Clinical and Genetic Correlates of Aldosterone-to-Renin Ratio and Relations to Blood Pressure in a Community Sample

Aldosterone:renin ratio (ARR) is used to screen for hyperaldosteronism. Data regarding correlates of ambulatory ARR in the community and its relation to hypertension incidence are limited. We defined clinical correlates of ARR, determined its heritability, tested for association and linkage, and related ARR to blood pressure (BP) progression in nonhypertensive individuals among 3326 individuals from the Framingham Heart Study (53% women; mean age: 59 years). Ambulatory morning ARR (serum aldosterone and plasma renin concentrations) were related to clinical covariates, genetic variation across the REN locus, a 10-cM linkage map, and among nonhypertensive participants (n=1773) to progression of ≥1 Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure BP category (optimal: <120/80 mm Hg, normal: 120 to 129/80 to 84 mm Hg, high normal: 130 to 139/85 to 89 mm Hg, hypertension: ≥140/90 mm Hg), or incident hypertension (systolic BP: ≥140 mm Hg, diastolic BP: ≥90 mm Hg, or use of antihypertensive treatment). ARR was positively associated with age, female sex, untreated hypertension, total/high-density lipoprotein cholesterol ratio, hormone replacement therapy, and &bgr;-blocker use, but negatively associated with angiotensin-converting enzyme inhibitor and diuretic use. ARR was heritable (h2=0.40), had modest linkage to chromosome 11p (logarithm of the odds: 1.89), but was not associated with 17 common variants in REN (n=1729). On follow-up (mean: 3 years), 607 nonhypertensive individuals (34.2%) developed BP progression, and 283 (16.0%) developed hypertension. Higher baseline logARR was associated with increased risk of BP progression (odds ratio per SD increment: 1.23; 95% CI: 1.11 to 1.37) and hypertension incidence (odds ratio per SD increment: 1.16; 95% CI: 1.00 to 1.33). ARR is a heritable trait influenced by clinical and genetic factors. There is a continuous gradient of increasing risk of BP progression across ARR levels in nonhypertensive individuals.

[1]  D. Duffy,et al.  Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity , 2005, Journal of hypertension.

[2]  F. Veglio,et al.  Drug Effects on Aldosterone/Plasma Renin Activity Ratio in Primary Aldosteronism , 2002, Hypertension.

[3]  W. Kannel,et al.  An investigation of coronary heart disease in families. The Framingham offspring study. , 1979, American journal of epidemiology.

[4]  W. Young,et al.  Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. , 2004, The Journal of clinical endocrinology and metabolism.

[5]  L. Lind,et al.  Metabolic cardiovascular risk factors and the renin-aldosterone system in essential hypertension. , 1992, Journal of human hypertension.

[6]  M. Yasujima,et al.  Effect of age on the renin-angiotensin-aldosterone system in normal subjects: simultaneous measurement of active and inactive renin, renin substrate, and aldosterone in plasma. , 1986, The Journal of clinical endocrinology and metabolism.

[7]  Anita L. DeStefano,et al.  Evidence for a Gene Influencing Blood Pressure on Chromosome 17: Genome Scan Linkage Results for Longitudinal Blood Pressure Phenotypes in Subjects From the Framingham Heart Study , 2000, Hypertension.

[8]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[9]  P. Whelton,et al.  The renin-angiotensin system and blood pressure: differences between blacks and whites. , 1999, American journal of hypertension.

[10]  D. Levy,et al.  Serum aldosterone and the incidence of hypertension in nonhypertensive persons. , 2004, The New England journal of medicine.

[11]  J. Norris,et al.  Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study , 2003, BMC Genetics.

[12]  M. Stowasser,et al.  Primary aldosteronism: learning from the study of familial varieties. , 2000, Journal of hypertension.

[13]  L. Lind,et al.  Serum aldosterone changes during hyperinsulinemia are correlated to body mass index and insulin sensitivity in patients with essential hypertension , 2001, Journal of hypertension.

[14]  J. Conn.  Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. , 1955, The Journal of laboratory and clinical medicine.

[15]  L Kruglyak,et al.  Exact multipoint quantitative-trait linkage analysis in pedigrees by variance components. , 2000, American journal of human genetics.

