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 -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 -cell function. Individuals who gain weight may be more susceptible to the cumulative impact of type 2 diabetes risk variants on fasting plasma glucose.
Diabetes, 2013, Vol 62, Issue 10, p. 3610-3617
Adult; Blood Glucose; Body Mass Index; Denmark; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Glucose Tolerance Test; Hemoglobin A, Glycosylated; Humans; Incidence; Insulin-Secreting Cells; Life Style; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Time Factors; INTER99 POLYMORPHISMS POPULATION PREVENTION PREDICTION AGE; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't