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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2016

Open Access 01-12-2016 | Research article

Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system

Authors: Nilima Biswas, Adam X. Maihofer, Saiful Anam Mir, Fangwen Rao, Kuixing Zhang, Srikrishna Khandrika, Manjula Mahata, Ryan S. Friese, C. Makena Hightower, Sushil K. Mahata, Dewleen G. Baker, Caroline M. Nievergelt, Sucheta M. Vaingankar, Daniel T. O’Connor

Published in: BMC Medical Genetics | Issue 1/2016

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Abstract

Background

Plasma coagulation Factor XIIa (Hageman factor; encoded by F12) and kallikrein (KAL or Fletcher factor; encoded by KLKB1) are proteases of the kallikerin-kinin system involved in converting the inactive circulating prorenin to renin. Renin is a key enzyme in the formation of angiotensin II, which regulates blood pressure, fluid and electrolyte balance and is a biomarker for cardiovascular, metabolic and renal function. The renin-angiotensin system is implicated in extinction learning in posttraumatic stress disorder.

Methods & Results

Active plasma renin was measured from two independent cohorts- civilian twins and siblings, as well as U.S. Marines, for a total of 1,180 subjects. Genotyping these subjects revealed that the carriers of the minor alleles at the two loci- F12 and KLKB1 had a significant association with reduced levels of active plasma renin. Meta-analyses confirmed the association across cohorts. In vitro studies verified digestion of human recombinant pro-renin by kallikrein (KAL) to generate active renin. Subsequently, the active renin was able to digest the synthetic substrate angiotensinogen to angiotensin-I. Examination of mouse juxtaglomerular cell line and mouse kidney sections showed co-localization of KAL with renin. Expression of either REN or KLKB1 was regulated in cell line and rodent models of hypertension in response to oxidative stress, interleukin or arterial blood pressure changes.

Conclusions

The functional variants of KLKB1 (rs3733402) and F12 (rs1801020) disrupted the cascade of enzymatic events, resulting in diminished formation of active renin. Using genetic, cellular and molecular approaches we found that conversion of zymogen prorenin to renin was influenced by these polymorphisms. The study suggests that the variant version of protease factor XIIa due to the amino acid substitution had reduced ability to activate prekallikrein to KAL. As a result KAL has reduced efficacy in converting prorenin to renin and this step of the pathway leading to activation of renin affords a potential therapeutic target.
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Metadata
Title
Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system
Authors
Nilima Biswas
Adam X. Maihofer
Saiful Anam Mir
Fangwen Rao
Kuixing Zhang
Srikrishna Khandrika
Manjula Mahata
Ryan S. Friese
C. Makena Hightower
Sushil K. Mahata
Dewleen G. Baker
Caroline M. Nievergelt
Sucheta M. Vaingankar
Daniel T. O’Connor
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2016
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/s12881-016-0283-5

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