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

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

Circulation. Cardiovascular genetics (2012-11-16)

Karl Gertow, Bengt Sennblad, Rona J Strawbridge, John Ohrvik, Delilah Zabaneh, Sonia Shah, Fabrizio Veglia, Cristiano Fava, Maryam Kavousi, Stela McLachlan, Mika Kivimäki, Jennifer L Bolton, Lasse Folkersen, Bruna Gigante, Karin Leander, Max Vikström, Malin Larsson, Angela Silveira, John Deanfield, Benjamin F Voight, Pierre Fontanillas, Maria Sabater-Lleal, Gualtiero I Colombo, Meena Kumari, Claudia Langenberg, Nick J Wareham, André G Uitterlinden, Anders Gabrielsen, Ulf Hedin, Anders Franco-Cereceda, Kristiina Nyyssönen, Rainer Rauramaa, Tomi-Pekka Tuomainen, Kai Savonen, Andries J Smit, Philippe Giral, Elmo Mannarino, Christine M Robertson, Philippa J Talmud, Bo Hedblad, Albert Hofman, Jeanette Erdmann, Muredach P Reilly, Christopher J O'Donnell, Martin Farrall, Robert Clarke, Maria Grazia Franzosi, Udo Seedorf, Ann-Christine Syvänen, Göran K Hansson, Per Eriksson, Nilesh J Samani, Hugh Watkins, Jacqueline F Price, Aroon D Hingorani, Olle Melander, Jacqueline C M Witteman, Damiano Baldassarre, Elena Tremoli, Ulf de Faire, Steve E Humphries, Anders Hamsten

PMID23152477

摘要

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. 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 (IMT(mean), IMT(max), and IMT(mean-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 IMT(max); 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.