Abstract
IntroductionSingle nucleotide polymorphisms (SNPs) in approximately 40 genes have been associated with an increased risk for type 2 diabetes (T2D) in genome-wide association studies. It is not known whether a similar genetic impact on the risk of prediabetes (impaired glucose tolerance [IGT] or impaired fasting glycemia [IFG]) exists.MethodsIn our cohort of 1442 non-diabetic subjects of European origin (normal glucose tolerance [NGT] n = 1046, isolated IFG n = 142, isolated IGT n = 140, IFG+IGT n = 114), an impact on glucose homeostasis has been shown for 9 SNPs in previous studies in this specific cohort. We analyzed these SNPs (within or in the vicinity of the genes TCF7L2, KCNJ11, HHEX, SLC30A8, WFS1, KCNQ1, MTNR1B, FTO, PPARG) for association with prediabetes.ResultsThe genetic risk load was significantly associated with the risk for IGT (p = 0.0006) in a model including gender, age, BMI and insulin sensitivity. To further evaluate potential confounding effects, we stratified the population on gender, BMI and insulin sensitivity. The association of the risk score with IGT was present in female participants (p = 0.008), but not in male participants. The risk score was significantly associated with IGT (p = 0.008) in subjects with a body mass index higher than 30 kg/m2 but not in non-obese individuals. Furthermore, only in insulin resistant subjects a significant association between the genetic load and the risk for IGT (p = 0.01) was found.DiscussionWe found that T2D genetic risk alleles cause an increased risk for IGT. This effect was not present in male, lean and insulin sensitive subjects, suggesting a protective role of beneficial environmental factors on the genetic risk.
Highlights
Single nucleotide polymorphisms (SNPs) in approximately 40 genes have been associated with an increased risk for type 2 diabetes (T2D) in genome-wide association studies
Seeking to answer the question whether T2D-related genetic risk determines risk for Impaired glucose tolerance (IGT) or prediabetes, we summed up weighted risk alleles from 9 established diabetes-risk single nucleotide polymorphisms (SNPs) for each of the 1442 non-diabetic subjects, and ascertained the clinical atrisk status from an Oral glucose tolerance tests (OGTT) according to recommendations of the ADA
It is worthwhile to pose this question because the genetic risk for impairing glycemia may become relevant only when impaired glucose tolerance progresses to diabetes, but not when normal glucose tolerance progresses to impaired glucose tolerance
Summary
Single nucleotide polymorphisms (SNPs) in approximately 40 genes have been associated with an increased risk for type 2 diabetes (T2D) in genome-wide association studies. It is not known whether a similar genetic impact on the risk of prediabetes (impaired glucose tolerance [IGT] or impaired fasting glycemia [IFG]) exists. Most of the approximately 40 known genetic variants conferring increased risk for T2D have been discovered by genome-wide association studies (GWAS) [4]. With this method, associations between genomic variants and diabetes prevalence or quantitative glycemic traits like increased fasting plasma glucose or 2-hour plasma glucose can be established [5]. Most discovered diabetes-risk variants have a predominant effect on insulin secretion, and there are only few that markedly influence body adiposity and insulin sensitivity [2]
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