Functional Captures of Multiple Human Quantitative Trait Loci Regulating Blood Pressure with the Use of Orthologs in Genetically Defined Rat Models

Abstract

BackgroundMost 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. MethodsFor the first time, we used quantitative trait loci (QTLs) from Dahl salt-sensitive (DSS) rats as functional surrogates to capture human BP QTLs. ResultsA 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. ConclusionsThe 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.