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

TitleAssociation of a fasting glucose genetic risk score with subclinical atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) study.
Publication TypeJournal Article
Year of Publication2011
AuthorsRasmussen-Torvik LJ, Li M, Kao WH, Couper D, Boerwinkle E, Bielinski SJ, Folsom AR, Pankow JS
JournalDiabetes
Volume60
Issue1
Pagination331-5
Date Published2011 Jan
ISSN1939-327X
KeywordsAfrican Continental Ancestry Group, Atherosclerosis, Blood Glucose, Carotid Arteries, European Continental Ancestry Group, Fasting, Female, Genome-Wide Association Study, Genotype, Humans, Hyperglycemia, Male, Middle Aged, Patient Selection, Phenotype, Polymorphism, Single Nucleotide, Risk Assessment, Tunica Intima, Tunica Media, Ultrasonography
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.

DOI10.2337/db10-0839
Alternate JournalDiabetes
PubMed ID21036910
PubMed Central IDPMC3012190
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
T32HL07779 / HL / NHLBI NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
T32 HL007779 / HL / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States