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Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk
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2012 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, Vol. 5, no 6, 656-665 p.Article in journal (Refereed) Published
Abstract [en]


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).


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.

Place, publisher, year, edition, pages
2012. Vol. 5, no 6, 656-665 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-188805DOI: 10.1161/CIRCGENETICS.112.963660ISI: 000312774800014PubMedID: 23152477OAI: oai:DiVA.org:uu-188805DiVA: diva2:579260
Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2013-02-04Bibliographically approved

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Syvänen, Ann-Christine
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Molecular MedicineScience for Life Laboratory, SciLifeLab
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