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., Ohrvik, John, Zabaneh, Delilah, Shah, Sonia, Veglia, Fabrizio, Fava, Cristiano, Kavousi, Maryam, McLachlan, Stela, Kivimaki, Mika, Bolton, Jennifer L., Folkersen, Lasse, Gigante, Bruna, Leander, Karin, Vikstrom, Max, Larsson, Malin, Silveira, Angela, Deanfield, John, Voight, Benjamin F., Fontanillas, Pierre, Sabater-Lleal, Maria, Colombo, Gualtiero I., Kumari, Meena, Langenberg, Claudia, Wareham, Nick J., Uitterlinden, André G., Gabrielsen, Anders, Hedin, Ulf, Franco-Cereceda, Anders, Nyyssonen, Kristiina, Rauramaa, Rainer, Tuomainen, Tomi-Pekka, Savonen, Kai, Smit, Andries J., Giral, Philippe, Mannarino, Elmo, Robertson, Christine M., Talmud, Philippa J., Hedblad, Bo, Hofman, Albert, Erdmann, Jeanette, Reilly, Muredach P., O'Donnell, Christopher J., Farrall, Martin, Clarke, Robert, Franzosi, Maria Grazia, Seedorf, Udo, Syvanen, Ann-Christine, Hansson, Göran K., Eriksson, Per, Samani, Nilesh J., Watkins, Hugh, Price, Jacqueline F., Hingorani, Aroon D., Melander, Olle, Witteman, Jacqueline C. M., Baldassarre, Damiano, Tremoli, Elena, de Faire, Ulf, Humphries, Steve E. and Hamsten, Anders (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. doi:10.1161/CIRCGENETICS.112.963660

Author Gertow, Karl
Sennblad, Bengt
Strawbridge, Rona J.
Ohrvik, John
Zabaneh, Delilah
Shah, Sonia
Veglia, Fabrizio
Fava, Cristiano
Kavousi, Maryam
McLachlan, Stela
Kivimaki, Mika
Bolton, Jennifer L.
Folkersen, Lasse
Gigante, Bruna
Leander, Karin
Vikstrom, Max
Larsson, Malin
Silveira, Angela
Deanfield, John
Voight, Benjamin F.
Fontanillas, Pierre
Sabater-Lleal, Maria
Colombo, Gualtiero I.
Kumari, Meena
Langenberg, Claudia
Wareham, Nick J.
Uitterlinden, André G.
Gabrielsen, Anders
Hedin, Ulf
Franco-Cereceda, Anders
Nyyssonen, Kristiina
Rauramaa, Rainer
Tuomainen, Tomi-Pekka
Savonen, Kai
Smit, Andries J.
Giral, Philippe
Mannarino, Elmo
Robertson, Christine M.
Talmud, Philippa J.
Hedblad, Bo
Hofman, Albert
Erdmann, Jeanette
Reilly, Muredach P.
O'Donnell, Christopher J.
Farrall, Martin
Clarke, Robert
Franzosi, Maria Grazia
Seedorf, Udo
Syvanen, Ann-Christine
Hansson, Göran K.
Eriksson, Per
Samani, Nilesh J.
Watkins, Hugh
Price, Jacqueline F.
Hingorani, Aroon D.
Melander, Olle
Witteman, Jacqueline C. M.
Baldassarre, Damiano
Tremoli, Elena
de Faire, Ulf
Humphries, Steve E.
Hamsten, Anders
Title Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk
Journal name Circulation: Cardiovascular Genetics   Check publisher's open access policy
ISSN 1942-325X
Publication date 2012-01-01
Year available 2012
Sub-type Article (original research)
DOI 10.1161/CIRCGENETICS.112.963660
Open Access Status Not yet assessed
Volume 5
Issue 6
Start page 656
End page 665
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted 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=6.75×10 -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.)
Keyword Atherosclerosis
Carotid intima-media thickness
Coronary artery disease
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID ID 85374
014-93-015; RIDE2
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 19 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 18 times in Scopus Article | Citations
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