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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #161802
Title: GENOMEWIDE LINKAGE ANALYSIS FOR INTERNAL CAROTID ARTERY INTIMAL MEDIAL THICKNESS: EVIDENCE FOR LINKAGE TO CHROMOSOME 12

Author
item FOX, C - FRAMINGHAM HEART STUDY
item CUPPLES, L - FRAMINGHAM HEART STUDY
item CHAZARO, I - BOSTON UNIVERISTY
item POLAK, J - BRIGHAM WOMEN'S HOSPITAL
item WOLF, P - FRAMINGHAM HEART STUDY
item D'AGOSTINO, R - FRAMINGHAM HEART STUDY
item ORDOVAS, JOSE - TUFTS-HNRCA
item O'DONNELL, C - FRAMINGHAM HEART STUDY

Submitted to: The American Journal of Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/17/2003
Publication Date: 2/1/2004
Citation: Fox, C.S., Cupples, L.A., Chazaro, I., Polak, J.F., Wolf, P.A., D'Agostino, R.B., Ordovas, J.M., O'Donnell, C.J. 2004. Genomewide linkage analysis for internal carotid artery intimal medial thickness: evidence for linkage to chromosome 12. The American Journal of Human Genetics 2004;74:253-261.

Interpretive Summary: Coronary heart disease risk is modulated by genetic and environmental factors, namely, diet, physical activity, smoking and alcohol drinking. Many genes have been implicated in the regulation of blood lipids and thus in heart disease risk. Some of them are already known and are called candidate genes. However, many of the genes involved in heart disease remain unknown. We have been involved in the discovery of such genes with the ultimate goal of building a panel of genetic markers that will provide early assessment of risk and the ability to implement early prevention. As part of this effort we have examined the entire genome in over 1000 subjects participating in the Framingham Heart Study to uncover genes involved in the development of heart disease. These analyses have pointed us towards a region of chromosome number 12 which may contain important genes for disease risk. One of the genes contained in that region is known as SCARB1 or the high density lipoprotein receptor gene. Further work is in place to uncover other genes in that region also implicated in the disease process.

Technical Abstract: 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.