Is Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension?

HomeCirculation: Genomic and Precision MedicineVol. 11, No. 4Is Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIs Plasma Renin Activity Genetically Determined and How Much Does It Matter for Treating Hypertension? Francois Alhenc-Gelas, MD and Joel Menard, MD Francois Alhenc-GelasFrancois Alhenc-Gelas INSERM U1138, Paris-Descartes University, Sorbonne University, France. and Joel MenardJoel Menard INSERM U1138, Paris-Descartes University, Sorbonne University, France. Originally published12 Apr 2018https://doi.org/10.1161/CIRCGEN.118.002139Circulation: Genomic and Precision Medicine. 2018;11:e002139See Article by McDonough et alAbundance of a protein in tissues or fluids is probably a quantitative genetic trait in most or even all cases. This can, however, be difficult recognizing and quantifying, depending on whether cellular or secreted proteins are considered and whether synthesis is mainly constitutive or also under the influence of potent physiological, lifestyle-related factors.The issue can be exemplified by protein components of vasomotor peptide systems, renin–angiotensin, and kallikrein–kinin. Genetic determinism of angiotensin-converting enzyme (kininase II) level in plasma or kallikrein activity in urine has been recognized long ago, through familial transmission studies.1,2 Molecular basis for the genetic variability was documented later when gene structure became known.3,4 Genetic polymorphism of plasma angiotensinogen level has also been documented, in that case through genotype–phenotype association study and further gene studies addressing causality and mechanism.5,6These cellular and secreted proteins, angiotensin-converting enzyme, kallikrein, and angiotensinogen are mainly synthesized constitutively, only submitted to mild hormonal influences. There is little or no interference of hemodynamic status and dietary factors with the effect of genetic background, explaining the observation of a strong heritable component of the population variance of plasma or urinary level in transmission and genomic association studies.7 What about renin?Renin Level As a Genetic Trait?Renin synthesis and secretion are largely modulated, acutely and chronically, by renal hemodynamic status, sympathetic nervous system activity, and sodium balance. Renin is synthesized as prorenin in various tissues, but prorenin is only activated in the kidney, in juxtaglomerular cells. Both prorenin and active renin are secreted in plasma. Measurement of active renin has both physiological and clinical relevance and is used, routinely for diagnosis of secondary forms of hypertension. Excess renin secretion is the primary cause of hypertension in renal artery stenosis, and deregulation of the renin-extracellular fluid volume balance is considered to play a prominent role in essential hypertension, a well-established genetic disorder.8 Accordingly, documenting genetic variability in renin level may not only have cognitive interest but also diagnosis application.However, although renin secretion displays large intersubject variability but good within-subject reproducibility,9 there is no strong evidence for a genetic determinism of plasma renin level. Renin is influenced by ethnicity, but this may be linked to renal physiological status. No familial transmission of prorenin or active renin level has been documented to date, albeit mild evidence for heritability was obtained in a twin study.10,11 Instead, intersubject variability in plasma renin activity (PRA) has been linked, in hypertensive subjects, to urinary sodium excretion, a typical lifestyle-related parameter reflecting dietary sodium intake and, at steady state, extracellular fluid volume.8The issue of genetic influence on PRA can nevertheless be addressed through genomic association studies. The approach can now benefit from whole genome scanning.12Renin As a Pharmacogenomic Biomarker?A genome-wide association study (GWAS) of renin is reported by Mc Donough et al13 in the present issue of Circulation: Genomic and Precision Medicine. The study was performed in hypertensive subjects from the PEAR I and PEAR II cohorts (Pharmacogenomic Evaluation of Antihypertensive Responses) and comprises an interesting attempt at the pharmacogenomic extension.Strength of the Mc Donough et al13 study relies on the quality of the cohorts and use of a centralized, reference method for measuring PRA. The PEAR studies address pharmacogenomic evaluation of antihypertensive responses. In PEAR I, the discovery cohort for the renin study, hydrochlorothiazide, a diuretic, or atenolol, a β-blocking agent, were administered as first-line treatment.Several single-nucleotide polymorphisms (SNPs) in several different genomic regions were found to be associated, at a reasonable level of statistical confidence, with baseline PRA, especially in white subjects. Introduction in the analysis of urinary sodium excretion did not alter the main associations. Some of the PRA-associated variants were further tested, through an original prioritization procedure, for functionality by expression quantitative trait locus analysis in RNA from blood cells and for replication of association with PRA in PEAR II.The pharmacogenomic-based prioritization system used for testing SNPs is worth commenting on because of its clinical basis. Prioritization was based on the association of SNP with blood pressure response to hydrochlorothiazide and atenolol. Studies have indeed documented that, at the population level, hypertensive subjects having high PRA respond better to β-blocking agents, whereas those having low PRA respond better to diuretics.14 The former are considered to have renin rather than volume dependent