Genomewide linkage and peakwide association analyses of carotid plaque in Caribbean Hispanics.
OBJECTIVE
Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic component. This study sought to identify genetic loci influencing carotid plaque in 2 independent samples.


METHODS
B-mode ultrasound was performed to determine the presence and area of carotid plaque. Variance components analysis was used to test for linkage using 383 autosomal microsatellite markers in 1308 subjects from 100 Dominican families. Multiple linear and logistic regression models were used to investigate the association between plaque traits and 18,904 single nucleotide polymorphisms under the 1-logarithm of odds unit down regions of linkage peaks in an independent community-based data set (N = 941, 41% Dominicans) from the Northern Manhattan Study.


RESULTS
After adjustment for age, hypertension, diabetes mellitus, cigarette pack-years, body mass index, and waist-to-hip ratio, significant heritability was detected for plaque presence (h² = 0.50 ± 0.14, P < 0.0001) and plaque area (h²=0.17 ± 0.04, P < 0.0001). Quantitative and dichotomous trait linkage analyses obtained similar results and identified 4 regions with multipoint logarithm of odds scores ≥ 2.00 on 7q36, 11p15, 14q32, and 15q23. In the association analysis of the 4 linkage peaks, several single nucleotide polymorphisms in or near SOX6, FSD2, AP3S2, EFTUD1, and MYOD1 were associated with carotid plaque traits with a nominal P ≤ 0.0005 in the Northern Manhattan Study data set and with a P ≤ 0.01 in Northern Manhattan Study Dominican subset.


CONCLUSIONS
Carotid plaque has considerable heritability and may be influenced by loci on chromosomes 11p15, 14q32, and 15q23. The SOX6 gene within the bone morphogenic protein pathway could be a candidate for carotid plaque. Larger independent studies are needed to validate these findings.
Evelyn F. McKnight Center for Age-Related Memory Loss, Department of Neurology, Miller Schoolof Medicine, University of Miami, Miami, FL, USA.
Chuanhui
C
Dong
Ashley
A
Beecham
Susan
S
Slifer
Liyong
L
Wang
Susan H
SH
Blanton
Clinton B
CB
Wright
Tatjana
T
Rundek
Ralph L
RL
Sacco
D000328:Adult; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D015331:Cohort Studies; D004293:Dominican Republic / Q000453:epidemiology; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006630:Hispanic or Latino; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009519:New York City / Q000453:epidemiology; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D011786:Quality Control; D012307:Risk Factors; D055755:SOXD Transcription Factors / Q000235:genetics; D014463:Ultrasonography; D014900:West Indies / Q000453:epidemiology
D019485:Bone Morphogenetic Proteins; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors