Multi-ethnic genetic association study of carotid intima-media thickness using a targeted cardiovascular SNP microarray.
OBJECTIVE
Identification of subclinical atherosclerosis by ultrasonographic measurement of carotid intima-media thickness (IMT) is a validated tool, in conjunction with traditional risk factors, for clinical assessment of cardiovascular disease risk. IMT has also been recognized as a quantitative measure of cardiovascular disease progression in asymptomatic individuals, and many candidate gene association studies have attempted to identify genetic variants associated with interindividual differences in IMT with limited success. We sought to test the association between subclinical atherosclerosis measured by IMT and approximately 50,000 SNPs, densely mapping approximately 2100 genes found on the gene-centric Illumina cardiovascular disease beadchip in a multi-ethnic population-based sample.


METHODS
IMT was measured by B-mode ultrasound and DNA was collected from a population-based sample of South Asian (n=328), Chinese (n=302), and European Caucasian (n=268) participants. Genetic association was measured using multivariate linear regression including adjustment for covariates.


RESULTS
The most robust association across all models tested was observed for a SNP (rs3791398) in histone deacetylase 4 (HDAC4; P=1.8e-5 to P=3.6e-5), while another strong association signal was observed with natriuretic peptide receptor a/guanylate cyclase A (NPR1) (rs10082235, P=5.4e-5). Seven of 13 previously reported functional candidate genes contained a SNP that was marginally associated (0.01 < P < or = 0.05).


CONCLUSIONS
This initial multi-ethnic high-density association study of carotid IMT suggests some novel loci requiring further evaluation in follow-up studies.
Lanktree
Matthew B
MB
Robarts Research Institute and Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Hegele
Robert A
RA
Yusuf
Salim
S
Anand
Sonia S
SS
D000328:Adult; D000368:Aged; D044466:Asian People; D002339:Carotid Arteries / Q000000981:diagnostic imaging* / Q000473:pathology / Q000503:physiopathology; D016893:Carotid Stenosis / Q000000981:diagnostic imaging* / Q000208:ethnology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044469:Racial Groups; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012307:Risk Factors; D017539:Tunica Intima / Q000000981:diagnostic imaging* / Q000473:pathology; D014463:Ultrasonography; D044465:White People
D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A