Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk

Gertow, K. et al. (2012) Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk. Circulation: Cardiovascular Genetics, 5(6), pp. 656-665. (doi:10.1161/CIRCGENETICS.112.963660) (PMID:2315247)

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Abstract

Background—Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results—To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75×10−7 for IMTmax; replication P=7.24×10−6 for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77–0.90], P=6.53×10−6, n=13 591; and 0.95 [0.92–0.98], P=1.83×10−4, n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126–138). Conclusions—This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Strawbridge, Dr Rona
Authors: Gertow, K., Sennblad, B., Strawbridge, R.J., Ohrvik, J., Zabaneh, D., Shah, S., Veglia, F., Fava, C., Kavousi, M., McLachlan, S., Kivimaki, M., Bolton, J. L., Folkersen, L., Gigante, B., Leander, K., Vikstrom, M., Larsson, M., Silveira, A., Deanfield, J., Voight, B. F., Fontanillas, P., Sabater-Lleal, M., Colombo, G. I., Kumari, M., Langenberg, C., Wareham, N. J., Uitterlinden, A. G., Gabrielsen, A., Hedin, U., Franco-Cereceda, A., Nyyssonen, K., Rauramaa, R., Tuomainen, T.-P., Savonen, K., Smit, A. J., Giral, P., Mannarino, E., Robertson, C. M., Talmud, P. J., Hedblad, B., Hofman, A., Erdmann, J., Reilly, M. P., O'Donnell, C. J., Farrall, M., Clarke, R., Franzosi, M. G., Seedorf, U., Syvanen, A.-C., Hansson, G. K., Eriksson, P., Samani, N. J., Watkins, H., Price, J. F., Hingorani, A. D., Melander, O., Witteman, J. C. M., Baldassarre, D., Tremoli, E., de Faire, U., Humphries, S. E., and Hamsten, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Circulation: Cardiovascular Genetics
Publisher:American Heart Association
ISSN:1942-325X
ISSN (Online):1942-3268
Published Online:14 November 2012

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