Identification of a Genetic Locus on Chromosome 11 That Regulates Leukocyte Infiltration in Mouse Carotid Artery
Objective—We demonstrated that inflammatory cells and intima–media thickening are increased in carotids exposed to low-blood flow in the SJL/J (SJL) strain compared with other mouse strains. We hypothesized that the extent of inflammation associated with intima–media thickening is a genetically regulated trait.
Approach and Results—We performed a whole genome approach to measure leukocyte infiltration in the carotid intima as a quantitative trait in a genetic cross between C3HeB/FeJ (C3H/F) and SJL mice. Immunostaining for CD45+ (a pan-specific leukocyte marker) was performed on carotids from C3H/F, SJL, F1, and N2 progeny to measure leukocyte infiltration. We identified a nearly significant quantitative trait locus for CD45+ on chromosome (chr) 11 (17 cM, LOD=2.3; significance was considered at threshold P=0.05). Interval mapping showed that the CD45+ locus on chr 11 accounted for 8% of the variation in the C3H/FxSJL backcross. Importantly, the CD45+ locus colocalized with the intima-modifier 2 (Im2) locus, which controls 17% of intima variation. We created 2 Im2 congenic lines of mice (C3H/F.SJL.11.1 and C3H/F.SJL.11.2) to better understand the regulation of intima–media thickening by the chr 11 locus. The C3H/F.SJL.11.1 congenic mouse showed ≈30% of the SJL trait, confirming that CD45+ cell infiltration contributed to the intima trait.
Conclusions—We discovered a novel locus on chr 11 that controls leukocyte infiltration in the carotid. Importantly, this locus overlaps with our previously published Im2 locus on chr 11. Our study reveals a potential mechanistic relationship between leukocyte infiltration and intima–media thickening in response to decreased blood flow.
- Received January 4, 2013.
- Accepted February 15, 2013.
- © 2013 American Heart Association, Inc.