TY - JOUR
T1 - Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk
AU - Gertow, Karl
AU - Sennblad, Bengt
AU - Strawbridge, Rona J.
AU - Öhrvik, John
AU - Zabaneh, Delilah
AU - Shah, Sonia
AU - Veglia, Fabrizio
AU - Fava, Cristiano
AU - Kavousi, Maryam
AU - McLachlan, Stela
AU - Kivimäki, Mika
AU - Bolton, Jennifer L.
AU - Folkersen, Lasse
AU - Gigante, Bruna
AU - Leander, Karin
AU - Vikström, Max
AU - Larsson, Malin
AU - Silveira, Angela
AU - Deanfield, John
AU - Voight, Benjamin F.
AU - Fontanillas, Pierre
AU - Sabater-Lleal, Maria
AU - Colombo, Gualtiero I.
AU - Kumari, Meena
AU - Langenberg, Claudia
AU - Wareham, Nick J.
AU - Uitterlinden, André G.
AU - Gabrielsen, Anders
AU - Hedin, Ulf
AU - Franco-Cereceda, Anders
AU - Nyyssönen, Kristiina
AU - Rauramaa, Rainer
AU - Tuomainen, Tomi Pekka
AU - Savonen, Kai
AU - Smit, Andries J.
AU - Giral, Philippe
AU - Mannarino, Elmo
AU - Robertson, Christine M.
AU - Talmud, Philippa J.
AU - Hedblad, Bo
AU - Hofman, Albert
AU - Erdmann, Jeanette
AU - Reilly, Muredach P.
AU - O'Donnell, Christopher J.
AU - Farrall, Martin
AU - Clarke, Robert
AU - Franzosi, Maria Grazia
AU - Seedorf, Udo
AU - Syvänen, Ann Christine
AU - Hansson, Göran K.
AU - Eriksson, Per
AU - Samani, Nilesh J.
AU - Watkins, Hugh
AU - Price, Jacqueline F.
AU - Hingorani, Aroon D.
AU - Melander, Olle
AU - Witteman, Jacqueline C.M.
AU - Baldassarre, Damiano
AU - Tremoli, Elena
AU - De Faire, Ulf
AU - Humphries, Steve E.
AU - Hamsten, Anders
PY - 2012/12
Y1 - 2012/12
N2 - 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 (IMTmean, IMTmax, and IMTmean-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 IMTmax; 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. (Circ Cardiovasc Genet. 2012;5:656-665.)
AB - 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 (IMTmean, IMTmax, and IMTmean-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 IMTmax; 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. (Circ Cardiovasc Genet. 2012;5:656-665.)
UR - http://www.scopus.com/inward/record.url?scp=84873898932&partnerID=8YFLogxK
U2 - 10.1161/CIRCGENETICS.112.963660
DO - 10.1161/CIRCGENETICS.112.963660
M3 - Journal articles
C2 - 23152477
AN - SCOPUS:84873898932
SN - 1942-325X
VL - 5
SP - 656
EP - 665
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 6
ER -
