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Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk

Gertow, Karl; Sennblad, Bengt; Strawbridge, Rona J.; Oehrvik, John; Zabaneh, Delilah; Shah, Sonia; Veglia, Fabrizio; Fava, Cristiano LU ; Kavousi, Maryam and McLachlan, Stela, et al. (2012) In Circulation: Cardiovascular Genetics 5(6). p.656-665
Abstract
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... (More)
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=6.75x10(-7) for IMTmax; replication P=7.24x10(-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=6.53x10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83x10(-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.) (Less)
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keywords
atherosclerosis, carotid intima-media thickness, coronary artery, disease, genetics
in
Circulation: Cardiovascular Genetics
volume
5
issue
6
pages
656 - 665
publisher
American Heart Association
external identifiers
  • wos:000312774800014
  • scopus:84873898932
ISSN
1942-325X
DOI
10.1161/CIRCGENETICS.112.963660
language
English
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d1a2e18a-cfac-4cd6-9713-2bf5094d47e8 (old id 3512303)
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2013-03-01 07:52:47
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@article{d1a2e18a-cfac-4cd6-9713-2bf5094d47e8,
  abstract     = {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=6.75x10(-7) for IMTmax; replication P=7.24x10(-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=6.53x10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83x10(-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.)},
  author       = {Gertow, Karl and Sennblad, Bengt and Strawbridge, Rona J. and Oehrvik, John and Zabaneh, Delilah and Shah, Sonia and Veglia, Fabrizio and Fava, Cristiano and Kavousi, Maryam and McLachlan, Stela and Kivimaeki, Mika and Bolton, Jennifer L. and Folkersen, Lasse and Gigante, Bruna and Leander, Karin and Vikstrom, Max and Larsson, Malin and Silveira, Angela and Deanfield, John and Voight, Benjamin F. and Fontanillas, Pierre and Sabater-Lleal, Maria and Colombo, Gualtiero I. and Kumari, Meena and Langenberg, Claudia and Wareham, Nick J. and Uitterlinden, Andre G. and Gabrielsen, Anders and Hedin, Ulf and Franco-Cereceda, Anders and Nyyssonen, Kristiina and Rauramaa, Rainer and Tuomainen, Tomi-Pekka and Savonen, Kai and Smit, Andries J. and Giral, Philippe and Mannarino, Elmo and Robertson, Christine M. and Talmud, Philippa J. and Hedblad, Bo and Hofman, Albert and Erdmann, Jeanette and Reilly, Muredach P. and O'Donnell, Christopher J. and Farrall, Martin and Clarke, Robert and Franzosi, Maria Grazia and Seedorf, Udo and Syvanen, Ann-Christine and Hansson, Goran K. and Eriksson, Per and Samani, Nilesh J. and Watkins, Hugh and Price, Jacqueline F. and Hingorani, Aroon D. and Melander, Olle and Witteman, Jacqueline C. M. and Baldassarre, Damiano and Tremoli, Elena and de Faire, Ulf and Humphries, Steve E. and Hamsten, Anders},
  issn         = {1942-325X},
  keyword      = {atherosclerosis,carotid intima-media thickness,coronary artery,disease,genetics},
  language     = {eng},
  number       = {6},
  pages        = {656--665},
  publisher    = {American Heart Association},
  series       = {Circulation: Cardiovascular Genetics},
  title        = {Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk},
  url          = {http://dx.doi.org/10.1161/CIRCGENETICS.112.963660},
  volume       = {5},
  year         = {2012},
}