Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk.
Gertow K., Sennblad B., Strawbridge RJ., Ohrvik J., Zabaneh D., Shah S., Veglia F., Fava C., Kavousi M., McLachlan S., Kivimäki M., Bolton JL., Folkersen L., Gigante B., Leander K., Vikström M., Larsson M., Silveira A., Deanfield J., Voight BF., Fontanillas P., Sabater-Lleal M., Colombo GI., Kumari M., Langenberg C., Wareham NJ., Uitterlinden AG., Gabrielsen A., Hedin U., Franco-Cereceda A., Nyyssönen K., Rauramaa R., Tuomainen TP., Savonen K., Smit AJ., Giral P., Mannarino E., Robertson CM., Talmud PJ., Hedblad B., Hofman A., Erdmann J., Reilly MP., O'Donnell CJ., Farrall M., Clarke R., Franzosi MG., Seedorf U., Syvänen AC., Hansson GK., Eriksson P., Samani NJ., Watkins H., Price JF., Hingorani AD., Melander O., Witteman JC., Baldassarre D., Tremoli E., de Faire U., Humphries SE., Hamsten A.
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.