Genetic Risk Score of 46 Type 2 Diabetes Risk Variants Associates With Changes in Plasma Glucose and Estimates of Pancreatic β-Cell Function Over 5 Years of Follow-Up

Abstract

More than 40 genetic risk variants for type 2 diabetes have been validated. We aimed to test whether a genetic risk score associates with the incidence of type 2 diabetes and with 5-year changes in glycemic traits and whether the effects were modulated by changes in BMI and lifestyle. The Inter99 study population was genotyped for 46 variants, and a genetic risk score was constructed. During a median follow-up of 11 years, 327 of 5,850 individuals developed diabetes. Physical examinations and oral glucose tolerance tests were performed at baseline and after 5 years (n = 3,727). The risk of incident type 2 diabetes was increased with a hazard ratio of 1.06 (95% CI 1.03–1.08) per risk allele. While the population in general had improved glucose regulation during the 5-year follow-up period, each additional allele in the genetic risk score was associated with a relative increase in fasting, 30-min, and 120-min plasma glucose values and a relative decrease in measures of β-cell function over the 5-year period, whereas indices of insulin sensitivity were unaffected. The effect of the genetic risk score on 5-year changes in fasting plasma glucose was stronger in individuals who increased their BMI. In conclusion, a genetic risk score based on 46 variants associated strongly with incident type 2 diabetes and 5-year changes in plasma glucose and β-cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose.

Role of Conventional Childhood Risk Factors Versus Genetic Risk in the Development of Type 2 Diabetes and Impaired Fasting Glucose in Adulthood: The Cardiovascular Risk in Young Finns Study

“…In addition, the SNP rs3132524 at POU5F1/TCF19 was not available among genotyped or imputed SNPs, and a proxy SNP, rs3130501, in high linkage equilibrium was used instead (r 2 = 1.0). We replicated all analyses using another previously published weighted genotype score comprising 46 SNPs found to be associated with type 2 diabetes in populations of European origin (19). In general, the salient results were similar with this score; however, it showed slightly stronger associations with the outcomes and better prediction value possibly because it includes fewer variants with very small effect sizes.…”

A novel polymorphism in protein kinase AMP‐activated catalytic subunit alpha 2 (PRKAA2) is associated with type 2 diabetes in the Han Chinese population

“…Type 2 diabetes mellitus is characterized by elevated FPG accompanied by peripheral insulin resistance and is highly prevalent worldwide . In recent decades, genetic studies of diabetes have become a hot topic, and many susceptible genetic loci related to T2DM have been identified . It is known that AMPK is a master regulator of cellular and whole‐body energy metabolism, and this energy‐sensing kinase is activated by numerous physiological and pharmacological stimuli, including muscle contraction, calorie restriction, biguanides, thiazolidinediones, and adipokines, when energy levels are low .…”

Gene‐diet quality interactions on haemoglobin A1c and type 2 diabetes risk: The Airwave Health Monitoring Study

“…1 The aetiology of T2D is multifactorial, with obesity, poor diet quality, physical inactivity and genetic factors identified as key risk factors. 3,7,8 To increase the predictability, SNPs are combined into genetic risk scores. Single nucleotide polymorphisms (SNP) have small-to-moderate effects and account for only a small proportion of the heritability of T2D.…”