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: -In order to identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3,430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE study. Segment-specific IMT measurements of common carotid (CC), bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analysed. A replication stage investigating 42 single nucleotide polymorphisms (SNPs) for association with CC-IMT was undertaken in five independent European cohorts (total n=11,590). A locus on chromosome 16 (lead SNP rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple-testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMT(max); replication P=7.24x10(-6) for CC-IMT; 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 (CAD) risk in two case-control studies of subjects with European ancestry (odds ratio [95%CI] 0.83 [0.77-0.90], P=6.53x10(-6); n=13,591, and 0.95 [0.92-0.98], P=1.83x10(-4), n=82,297, respectively). Queries of human biobank datasets (n=126-138) revealed associations of rs4888378 with nearby gene expression in vascular tissues. CONCLUSIONS: -This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and CAD risk in individuals of European descent.
Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk / K. Gertow, B. Sennblad, R.J. Strawbridge, J. Ohrvik, D. Zabaneh, S. Shah, F. Veglia, C. Fava, M. Kavousi, S. Mclachlan, M. Kivimäki, J.L. Bolton, L. Folkersen, B. Gigante, K. Leander, M. Vikström, M. Larsson, A. Silveira, J. Deanfield, B.F. Voight, P. Fontanillas, M. Sabater Lleal, G.I. Colombo, M. Kumari, C. Langenberg, N.J. Wareham, A.G. Uitterlinden, A. Gabrielsen, U. Hedin, A. Franco Cereceda, K. Nyyssönen, R. Rauramaa, T. Tuomainen, K. Savonen, A.J. Smit, P. Giral, E. Mannarino, C.M. Robertson, P.J. Talmud, B. Hedblad, A. Hofman, J. Erdmann, M.P. Reilly, C.J. O'Donnell, M. Farrall, R. Clarke, M.G. Franzosi, U. Seedorf, A. Syvänen, G.K. Hansson, P. Eriksson, N.J. Samani, H. Watkins, J.F. Price, A.D. Hingorani, O. Melander, J.C.M. Witteman, D. Baldassarre, E. Tremoli, U. de Faire, S.E. Humphries, A. Hamsten. - In: CIRCULATION, CARDIOVASCULAR GENETICS. - ISSN 1942-325X. - 5:6(2012), pp. 656-665. [10.1161/CIRCGENETICS.112.963660]
Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk
D. Baldassarre;E. Tremoli;
2012
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: -In order to identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3,430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE study. Segment-specific IMT measurements of common carotid (CC), bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analysed. A replication stage investigating 42 single nucleotide polymorphisms (SNPs) for association with CC-IMT was undertaken in five independent European cohorts (total n=11,590). A locus on chromosome 16 (lead SNP rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple-testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMT(max); replication P=7.24x10(-6) for CC-IMT; 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 (CAD) risk in two case-control studies of subjects with European ancestry (odds ratio [95%CI] 0.83 [0.77-0.90], P=6.53x10(-6); n=13,591, and 0.95 [0.92-0.98], P=1.83x10(-4), n=82,297, respectively). Queries of human biobank datasets (n=126-138) revealed associations of rs4888378 with nearby gene expression in vascular tissues. CONCLUSIONS: -This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and CAD risk in individuals of European descent.
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