December 20th, 2010 
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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 principal 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.
The sample was drawn from the ARIC study and included7260 non-diabetic Caucasian individuals with IMT measurements and relevant genotyping. Components of the fasting glucose genetic risk score (FGGRS) were selected from a fasting glucose GWAS in ARIC. The score was created by combining five 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.
The FGGRS was significantly associated (p = .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.
The significant association of the fasting glucose genetic risk score with IMT suggests a possible a causal association of elevated fasting glucose with atherosclerosis although it may be that these loci influence IMT through non-glucose pathways.
Diabetes Journal publish ahead of print articles
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