Bell Rebecca, Herring Stacy M, Gokul Nisha, Monita Monique, Grove Megan L, Boerwinkle Eric, Doris Peter A
Institute of Molecular Medicine, University of Texas HSC at Houston, Houston, TX 77030, USA.
Circ Cardiovasc Genet. 2011 Jun;4(3):223-31. doi: 10.1161/CIRCGENETICS.110.958934. Epub 2011 Mar 15.
The recent development of a large panel of genome-wide single nucleotide polymorphisms (SNPs) provides the opportunity to examine genetic relationships between distinct SHR lines that share hypertension but differ in their susceptibility to hypertensive end-organ disease.
We compared genotypes at nearly 10,000 SNPs obtained for the hypertension end-organ injury-susceptible spontaneously hypertensive rat (SHR)-A3 (SHRSP, SHR-stroke prone) line and the injury-resistant SHR-B2 line. This revealed that that the 2 lines were genetically identical by descent (IBD) across 86.6% of the genome. Areas of the genome that were not IBD were distributed across 19 of the 20 autosomes and the X chromosome. A block structure of non-IBD comprising a total of 121 haplotype blocks was formed by clustering of SNPs inherited from different ancestors. To test the null hypothesis that distinct SHR lines share a common set of hypertension susceptibility alleles, we compared blood pressure in adult SHR animals from both lines and their F1 and F2 progeny using telemetry. In 16- to 18-week-old animals fed a normal diet, systolic blood pressure (SBP, mm Hg) in SHR-A3 was 205.7 ± 3.86 (mean ± SEM, n = 26), whereas in similar SHR-B2 animals, SBP was 186.7 ± 2.53 (n = 20). In F1 and F2 animals, SBP was 188.2 ± 4.23 (n = 19) and 185.6 ± 1.1 (n = 211), respectively (P<10(-6), ANOVA). To identify non-IBD haplotype blocks contributing to blood pressure differences between these SHR lines, we developed a high-throughput SNP genotyping system to genotype SNPs marking non-IBD blocks. We mapped a single non-IBD block on chromosome 17 extending over <10 Mb, at which SHR-A3 alleles significantly elevate blood pressure compared with SHR-B2.
Thus hypertension in SHR-A3 and -B2 appears to arise from an overlapping set of susceptibility alleles, with SHR-A3 possessing an additional hypertension locus that contributes to further increase blood pressure.
最近大量全基因组单核苷酸多态性（SNP）的发展为研究具有高血压但对高血压终末器官疾病易感性不同的不同自发性高血压大鼠（SHR）品系之间的遗传关系提供了机会。
我们比较了高血压终末器官损伤易感的自发性高血压大鼠（SHR）-A3（SHRSP，SHR-易中风）品系和抗损伤的SHR-B2品系在近10000个SNP位点的基因型。这表明这两个品系在86.6%的基因组上通过遗传同源（IBD）。基因组中不是IBD的区域分布在20条常染色体中的19条和X染色体上。由来自不同祖先的SNP聚类形成了一个总共121个单倍型块的非IBD块结构。为了检验不同SHR品系共享一组共同的高血压易感等位基因的零假设，我们使用遥测技术比较了这两个品系及其F1和F2后代成年SHR动物的血压。在喂食正常饮食的16至18周龄动物中，SHR-A3的收缩压（SBP，mmHg）为205.7±3.86（平均值±标准误，n = 26），而在类似的SHR-B2动物中，SBP为186.7±2.53（n = 20）。在F1和F2动物中，SBP分别为188.2±4.23（n = 19）和185.6±1.1（n = 211）（P<10^(-6)，方差分析）。为了确定导致这些SHR品系血压差异的非IBD单倍型块，我们开发了一种高通量SNP基因分型系统，对标记非IBD块的SNP进行基因分型。我们在17号染色体上定位了一个延伸小于10 Mb的单个非IBD块，与SHR-B2相比，SHR-A3等位基因在该区域显著升高血压。
因此，SHR-A3和-B2中的高血压似乎源于一组重叠的易感等位基因，SHR-A3拥有一个额外的高血压基因座，有助于进一步升高血压。
