title: Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system.
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.
  
  
  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.
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA. nbiswas33@gmail.com.
authors.forename: Nilima
authors.initials: N
authors.lastname: Biswas
authors.affiliation: Veteran Affairs (VA) San Diego Health Care System and VA Center of Excellence for Stress and Mental Health, 3350 La Jolla Village Drive, San Diego, 92161, USA.
authors.forename: Adam X
authors.initials: AX
authors.lastname: Maihofer
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Saiful Anam
authors.initials: SA
authors.lastname: Mir
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Srikrishna
authors.initials: S
authors.lastname: Khandrika
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Friese
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: C Makena
authors.initials: CM
authors.lastname: Hightower
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.|Department of Psychiatry, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.affiliation: Veteran Affairs (VA) San Diego Health Care System and VA Center of Excellence for Stress and Mental Health, 3350 La Jolla Village Drive, San Diego, 92161, USA.|Department of Psychiatry, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Dewleen G
authors.initials: DG
authors.lastname: Baker
authors.affiliation: Veteran Affairs (VA) San Diego Health Care System and VA Center of Excellence for Stress and Mental Health, 3350 La Jolla Village Drive, San Diego, 92161, USA. cnievergelt@ucsd.edu.|Department of Psychiatry, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA. cnievergelt@ucsd.edu.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA. svaingankar@ucsd.edu.
authors.forename: Sucheta M
authors.initials: SM
authors.lastname: Vaingankar
authors.affiliation: Departments of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.|Departments of Pharmacology, Institute of Genomic Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093-0838, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000803:Angiotensin I / Q000097:blood; D000808:Angiotensinogen / Q000097:blood; D000818:Animals; D001794:Blood Pressure; D018797:Cell Cycle Proteins; D002460:Cell Line; D015956:Factor XIIa / Q000235:genetics*; D005786:Gene Expression Regulation; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007606:Juxtaglomerular Apparatus / Q000166:cytology; D007610:Kallikreins / Q000097:blood / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011288:Prekallikrein / Q000378:metabolism; D012083:Renin / Q000097:blood* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D012697:Serine Endopeptidases / Q000378:metabolism; D014166:Transferases; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D000808:Angiotensinogen; D000803:Angiotensin I; D011288:Prekallikrein; C466095:Kctd11 protein, mouse; D014166:Transferases; D007610:Kallikreins; D012697:Serine Endopeptidases; C028736:zymogen E; D015956:Factor XIIa; D012083:Renin
keywords: FXIIa (active protease encoded by gene F12 or Hageman factor); Hypertension; Kallikrein/KAL (active protease encoded for by gene KLKB1 or Fletcher factor); PTSD (posttraumatic stress disorder); rs1801020; rs3733402