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Circulation Research

Year: 2010  |  Volume: 107  |  Issue: 4  |  Page No.: 558 - 568

Genetic Architecture Underlying Variation in Extent and Remodeling of the Collateral Circulation

S Wang, H Zhang, X Dai, R Sealock and J. E. Faber

Abstract

Rationale:

Collaterals are arteriole-to-arteriole anastomoses that connect adjacent arterial trees. They lessen ischemic tissue injury by serving as endogenous bypass vessels when the trunk of 1 tree becomes narrowed by vascular disease. The number and diameter ("extent") of native (preexisting) collaterals, plus their amount of lumen enlargement (growth/remodeling) in occlusive disease, show remarkably wide variation among inbred mouse strains (eg, C57BL/6 and BALB/c), resulting in large differences in tissue injury in models of occlusive disease. Evidence suggests similar large differences exist among healthy humans.

Objective:

To identify candidate loci responsible for genetic-dependent collateral variation.

Methods and Results:

Cerebral collateral number and diameter were determined in 221 C57BL/6xBALB/c F2 progeny, followed by linkage analysis to identify quantitative trait loci (QTL) for collateral number and diameter. Four QTL were obtained for collateral number, including epistasis between 2 loci. A QTL that was identical to the strongest QTL for collateral number on chromosome 7 (logarithm of the odds [LOD]=29, effect size=37%) was also mapped for collateral diameter (LOD=17, effect size=30%). Chromosome substitution strain analysis confirmed this locus. We also obtained a unique QTL on chromosome 11 for collateral remodeling after middle cerebral artery occlusion. Association mapping within the chromosome 7 QTL interval using collateral traits measured for 15 inbred strains delineated 172-kbp (P=0.00002) and 290-kbp (P=0.0004) regions on chromosome 7 containing 2 and 7 candidate genes, respectively.

Conclusions:

We conclude that collateral extent and remodeling are unique, highly heritable complex traits, with 1 QTL predominantly affecting native collateral number and diameter.

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