hypertension and the latter the opposite, although this may be sort of an oversimplification. β-blocking agents lower blood pressure in large part through inhibition of renin secretion.15 Therefore, combining the 2 phenotypes, PRA and PRA-dependent therapeutic response may seem logical, providing dual biochemical, and functional (pharmacological) appraisal of renin status in hypertensive subjects. In addition, the approach can identify pharmacogenomic biomarkers.The result of this prioritization attempt is interesting but probably less impressive than may have been expected by the authors: association of candidate SNPs with the expected therapeutic response was observed for 8 SNPs in Whites and 4 in Blacks but in all cases effect was dissociated among the 2 drugs, in partial disagreement with the renin hypothesis. No perfect SNP associated with PRA and with both atenolol and hydrochlorothiazide responses, in the expected directions, was identified in the study. It can be also noted that the variants previously found to be associated with blood pressure response to these drugs in PEAR did not come out in the renin GWAS.13PRA and therapeutic response to antihypertensive agents are 2 different, only partly overlapping phenotypes and this may explain dissociation among drugs, among ethnic groups and among studies. Also, issues of power and multiple testing arise, and chance finding may not be excluded in all cases. Replication of the pharmacogenomic associations has not been tested, but this may be eventually done in PEAR II.Accordingly, SNPs that passed pharmacogenomic prioritization are good candidates for physiological and pharmacological studies, especially if they displayed functionality and replication in PEAR II. The corresponding genomic regions can be further studied for identifying candidate genes and approaching causality. But those that did not pass prioritization should nevertheless be considered for replication of association with PRA in PEAR II and in other studies.Renin and GWASThere have been to date 2 GWAS of renin, performed either in normotensive or in hypertensive populations. Both were published in the Journal.12,13 Results do not overlap between studies. This may tentatively be explained by differences in ethnic composition and health status between the populations studied. In the first study,12 the plasma (pre)kallikrein gene (not to be confounded with tissue kallikrein discussed above) and the kininogen gene were found to be associated with active renin level. The corresponding locus did not come out in the present study.It is interesting to note that prekallikrein is activated during blood sampling in the contact system of coagulation and can convert prorenin to active renin, in vitro.16 It is not known whether this may have influenced the data in both studies.Overall, renin GWAS illustrate the difficulty of documenting genotype–phenotype relationship for proteins that may not have a strong genetic determinism. The authors have addressed the issue in well-phenotyped populations and by using powerful genome analysis procedures. As usual, let's wait for replication and further gene identification.Considering plasma prorenin as a phenotype in studies might also clarify the issue. Clinical investigation of the renin–angiotensin system has been characterized by the extreme precautions taken to correct results of active renin measurement, either by enzymatic or immunoradiometric assays, according to age, position, time of the day, sodium intake, or urinary sodium excretion. These conditions, necessary for providing accurate diagnosis information, are not fulfilled in most epidemiological studies and many therapeutic trials. Nevertheless, in less stringent conditions than for clinical care, measurement of active renin has been able to predict the incidence of hypertension and major cardiovascular events.17,18But the measurement of active renin might not be the most suitable phenotype for investigating the association of renin level with polymorphisms or mutations in molecular genetic studies. The protein gene product is prorenin, which is subsequently activated and released by the kidney. Prorenin is also produced outside the kidney and is less sensitive to physiological variations governing active renin release. Large samples of subjects will still be necessary for detecting relevant association, but prorenin measurement is easy to perform by trypsin activation or immunometric assay.19 Measuring prorenin should allow investigating a different genetic association than that of active renin release by the kidney.20 Both prorenin and active renin are key regulators of the sodium-pressure loop, with a very likely genetic component.The study by McDonough et al13 is the second attempt to look at GWA of renin, but for several reasons, statistical power and choice of phenotype, it should open an avenue rather than close a research.Sources of FundingThis study supported by INSERM, Paris-Descartes University, Sorbonne University.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circgenetics.ahajournals.orgFrancois Alhenc-Gelas, MD, INSERM U1138, Paris-Descartes University, Sorbonne University, Cordeliers Research Center, 15 Rue de l'Ecole de Medecine, 75006 Paris, France. 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April 2018Vol 11, Issue 4 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002139PMID: 29650769 Originally publishedApril 12, 2018 Keywordsessential hypertensionKallikrein-Kinin Systemrenin-angiotensin systemEditorialsGenome-Wide Association Studyreningenetic determinismpharmacogeneticsPDF download Advertisement SubjectsACE/Angiotensin Receptors/Renin Angiotensin SystemClinical StudiesGenetic, Association StudiesHypertensionPharmacology