Dissecting the Genetic Architecture of Complex Traits: Hot Spots and Vascular Collaterals

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  • March 22, 2019
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  • Wang, Shiliang
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Collateral arteries are endogenous “bypass vessels” that minimize tissue injury during arterial obstruction. Recent studies from our laboratory demonstrate that wide variation exists among individuals in the extent (number and diameter) of native (pre-existing) collaterals in healthy tissue and their outward remodeling (increase in anatomic diameter) in obstructive disease. Evidence suggests this variation contributes importantly to the wide variation in thromboembolic stroke, ischemic heart disease and peripheral arterial disease in humans. We hypothesized that genetic components contribute significantly to this variation. We tested this hypothesis in 243 C57BL/6 X BALB/c (CXB) F2 mice, wherein number and diameter of native cerebral collaterals and collateral remodeling after middle cerebral artery occlusion (MCAO) were measured. Linkage analysis identified a major QTL on chromosome 7 (Canq1) responsible for more than 30% of the variation in collateral extent. Three additional QTL were obtained for collateral number. Analysis of chromosome substitution and CXB recombinant inbred strains confirmed the dominant role of the Canq1 locus. We also identified a QTL on chromosome 11 linked to variation in collateral remodeling. Efficient mix model association mapping (EMMA) of collateral number among 15 inbred strains delineated 172k (p=0.00002) and 290k (p=0.0004) base-pair regions containing 2 and 7 candidate genes, respectively, within Canq1. Analysis of six additional inbred strains, chosen according to their haplotype within the 172 kb EMMA region, strengthened and narrowed the locus from 172 kb interval to 2 kb. In candidate gene analyses, we found that collateral extent, infarct volume after MCAO, bleeding and re-bleeding times did not differ between Itgal-/,-IL4-/- or IL4-receptor-α-/- and wildtype mice. mRNA expression of 120 genes within the 95% confidence interval of Canq1, measured in the pial vasculature of C57BL/6 and BALB/c at embryonic day-14.5, -16.5 and -18.5 when the collateral circulation forms, identified 19 differentially expressed genes. These results demonstrate that native collateral extent and collateral remodeling are heritable complex traits, with a highly significant QTL on chromosome 7 governing the majority of the variation in these traits. Furthermore, my work prioritizes a set of genes for future analysis as candidates underlying the process of collateral formation and its variation among individuals.
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  • ... in partial fulfillment of the requirements for the degree of Doctor Of Philosophy in the Department of Cell and Molecular Physiology.
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  • Faber, James
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