Association of a fasting glucose genetic risk score with subclinical atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) study

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.Elevated fasting glucose level is associated with increased carotid intima-media thickness (IMT) (1,2), a measure of subclinical atherosclerosis. However, it is still unclear if this relation is causal, due to unmeasured confounding by other cardiovascular risk factors, or due to the metabolic derangements of diabetes—a disease defined by fasting glucose level.Several recent fasting glucose genome-wide association studies (GWAS) (3–5) and a large GWAS meta-analysis (6) have identified multiple genetic variants with strong associations to fasting plasma glucose level. A recent GWAS in the Atherosclerosis Risk in Communities (ARIC) study found five variants significantly associated with fasting glucose after correction for genome-wide testing (7). Consistent associations for all five of the variants have been reported in other fasting glucose GWAS (6). We demonstrated that these variants are much more strongly associated with fasting glucose in the normal or prediabetic range than in the diabetic range (7).The discovery of genetic variants reproducibly associated with fasting glucose provides the opportunity to investigate a causal association between fasting glucose and cardiovascular disease (CVD) using the theory of Mendelian randomization. Because of random assortment of alleles at the time of gamete formation, genetic variants should not be associated with known and unknown confounders in association analyses. Genetic variants can also be measured very accurately and are thus subject to little measurement error. Finally, genetic variants are also not susceptible to issues of reverse causality (8). Therefore, the proxy use of single nucleotide polymorphisms (SNPs) significantly associated with a trait instead of the trait itself in association analyses can help to explore a causal association between a trait and disease (9). This technique was recently used in a meta-analysis to examine the causal relationship of C-reactive protein to heart disease (10). In this paper, we applied principles of Mendelian randomization to explore whether there is a causal relation between fasting glucose in the nondiabetic range and subclinical atherosclerosis. In order to reduce problems with multiple testing, to create a genetic variable that accounted for a substantive amount of variation in fasting glucose, and to attempt to account for pleiotropic effects of individual SNPs, a composite genetic risk score was used. However, Mendelian randomization results from single SNPs associated with fasting glucose are also presented in the online appendix available at http://diabetes.diabetesjournals.org/cgi/content/full/db10-0839/DC1.