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

  1. Oluf Pedersen1,3,7
  1. 1Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics
  2. 2Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
  3. 3Steno Diabetes Center A/S, Gentofte, Denmark
  4. 4Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  5. 5Faculty of Medicine, Aalborg University, Aalborg, Denmark
  6. 6Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  7. 7Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark.
  1. Corresponding author: Ehm A. Andersson, ehm.andersson{at}sund.ku.dk.

Abstract

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.

Footnotes

  • Received March 3, 2013.
  • Accepted June 26, 2013.

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  1. Diabetes vol. 62 no. 10 3610-3617
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