Identification of the
BCAR1-CFDP1-TMEM170A
Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk
Authors: Gertow Karl , Sennblad Bengt , Strawbridge Rona J. , Öhrvik John , Zabaneh Delilah , Shah Sonia , Veglia Fabrizio , Fava Cristiano , Kavousi Maryam , McLachlan Stela , Kivimäki Mika , Bolton Jennifer L. , Folkersen Lasse , Gigante Bruna , Leander Karin , Vikström 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 , Nyyssönen 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 , Syvänen 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 
Published: November 2012

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.