Genetic modifier loci linked to intima formation induced by low flow in the mouse carotid.

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 approximately 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.