Research Centre, Centre Hospitalier de l'Université de Montréal, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
Research Centre, Centre Hospitalier de l'Université de Montréal, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
Can J Cardiol. 2020 May;36(5):756-763. doi: 10.1016/j.cjca.2020.03.012. Epub 2020 Mar 18.
Most signals from human genome-wide association studies (GWAS) for blood pressure (BP) are single-nucleotide polymorphisms (SNPs). It was unknown if such SNPs can functionally affect BP. Because BP is similar between humans and rodents, unraveling basic mechanisms from rodents can reveal the same BP-modulating mechanisms in humans originating from their common ancestors while overcoming limitations in human epidemiology.
For the first time, we used quantitative trait loci (QTLs) from Dahl salt-sensitive (DSS) rats as functional surrogates to capture human BP QTLs.
A total of 107 human GWAS genes may be classified into 2 common pathways of hypertension pathogeneses. Among them, 4 DSS BP QTLs correspond to 4 human GWAS genes. Each of them independently showed a major impact on BP in vivo and thus functional redundancy. BP was altered by each of these 4 QTLs, but human GWAS SNPs marking these QTLs do not exist in the rat. They cannot be responsible for physiological changes in BP caused by these QTLs and are genome signposts marking positions of the QTLs nearby, rather than being QTLs themselves. These SNPs appeared during primate evolution, independently of BP regulation. Because the functional dosage of QTLs, not their gene dose, determined hypertension pathogenesis, a role for the noncoding GWAS SNPs in BP via regulating gene expressions can be discounted.
The human QTLs may function in a common pathway, with each involved in a different step in the pathway leading to BP control. These results may be conceptually paradigm shifting.
大多数血压（BP）全基因组关联研究（GWAS）的信号都是单核苷酸多态性（SNP）。这些 SNP 是否能在功能上影响 BP 尚不清楚。由于人类和啮齿动物之间的 BP 相似，从啮齿动物中解开基本机制可以揭示人类起源于共同祖先的相同的 BP 调节机制，同时克服了人类流行病学的局限性。
我们首次使用了达勒盐敏感（DSS）大鼠的数量性状基因座（QTL）作为功能替代物来捕获人类 BP QTL。
共有 107 个人类 GWAS 基因可分为高血压发病机制的 2 个共同途径。其中，4 个 DSS BP QTL 对应 4 个人类 GWAS 基因。它们各自独立地在体内对 BP 产生了重大影响，因此存在功能冗余。这些 QTL 中的每一个都改变了 BP，但标记这些 QTL 的人类 GWAS SNP 并不存在于大鼠中。它们不能对这些 QTL 引起的 BP 生理变化负责，而只是基因组标志，标记附近 QTL 的位置，而不是 QTL 本身。这些 SNP 出现在灵长类动物进化过程中，与 BP 调节无关。由于 QTL 的功能剂量，而不是基因剂量，决定了高血压的发病机制，因此可以排除非编码 GWAS SNP 通过调节基因表达在 BP 中发挥作用的可能性。
人类 QTL 可能在一个共同的途径中发挥作用，每个 QTL 都参与了导致 BP 控制的途径中的不同步骤。这些结果可能在概念上具有颠覆性。
