Genomewide linkage analysis for internal carotid artery intimal medial thickness: evidence for linkage to chromosome 12.
Carotid intimal medial thickness (IMT) is a heritable quantitative measure of atherosclerosis. A genomewide linkage analysis was conducted to localize a quantitative-trait locus (QTL) influencing carotid IMT. Carotid IMT was measured in 596 men and 629 women from 311 extended families (1,242 sib pairs) in the Framingham Heart Study Offspring cohort. B-mode carotid ultrasonography was used to define mean IMT of the carotid artery segments. Multipoint variance-component linkage analysis was performed. Evidence for significant linkage to internal carotid artery (ICA) IMT (two-point log odds [LOD] score 4.1, multipoint LOD score 3.4) was found 161 cM from the tip of the short arm of chromosome 12; these results were confirmed using the GENEHUNTER package (multipoint LOD score 4.3). No LOD scores >2.0 were observed for common carotid artery (CCA) IMT. Association analysis of a single-nucleotide-polymorphism variant of SCARB1 (minor allele frequency 0.13), a gene in close proximity to the region of peak linkage, revealed a protective association of the missense variant allele in exon 1 of SCARB1, with decreased ICA IMT compared with subjects homozygous for the common allele. Although the exon 1 variant contributed 2% to overall variation in ICA IMT, there was no significant change in the peak LOD score after adjustment in the linkage analyses. These data provide substantial evidence for a QTL on chromosome 12 influencing ICA IMT and for association of a rare variant of SCARB1, or a nearby locus, with ICA IMT. Because this rare SCARB1 variant does not account for our observed linkage, further investigations are warranted to identify additional candidate-gene variants on chromosome 12 predisposing to atherosclerosis phenotypes and clinical vascular disease.
Fox
Caroline S
CS
National Heart, Lung, and Blood Institute's Framingham Heart Study, National Institutes of Health, MA 01702, USA.
Cupples
L Adrienne
LA
Chazaro
Irmarie
I
Polak
Joseph F
JF
Wolf
Philip A
PA
D'Agostino
Ralph B
RB
Ordovas
Jose M
JM
O'Donnell
Christopher J
CJ
D000368:Aged; D002881:Chromosomes, Human, Pair 12; D015331:Cohort Studies; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D040641:Quantitative Trait Loci; D017539:Tunica Intima / Q000473:pathology*