Physiological Genomics Laboratory, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
Hypertens Res. 2011 Dec;34(12):1263-70. doi: 10.1038/hr.2011.116. Epub 2011 Aug 4.
Previously linkage and substitution mapping were conducted between the Dahl Salt-sensitive (S) rat and the Spontaneously Hypertensive Rat (SHR) to address the hypothesis that genetic contributions to blood pressure (BP) in two genetically hypertensive rat strains are different. Among the BP quantitative trait loci (QTLs) detected, two are located on chromosome 9 within large genomic segments. The goal of the current study was to develop new iterations of congenic substrains, to further resolve both of these BP QTLs on chromosome 9 as independent congenic segments. A total of 10 new congenic substrains were developed and characterized. The newly developed congenic substrains S.SHR(9)x8Ax11A and S.SHR(9)x10Ax1, with introgressed segments of 2.05 and 6.14 Mb, represented the shortest genomic segments. Both of these congenic substrains, S.SHR(9)x8Ax11A and S.SHR(9)x10Ax1 lowered BP of the S rat by 56 mm Hg (P<0.001) and 15 mm Hg (P<0.039), respectively. The BP measurements were corroborated by radiotelemetry. Urinary protein excretion was significantly lowered by SHR alleles within S.SHR(9)x10Ax1 but not by S.SHR(9)x8Ax11A. The shorter of the two congenic segments, 2.05 Mb was further characterized and found to contain a single differentially expressed protein-coding gene, Tomoregulin-2 (Tmeff2). The protein expression of Tmeff2 was higher in the S rat compared with S.SHR(9)x8Ax11A, which also had lower cardiac hypertrophy as measured by echocardiography. Tmeff2 is known to be upregulated in patients from multiple cohorts with cardiac hypertrophy. Taken together, Tmeff2 can be prioritized as a candidate gene for hypertension and associated cardiac hypertrophy in both rats and in humans.
先前进行了达尔盐敏感（S）大鼠与自发性高血压大鼠（SHR）之间的连锁和替代作图，以验证遗传因素对两种遗传性高血压大鼠血压的贡献不同的假设。在检测到的血压数量性状基因座（QTL）中，有两个位于染色体 9 上的大基因组片段内。目前研究的目的是开发新的同系亚系，以进一步将这两个位于染色体 9 上的 BP QTL 分别作为独立的同系片段来解析。总共开发和表征了 10 个新的同系亚系。新开发的同系亚系 S.SHR（9）x8Ax11A 和 S.SHR（9）x10Ax1 分别具有 2.05 和 6.14 Mb 的导入片段，代表最短的基因组片段。这两个同系亚系 S.SHR（9）x8Ax11A 和 S.SHR（9）x10Ax1 分别使 S 大鼠的血压降低了 56mmHg（P<0.001）和 15mmHg（P<0.039）。血压测量结果得到无线电遥测的证实。S.SHR（9）x10Ax1 中的 SHR 等位基因显著降低了尿蛋白排泄，但 S.SHR（9）x8Ax11A 则没有。在这两个同系亚系中，较短的 2.05 Mb 进一步进行了特征描述，发现其中包含一个单个性表达蛋白编码基因 Tomoregulin-2（Tmeff2）。与 S.SHR（9）x8Ax11A 相比，Tmeff2 在 S 大鼠中的蛋白表达更高，超声心动图也显示 S.SHR（9）x8Ax11A 的心脏肥大程度更低。Tmeff2 在多个伴有心脏肥大的患者队列中表达上调。综上所述，Tmeff2 可以被优先作为大鼠和人类高血压及相关心脏肥大的候选基因。
