Congenic fine-mapping identifies a major causal locus for variation in the native collateral circulation and ischemic injury in brain and lower extremity.
Congenic fine-mapping identifies a major causal locus for variation in the native collateral circulation and ischemic injury in brain and lower extremity.
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DOI：
10.1161/circresaha.114.302931
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发表时间：
2014-02-14
影响因子：
20.1
通讯作者：
Faber JE
中科院分区：
文献类型：
--
作者：
Sealock R;Zhang H;Lucitti JL;Moore SM;Faber JE
闭塞性疾病中组织损伤的严重程度取决于侧支血管的范围（数量和直径），这在健康小鼠和人类中差异很大。然而，致病的遗传因素是未知的。最近，不同小鼠品系之间的许多变异，包括C57 Bl/6 J（B6，高程度）和BALB/cByJ（Bc，低程度），与第7染色体上的QTL（Candq 1）连锁。我们使用同源作图来改进Candq 1及其候选基因，并创建一个在侧支程度上存在较大差异的“等基因”菌株集，以评估它们和Candq 1单独对缺血性损伤的影响。产生了6个具有从B6渗入Bc的Candq 1部分的同源菌株并进行表型分析。Candq 1从27 Mb精确到0.737 Mb，完全保留了作用，即在B6/B6同源小鼠中，将表型从Bc中的差值恢复/拯救到接近野生型B6的表型：83%的低软脑膜侧支范围的拯救，以及大脑中动脉闭塞后4.5倍的血流量增加和85%的梗死体积减少; 54%的低位骨骼肌侧支循环得到挽救，股动脉结扎后灌注和功能恢复增加（83%）。基因缺失和计算机模拟分析进一步确定了候选基因。我们已经显着完善Candq 1（现在指定的决定因素的侧支范围-1，Dce 1），证明了侧支的遗传背景依赖性变异是缺血性组织损伤差异的主要因素，并产生了一个同源的应变集与广泛的，等位基因剂量依赖性变异的侧支范围用于侧支循环的调查。
Severity of tissue injury in occlusive disease is dependent on the extent (number and diameter) of collateral vessels, which varies widely among healthy mice and humans. However, the causative genetic elements are unknown. Recently, much of the variation among different mouse strains, including C57Bl/6J (B6, high extent) and BALB/cByJ (Bc, low), was linked to a QTL on chromosome 7 (Candq1). We used congenic mapping to refine Candq1 and its candidate genes and create an “isogenic” strain-set with large differences in collateral extent to assess their and Candq1’s impact, alone, on ischemic injury. Six congenic strains possessing portions of Candq1 introgressed from B6 into Bc were generated and phenotyped. Candq1 was refined from 27 to 0.737 Mb with full retention of effect, ie, return/rescue of phenotypes from the poor values in Bc to nearly those of wildtype B6 in the B6/B6 congenic mice: 83% rescue of low pial collateral extent, and 4.5-fold increase in blood flow and 85% reduction of infarct volume after middle cerebral artery occlusion; 54% rescue of low skeletal muscle collaterals, and augmented recovery of perfusion (83%) and function after femoral artery ligation. Gene deletion and in-silico analysis further delineated the candidate genes. We have significantly refined Candq1 (now designated Determinant of collateral extent-1, Dce1), demonstrated that genetic background-dependent variation in collaterals is a major factor underlying differences in ischemic tissue injury, and generated a congenic strain-set with wide, allele-dose-dependent variation in collateral extent for use in investigations of the collateral circulation.