Biological convergence of three human and animal model quantitative trait loci for blood pressure.

Alan Y Deng, Annie Ménard

Journal of hypertension 2020 Feb

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Blood pressure (BP) is comparable among different mammalian orders, despite their evolution divergence. Because of it, fundamental mechanisms should connect humans and rodents by their shared BP physiology. We hypothesized that similar quantitative trait loci (QTLs) function in both humans and rodents in controlling BP. We utilized inbred hypertensive Dahl salt-sensitive rats (DSS) as a functional proxy to evaluate the relevance of human genome-wide association studies (GWAS) genes in BP regulation. First, three DSS BP QTLs functionally captured three specific human GWAS genes. Each QTL has a major biological impact, not a miniscule effect, on BP, in causation by function. Second, noncoding single-nucleotide polymorphisms (SNPs) found in GWAS are by products of primate evolution, instead of mechanistic drivers in regulating BP, because their absence did not impact on BP of mammals. Third, a missense mutation, rather than a noncoding GWAS SNP marking it nearby, is the priority functional basis for a given QTL. Depleting such a noncoding GWAS SNP had no impact, whereas eliminating the muscarinic cholinergic receptor 3 (M3R) signaling decreased BP. Finally, epistatic modularity biologically organizes multiple QTLs with redundant functions, and is the genetic mechanism that modulates the BP homeostasis when QTLs function collectively. Two pathogenic pathways of hypertension biologically unify mechanisms of BP regulations for humans and their functional surrogates. The mechanism-based biology for the M3R-mediated pathway in raising BP has established M3R as a novel pathogenesis-driven target for antihypertension therapies.

Citation

Alan Y Deng, Annie Ménard. Biological convergence of three human and animal model quantitative trait loci for blood pressure. Journal of hypertension. 2020 Feb;38(2):322-331