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
- Ehm A. Andersson1⇑,
- Kristine H. Allin1,
- Camilla H. Sandholt1,
- Anders Borglykke2,
- Cathrine J. Lau2,
- Rasmus Ribel-Madsen1,
- Thomas Sparsø1,
- Johanne M. Justesen1,
- Marie N. Harder1,
- Marit E. Jørgensen3,
- Torben Jørgensen2,4,5,
- Torben Hansen1,6 and
- Oluf Pedersen1,3,7
- 1Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics
- 2Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
- 3Steno Diabetes Center A/S, Gentofte, Denmark
- 4Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- 5Faculty of Medicine, Aalborg University, Aalborg, Denmark
- 6Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- 7Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark.
- Corresponding author: Ehm A. Andersson, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0362/-/DC1.
- Received March 3, 2013.
- Accepted June 26, 2013.
- © 2013 by the American Diabetes Association.
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