated with pediatric-onset T2D in Mexicans, with a small individual effect size. A genetic risk score (GRS) that combines these SNPs could serve as a predictor of the risk for pediatric-onset T2D.ObjectiveTo assess the clinical utility of a GRS that combines 10 SNPs to improve risk prediction of pediatric-onset T2D in Mexicans.MethodsThis case-control study included 97 individuals with pediatric-onset T2D and 84 controls below 18 years old without T2D. Information regarding family history of T2D, demographics, perinatal risk factors, anthropometric measurements, biochemical variables, lifestyle, and fitness scores were then obtained. Moreover, 10 single nucleotide polymorphisms (SNPs) previously associated with pediatric-onset T2D in Mexicans were genotyped. The GRS was calculated by summing the 10 risk alleles. Pediatric-onset T2D risk variance was assessed using multivariable logistic regression models and the area under the receiver operating characteristic curve (AUC).ResultsThe body mass index Z-score (Z-BMI) [odds ratio (OR) = 1.7; p = 0.009] and maternal history of T2D (OR = 7.1; p < 0.001) were found to be independently associated with pediatric-onset T2D. No association with other clinical risk factors was observed. The GRS also showed a significant association with pediatric-onset T2D (OR = 1.3 per risk allele; p = 0.006). The GRS, clinical risk factors, and GRS plus clinical risk factors had an AUC of 0.66 (95% CI 0.56–0.75), 0.72 (95% CI 0.62–0.81), and 0.78 (95% CI 0.70–0.87), respectively (p < 0.01).ConclusionThe GRS based on 10 SNPs was associated with pediatric-onset T2D in Mexicans and improved its prediction with modest significance. However, clinical factors, such the Z-BMI and family history of T2D, continue to have the highest predictive utility in this population.

Early Prediction for Prediabetes and Type 2 Diabetes Using the Genetic Risk Score and Oxidative Stress Score

“…The present study demonstrated that a GRS based on six diabetes-related SNPs greatly improved the risk prediction of prediabetes and T2DM compared to a single SNP after adjusting for clinical risk factors. This result is in line with the findings of other studies, wherein the GRS evaluated the cumulative effects of genetic factors [47,48]. While a single GRS model (Model 3) showed a lower predictive ability for prediabetes and T2DM compared to the single models of OSS (Model 2) and BMI (Model 1), combining the three factors (Model 6) prompted a modest increase in the current study.…”

“…While a single GRS model (Model 3) showed a lower predictive ability for prediabetes and T2DM compared to the single models of OSS (Model 2) and BMI (Model 1), combining the three factors (Model 6) prompted a modest increase in the current study. Miranda-Lora et al [47] suggested that the GRS alone or in combination with T2DM clinical factors increased the power of risk prediction models. Conclusively, the GRS will be helpful for future practical use in improving the prediction of prediabetes and T2DM, and additional susceptibility SNPs will contribute to further strengthening risk prediction models.…”

Cardiorespiratory Fitness and Physical Activity in Pediatric Diabetes

“…After all the conflicts were resolved, 130 articles were included for the full-article screen, and 54 studies were included for data extraction (eFigure 1 in Supplement 1). Details for each individual study are presented in eTables 2 to 5 in Supplement 1. For all 4 meta-analyses, cases and controls were similar in age and sex (Table 1), with limited data available for race and ethnicity across all studies (eTables 6 and 7 in Supplement 1).…”

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

“…34 Genetic risk scores (GRSs), which allow for the assessment of the aggregate genetic risk of a given trait, have demonstrated association of GRSs constructed from variants associated in adults with glycemic traits and/or T2D risk with fasting glucose and measures of b-cell function, [35][36][37] as well as measures of insulin resistance 35,36,38 in youth. Two studies have examined the ability of GRSs to identify children at risk of progressing to T2D; even though the scores were shown to be associated with T2D risk, 36,39 in one of the studies clinical factors such as body mass index (BMI) and family history of T2D had higher predictive utility. 34…”