Testing the Utility of Polygenic Risk Scores for Type 2 Diabetes and Obesity in Predicting Metabolic Changes in a Prediabetic Population: An Observational Study

Abstract

Prediabetes is an intermediate state of hyperglycemia during which glycemic parameters are above normal levels but below the T2D threshold. T2D and its precursor prediabetes affect 6.28% and 7.3% of the world’s population, respectively. The main objective of this paper was to create and compare two polygenic risk scores (PRSs) versus changes over time (Δ) in metabolic parameters related to prediabetes and metabolic complications. The genetics of 446 prediabetic patients from the Polish Registry of Diabetes cohort were investigated. Seventeen metabolic parameters were measured and compared at baseline and after five years using statistical analysis. Subsequently, genetic polymorphisms present in patients were determined to build a T2D PRS (68 SNPs) and an obesity PRS (21 SNPs). Finally, the association among the two PRSs and the Δ of the metabolic traits was assessed. After a multiple linear regression with adjustment for age, sex, and BMI at a nominal significance of (p < 0.05) and adjustment for multiple testing, the T2D PRS was found to be positively associated with Δ fat mass (FM) (p = 0.025). The obesity PRS was positively associated with Δ FM (p = 0.023) and Δ 2 h glucose (p = 0.034). The comparison of genotype frequencies showed that AA genotype carriers of rs10838738 were significantly higher in Δ 2 h glucose and in Δ 2 h insulin. Our findings suggest that prediabetic individuals with a higher risk of developing T2D experience increased Δ FM, and those with a higher risk of obesity experience increased Δ FM and Δ two-hour postprandial glucose. The associations found in this research could be a powerful tool for identifying prediabetic individuals with an increased risk of developing T2D and obesity.

Keywords: genomics; obesity; polygenic risk scores; prediabetes; prediction; type 2 diabetes.

Figure 1

Distribution of polygenic risk scores (PRSs) for T2D (A) and obesity (B) across 446 prediabetic individuals in PolRed.

Figure 2

Association of genotype rs10838738 with (A) Δ 2 h glucose (mg/dL) and (B) Δ 2 h insulin (uU/mL). Genotype rs2260000 with (C) Δ FM (kg) and (D) Δ VF (cm3). Genotype rs7647305 with (E) Δ 2 h glucose (mg/dL) and (F) Δ IPAQ (min/week). Genotype rs29941 with (G) Δ 2 h glucose (mg/dL).