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Two candidate genes for two quantitative trait loci epistatically attenuate hypertension in a novel pathway

Chauvet, Cristina; Ménard, Annie; Deng, Alan Y.

doi: 10.1097/HJH.0000000000000626
ORIGINAL PAPERS: Genetic aspects
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Objectives: Multiple quantitative trait loci (QTLs) for blood pressure (BP) have been detected in rat models of human polygenic hypertension. They influence BP physiologically via epistatic modules. Little is known about the causal genes and virtually nothing is known on modularized mechanisms governing their regulatory connections.

Methods and results: Two genes responsible for two individual BP QTLs on rat Chromosome 18 have been identified that belong to the same epistatic module. Treacher Collins-Franceschetti syndrome 1 (Tcof1) gene is the only function candidate for C18QTL3. Haloacid dehalogenase like hydrolase domain containing 2 (Hdhd2), although a gene of previously unknown function, is C18QTL4, and encodes a newly identified phosphatase. The current work has provided the premier evidence that Hdhd2/C18QTL4 and Tcof1/C18QTL3 may be involved in polygenic hypertension. Hdhd2/C18QTL4 can regulate the function of Tcof1/C18QTL3 via de-phosphorylation, and, for the first time, furbishes a molecular mechanism in support of a genetically epistatic hierarchy between two BP QTLs, and thus authenticates the epistasis-common pathway paradigm.

Conclusion: The pathway initiated by Hdhd2/C18QTL4 upstream of Tcof1/C18QTL3 reveals novel mechanistic insights into BP modulations. Their discovery might yield innovative therapeutic targets and diagnostic tools predicated on a novel BP cause and mechanism that is determined by a regulatory hierarchy. Optimizing the de-phosphorylation capability and its downstream target could be antihypertensive. The conceptual paradigm of an order and regulatory hierarchy may help unravel genetic and molecular relationships among certain human BP QTLs.

Research Centre, CRCHUM (Centre hospitalier de l’Université de Montréal), Department of Medicine, Université de Montréal, Montréal, Québec, Canada

Correspondence to Alan Y. Deng, Research Centre, Centre hospitalier de l’Université de Montréal (CHUM), 900 rue St. Denis Street, R08-432, Montréal, QC H2X 0A9, Canada. Tel: +1 514 890 8000 x23614; fax: +1 514 412 7655; e-mail: alan.deng@umontreal.ca

Abbreviations: BP, blood pressure; Chr, chromosome; DSS, Dahl salt-sensitive rats; GWAS, genome-wide association study; MAP, mean arterial pressure; QTL, quantitative trait locus

Received 10 December, 2014

Revised 10 April, 2015

Accepted 10 April, 2015

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