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Published Online
on October 23, 2008

Arteriosclerosis, Thrombosis, and Vascular Biology. 2008
Published online before print October 23, 2008, doi: 10.1161/ATVBAHA.108.178111
A more recent version of this article appeared on January 1, 2009
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Submitted on August 25, 2008
Accepted on October 10, 2008

Genetic Modifier Loci Linked to Intima Formation Induced by Low Flow in the Mouse Carotid

Vyacheslav A. Korshunov * and Bradford C. Berk

From the Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, NY.

* To whom correspondence should be addressed. E-mail: Slava_Korshunov{at}URMC.rochester.edu.

Objective—Previously we found dramatic strain-dependent differences in a low flow model of vascular remodeling. Specifically, intima formation in the left common carotid artery was {approx}30-fold greater in SJL compared to C3HeB/Fe (C3H/F) mice. We hypothesized that a few genes control intima formation in response to low flow. A C3H/F and SJL backcross resulted in broad range of N2 intima phenotypes.

Methods and Results—Using genome-wide scan we identified two highly significant quantitative trait loci (QTLs) for intima, Im1 (intima modifier 1 locus) on chromosome 2 (Chr2; 77.6 cM, LOD=6.4), and Im2 on Chr11 (17 cM, LOD=5.3). One significant QTL Im3 was found on Chr18 (6 cM, LOD=3.0), and two suggestive QTLs (LOD=1.5 and 1.8) were identified on Chr7 and Chr17, respectively. Interestingly, the intima/media ratio trait mapped to the same QTLs as the intima trait. Haplotype mapping predicted 40 candidate genes. Six of these genes contained SNPs that differed between C3H/F and SJL.

Conclusions—We have successfully mapped 3 QTLs (Im1, Im2, and Im3) that are associated with carotid intima formation in response to low blood flow. These results may be important in identifying genes that influence carotid intima-media thickening and predict cardiovascular disease in humans.
Key words: genetics • intima • low blood flow • mouse • SJL/J • C3HeB/FeJ






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