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


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 (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). 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.

DOI: 10.1161/CIRCGENETICS.112.963660

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@article{Gertow2012IdentificationOT, title={Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk.}, author={Karl Gertow and Bengt Sennblad and Rona J Strawbridge and John Ohrvik and Delilah Zabaneh and Sonia Shah and Fabrizio Veglia and Cristiano Fava and Maryam Kavousi and Stela McLachlan and Mika Kivim{\"a}ki and Jennifer L. Bolton and Lasse Folkersen and Bruna Gigante and Karin Leander and Max Vikstr{\"{o}m and Malin K. Larsson and Angela Silveira and John Eric Deanfield and Benjamin F. Voight and Pierre Fontanillas and Maria Sabater-Lleal and Gualtiero Ivanoe Colombo and Meena Kumari and Claudia Langenberg and Nicholas J Wareham and Andr{\'e} G. Uitterlinden and Anders Gabrielsen and Ulf Hedin and Anders Franco-Cereceda and Kristiina Nyyss{\"{o}nen and Rainer Rauramaa and Tomi-Pekka Tuomainen and Kai P Savonen and Andries J. Smit and Philippe Giral and Elmo Mannarino and Christine Robertson and Philippa J. Talmud and Bo Hedblad and Albert Hofman and Jeanette Erdmann and Muredach P. Reilly and Christopher J. O'Donnell and Martin Farrall and Robert Clarke and Maria Grazia Franzosi and Udo Seedorf and Ann-Christine Syv{\"a}nen and Goran K . Hansson and Per Eriksson and Nilesh J. Samani and Hugh C Watkins and Jackie F. Price and Aroon D. Hingorani and Olle Melander and Jacqueline C. M. Witteman and Damiano Baldassarre and Elena Tremoli and Ulf H de Faire and Steve E Humphries and Anders Hamsten}, journal={Circulation. Cardiovascular genetics}, year={2012}, volume={5 6}, pages={656-65} }