Successful isolation of a rat chromosome 1 blood pressure quantitative trait locus in reciprocal congenic strains
Successful isolation of a rat chromosome 1 blood pressure quantitative trait locus in reciprocal congenic strains
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DOI：
10.1161/01.hyp.32.4.639
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发表时间：
1998-10-01
期刊：
影响因子：
8.3
通讯作者：
Samani, NJ
中科院分区：
文献类型：
--
作者：
Frantz, SA;Kaiser, M;Samani, NJ
连锁分析在高血压和血压正常大鼠的实验交叉强烈建议的数量性状位点（QTL）的存在下，影响大鼠1号染色体上的血压，或附近的Sa基因。为了确认这种基因座的存在并进一步鉴定致病基因，我们通过使用Sa基因多态性在每一代选择育种者的10代以上的靶向育种，开发了2个同源品系，1个含有Wistar-Kyoto大鼠（WKY）遗传背景中的自发性高血压大鼠（SHR）1号染色体片段（WKY.SHR-Sa），另一个是SHR背景中的WKY 1号染色体片段（SHR.WKY-Sa）。SHR-Sa在标记物mD 7 mit 206和D1 Mit 2（并且包括Sa基因的SHR等位基因）之间含有至少约26 cM的SHR 1号染色体，并且SHR.WKY-Sa在mD 7 mit 206和D1 Wox 34（并且包括Sa基因的WKY等位基因）之间携带至少约15 cM的WKY 1号染色体。16、20、25周龄WKY、SHR-Sa大鼠血压均显著高于WKY，而SHR、WKY-Sa大鼠血压显著低于SHR。25周时，WKY、SHR-Sa和WKY之间收缩压和舒张压的平均差异分别为+11.5 mm Hg（P = 0.001）和+11.6 mm Hg（P < 0.001）。SHR、WKy-Sa和SHR之间的相应差异分别为-11.3 mmHg（P = 0.002）和-9.1 mmHg（P = 0.005）。这些差异约占SHR和WKY之间血压差异的五分之一。肾Sa基因表达水平反映了其Sa等位基因的表达水平，在WKY.SHR-Sa中表达水平较高，而在SHR.WKY-Sa中表达水平较低，这与Sa基因表达水平主要由Sa基因内或附近的顺式作用元件决定的结论一致。我们的研究结果表明，我们已经成功地分离出一个主要的大鼠1号染色体血压QTL位于附近的Sn基因的相互同源株来自SHR和WKY。这些菌株现在可用于进一步确定含有QTL的区域，并表征QTL影响血压的中间机制。此外，在我们的同源株中渗入的区域与来自我们的SHRxWKY杂交的第二代子代中的1号染色体血压QTL的峰值LOD得分的位置的比较表明，在该大鼠染色体上可能存在至少1个另外的影响血压的QTL。
Linkage analyses in experimental crosses of hypertensive and normotensive rats have strongly suggested the presence of a quantitative trait locus (QTL) influencing blood pressure on rat chromosome 1, at or near the Sa gene. To confirm the presence of such a locus and move toward identification of the causative gene, we have developed, through targeted breeding over 10 generations using an Sa gene polymorphism to select breeders at each generation, 2 congenic strains, 1 containing a segment of spontaneously hypertensive rat (SHR) chromosome 1 in a Wistar-Kyoto rat (WKY) genetic background (WKY.SHR-Sa), and the other a segment of WKY chromosome 1 in an SHR background (SHR.WKY-Sa). WKY.SHR-Sa contains at least approximate to 26 cM of SHR chromosome 1, between markers mD7mit206 and D1Mit2 (and including the SHR allele of the Sa gene), and SHR.WKY-Sa carries at least approximate to 15 cM of WKY chromosome I, between mD7mit206 and D1Wox34 (and including the WKY allele of the Sa gene). Blood pressure of WKY.SHR-Sa rats measured at 16, 20, and 25 weeks of age was significantly higher than that of WKY, whereas blood pressure of SHR.WKY-Sa rats was significantly lower than that of SHR. At 25 weeks, the mean differences in systolic and diastolic blood pressure between WKY.SHR-Sa and WKY were +11.5 mm Hg (P = 0.001) and +11.6 mm Hg mm Hg (P < 0.001), respectively. The corresponding differences between SHR.WKy-Sa and SHR were -11.3 mm Hg (P = 0.002) and -9.1 mm Hg (P = 0.005), respectively. The differences represent about one fifth of the blood pressure difference between SHR and WKY. Renal Sa mRNA levels in the congenic strains reflected their Sa allele with a high level in WKY.SHR-Sa and a low level in SHR.WKY-Sa, consistent with previous data suggesting that the level of Sa expression is primarily determined by cis-acting elements in or near the Sa gene. Our results show that we have successfully isolated a major rat chromosome 1 blood pressure QTL located in the vicinity of the Sn gene in reciprocal congenic strains derived-from SHR and WKY. The strains can now be used to further define the region containing the QTL and also to characterize intermediary mechanisms through which the QTL influences blood pressure. In addition, comparison of the regions introgressed in our congenic strains with the location of the peak LOD score for chromosome 1 blood pressure QTL in second filial generation progeny derived from our SHRxWKY cross suggests that there may be at least 1 further QTL influencing blood pressure on this rat chromosome.