Association of a Fasting Glucose Genetic Risk Score With Subclinical Atherosclerosis

The Atherosclerosis Risk in Communities (ARIC) Study

  1. James S. Pankow6
  1. 1Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;
  2. 2Division of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland;
  3. 3Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, North Carolina;
  4. 4Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas;
  5. 5Division of Epidemiology, Mayo Clinic, Rochester, Minnesota;
  6. 6Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota.
  1. Corresponding author: Laura J. Rasmussen-Torvik, ljrtorvik{at}northwestern.edu.

Abstract

OBJECTIVE Elevated fasting glucose level is associated with increased carotid intima-media thickness (IMT), a measure of subclinical atherosclerosis. It is unclear if this association is causal. Using the principle of Mendelian randomization, we sought to explore the causal association between circulating glucose and IMT by examining the association of a genetic risk score with IMT.

RESEARCH DESIGN AND METHODS The sample was drawn from the Atherosclerosis Risk in Communities (ARIC) study and included 7,260 nondiabetic Caucasian individuals with IMT measurements and relevant genotyping. Components of the fasting glucose genetic risk score (FGGRS) were selected from a fasting glucose genome-wide association study in ARIC. The score was created by combining five single nucleotide polymorphisms (SNPs) (rs780094 [GCKR], rs560887 [G6PC2], rs4607517 [GCK], rs13266634 [SLC30A8], and rs10830963 [MTNR1B]) and weighting each SNP by its strength of association with fasting glucose. IMT was measured through bilateral carotid ultrasound. Mean IMT was regressed on the FGGRS and on the component SNPs, individually.

RESULTS The FGGRS was significantly associated (P = 0.009) with mean IMT. The difference in IMT predicted by a 1 SD increment in the FGGRS (0.0048 mm) was not clinically relevant but was larger than would have been predicted based on observed associations between the FFGRS, fasting glucose, and IMT. Additional adjustment for baseline measured glucose in regression models attenuated the association by about one third.

CONCLUSIONS The significant association of the FGGRS with IMT suggests a possible causal association of elevated fasting glucose with atherosclerosis, although it may be that these loci influence IMT through nonglucose pathways.

Footnotes

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  • Received June 16, 2010.
  • Accepted October 18, 2010.

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