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. - 5:6(2012), pp. 656-665.
|Titolo:||Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk|
|Parole Chiave:||Atherosclerosis; Carotid intima-media thickness; Coronary artery disease; Genetics|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2012|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1161/CIRCGENETICS.112.963660|
|Appare nelle tipologie:||01 - Articolo su periodico|