title: Allele summation of diabetes risk genes predicts impaired glucose tolerance in female and obese individuals.
abstract: BACKGROUND
  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.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  The 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/m(2) 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.
  
  
  CONCLUSIONS
  We 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.
authors: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
authors: Katarzyna
authors: K
authors: Linder
authors: Robert
authors: R
authors: Wagner
authors: Erifili
authors: E
authors: Hatziagelaki
authors: Caroline
authors: C
authors: Ketterer
authors: Martin
authors: M
authors: Heni
authors: Fausto
authors: F
authors: Machicao
authors: Norbert
authors: N
authors: Stefan
authors: Harald
authors: H
authors: Staiger
authors: Hans-Ulrich
authors: HU
authors: Häring
authors: Andreas
authors: A
authors: Fritsche
mesh_terms: D000328:Adult; D000483:Alleles; D015331:Cohort Studies; D048909:Diabetes Complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D009765:Obesity / Q000150:complications* / Q000235:genetics*; D016017:Odds Ratio; D012307:Risk Factors