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

Karl Gertow; Bengt Sennblad; Rona J. Strawbridge; John Oehrvik; Delilah Zabaneh; Sonia Shah; Fabrizio Veglia; Cristiano Fava; Maryam Kavousi; Stela McLachlan; Mika Kivimaeki; Jennifer L. Bolton; Lasse Folkersen; Bruna Gigante; Karin Leander; Max Vikstrom; Malin Larsson; Angela Silveira; John Deanfield; Benjamin F. Voight; Pierre Fontanillas; Maria Sabater-Lleal; Gualtiero I. Colombo; Meena Kumari; Claudia Langenberg; Nick J. Wareham; Andre G. Uitterlinden; Anders Gabrielsen; Ulf Hedin; Anders Franco-Cereceda; Kristiina Nyyssonen; 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 Syvanen; Goran 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

doi:10.1161/CIRCGENETICS.112.963660

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

Karl Gertow^*, Bengt Sennblad, Rona J. Strawbridge, John Oehrvik, Delilah Zabaneh, Sonia Shah, Fabrizio Veglia, Cristiano Fava, Maryam Kavousi, Stela McLachlan, Mika Kivimaeki, Jennifer L. Bolton, Lasse Folkersen, Bruna Gigante, Karin Leander, Max Vikstrom, Malin Larsson, Angela Silveira, John Deanfield, Benjamin F. VoightPierre Fontanillas, Maria Sabater-Lleal, Gualtiero I. Colombo, Meena Kumari, Claudia Langenberg, Nick J. Wareham, Andre G. Uitterlinden, Anders Gabrielsen, Ulf Hedin, Anders Franco-Cereceda, Kristiina Nyyssonen, 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 Syvanen, Goran 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.)

Original language	English
Pages (from-to)	656-665
Number of pages	10
Journal	Circulation: Cardiovascular Genetics
Volume	5
Issue number	6
DOIs	https://doi.org/10.1161/CIRCGENETICS.112.963660
Publication status	Published - 14 Dec 2012

Keywords / Materials (for Non-textual outputs)

atherosclerosis
carotid intima-media thickness
coronary artery disease
genetics
GENOME-WIDE ASSOCIATION
VASCULAR SMOOTH-MUSCLE
CARDIOVASCULAR RISK
MYOCARDIAL-INFARCTION
WHITEHALL-II
ATHEROSCLEROSIS
SUSCEPTIBILITY
METAANALYSIS
ROTTERDAM
CALCIFICATION

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10.1161/CIRCGENETICS.112.963660

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Gertow, K., Sennblad, B., Strawbridge, R. J., Oehrvik, J., Zabaneh, D., Shah, S., Veglia, F., Fava, C., Kavousi, M., McLachlan, S., Kivimaeki, M., Bolton, J. L., Folkersen, L., Gigante, B., Leander, K., Vikstrom, M., Larsson, M., Silveira, A., Deanfield, J., ... Hamsten, A. (2012). Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk. Circulation: Cardiovascular Genetics, 5(6), 656-665. https://doi.org/10.1161/CIRCGENETICS.112.963660

@article{be49b6ae018e419d9259d156d52b48b9,

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

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.)",

keywords = "atherosclerosis, carotid intima-media thickness, coronary artery disease, genetics, GENOME-WIDE ASSOCIATION, VASCULAR SMOOTH-MUSCLE, CARDIOVASCULAR RISK, MYOCARDIAL-INFARCTION, WHITEHALL-II, ATHEROSCLEROSIS, SUSCEPTIBILITY, METAANALYSIS, ROTTERDAM, CALCIFICATION",

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

year = "2012",

month = dec,

day = "14",

doi = "10.1161/CIRCGENETICS.112.963660",

language = "English",

volume = "5",

pages = "656--665",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

number = "6",

}

Gertow, K, Sennblad, B, Strawbridge, RJ, Oehrvik, J, Zabaneh, D, Shah, S, Veglia, F, Fava, C, Kavousi, M, McLachlan, S, Kivimaeki, M, Bolton, JL, Folkersen, L, Gigante, B, Leander, K, Vikstrom, 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, Nyyssonen, K, Rauramaa, R, Tuomainen, T-P, 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, Syvanen, A-C, Hansson, GK, Eriksson, P, Samani, NJ, Watkins, H, Price, JF, Hingorani, AD, Melander, O, Witteman, JCM, Baldassarre, D, Tremoli, E, de Faire, U, Humphries, SE & Hamsten, A 2012, 'Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk', Circulation: Cardiovascular Genetics, vol. 5, no. 6, pp. 656-665. https://doi.org/10.1161/CIRCGENETICS.112.963660

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 - Oehrvik, John

AU - Zabaneh, Delilah

AU - Shah, Sonia

AU - Veglia, Fabrizio

AU - Fava, Cristiano

AU - Kavousi, Maryam

AU - McLachlan, Stela

AU - Kivimaeki, Mika

AU - Bolton, Jennifer L.

AU - Folkersen, Lasse

AU - Gigante, Bruna

AU - Leander, Karin

AU - Vikstrom, 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, Andre G.

AU - Gabrielsen, Anders

AU - Hedin, Ulf

AU - Franco-Cereceda, Anders

AU - Nyyssonen, 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 - Syvanen, Ann-Christine

AU - Hansson, Goran 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 - 2012/12/14

Y1 - 2012/12/14

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=6.75x10(-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.)

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=6.75x10(-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.)

KW - atherosclerosis

KW - carotid intima-media thickness

KW - coronary artery disease

KW - genetics

KW - GENOME-WIDE ASSOCIATION

KW - VASCULAR SMOOTH-MUSCLE

KW - CARDIOVASCULAR RISK

KW - MYOCARDIAL-INFARCTION

KW - WHITEHALL-II

KW - ATHEROSCLEROSIS

KW - SUSCEPTIBILITY

KW - METAANALYSIS

KW - ROTTERDAM

KW - CALCIFICATION

U2 - 10.1161/CIRCGENETICS.112.963660

DO - 10.1161/CIRCGENETICS.112.963660

M3 - Article

SN - 1942-325X

VL - 5

SP - 656

EP - 665

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 6

ER -

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

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