PT - JOURNAL ARTICLE AU - Andersson, Ehm A. AU - Allin, Kristine H. AU - Sandholt, Camilla H. AU - Borglykke, Anders AU - Lau, Cathrine J. AU - Ribel-Madsen, Rasmus AU - Sparsø, Thomas AU - Justesen, Johanne M. AU - Harder, Marie N. AU - Jørgensen, Marit E. AU - Jørgensen, Torben AU - Hansen, Torben AU - Pedersen, Oluf TI - 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 AID - 10.2337/db13-0362 DP - 2013 Oct 01 TA - Diabetes PG - 3610--3617 VI - 62 IP - 10 4099 - http://diabetes.diabetesjournals.org/content/62/10/3610.short 4100 - http://diabetes.diabetesjournals.org/content/62/10/3610.full SO - Diabetes2013 Oct 01; 62 AB - 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.