[16]  R. Schmieder,et al.  Aliskiren, a Novel Orally Effective Renin Inhibitor, Provides Dose-Dependent Antihypertensive Efficacy and Placebo-Like Tolerability in Hypertensive Patients , 2005, Circulation.

[17]  P. Weidmann,et al.  Age versus urinary sodium for judging renin, aldosterone, and catecholamine levels: studies in normal subjects and patients with essential hypertension. , 1978, Kidney international.

[18]  P. Hamet,et al.  Genetic determinants of hypertension: identification of candidate phenotypes. , 2000, Hypertension.

[19]  C. Gomez-Sanchez,et al.  The intravenous furosemide test: a simple way to evaluate renin responsiveness. , 1976, Annals of internal medicine.

[20]  David W. Hosmer,et al.  Best subsets logistic regression , 1989 .

[21]  O. M. Helmer.  RENIN ACTIVITY IN BLOOD FROM PATIENTS WITH HYPERTENSION. , 1964, Canadian Medical Association journal.

[22]  Detection.  The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) , 1997 .

[23]  J. Staessen,et al.  Effect of chronic diuretic treatment on the plasma renin-angiotensin-aldosterone system in essential hypertension. , 1981, British journal of clinical pharmacology.

[24]  Crane Mg,et al.  Effect of aging on renin activity and aldosterone excretion. , 1976 .

[25]  A. Kong,et al.  The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. , 2005, The Journal of clinical endocrinology and metabolism.

[26]  Christopher A. Haiman,et al.  Choosing Haplotype-Tagging SNPS Based on Unphased Genotype Data Using a Preliminary Sample of Unrelated Subjects with an Example from the Multiethnic Cohort Study , 2003, Human Heredity.

[27]  T. MacDonald,et al.  Potentially high prevalence of primary aldosteronism in a primary-care population , 1999, The Lancet.

[28]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[29]  E. Boerwinkle,et al.  Validity of the aldosterone-renin ratio used to screen for primary aldosteronism. , 2001, Mayo Clinic proceedings.

[30]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[31]  K. Narkiewicz,et al.  Genetic determinants of plasma ACE and renin activity in young normotensive twins. , 1999, Journal of hypertension.

[32]  C. Grim.  Evolution of diagnostic criteria for primary aldosteronism: Why is it more common in "drug-resistant" hypertension today? , 2004, Current hypertension reports.

[33]  J. Grose,et al.  Dissociation Between Renin and Aldosterone During Chronic Diuretic Therapy. Effect of the Addition of a Beta Blocker, Timolol , 1979, Journal of clinical pharmacology.

[34]  E. Tatum.  GENETIC DETERMINANTS , 1964 .

[35]  R. Lammintausta,et al.  The renin-aldosterone system in low-dose chlorothiazide treatment of hypertensive subjects. , 1980, International journal of clinical pharmacology, therapy, and toxicology.

[36]  D. Kleinbaum,et al.  Applied Regression Analysis and Other Multivariate Methods , 1978 .

[37]  H. Schunkert,et al.  Effects of estrogen replacement therapy on the renin-angiotensin system in postmenopausal women. , 1997, Circulation.

[38]  S. Reznikov,et al.  Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. , 1991, The Journal of clinical endocrinology and metabolism.

[39]  S. Umemura,et al.  Plasma angiotensinogen concentrations in obese patients. , 1997, American journal of hypertension.

[40]  D. Hosmer,et al.  Applied Logistic Regression , 1991 .

[41]  O. Olivieri,et al.  Aldosterone to Renin ratio in a primary care setting: the Bussolengo study. , 2004, The Journal of clinical endocrinology and metabolism.

[42]  J. Murabito,et al.  Clinical and genetic correlates of serum aldosterone in the community: the Framingham Heart Study. , 2005, American journal of hypertension.

[43]  S. Zeger,et al.  Longitudinal data analysis using generalized linear models , 1986 .

[44]  B. Egan,et al.  Aldosterone in obesity. , 1998, Endocrine research.

[45]  J. Laragh,et al.  Renin relationship to sex, race and age in a normotensive population. , 1986, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[46]  S. Hunt,et al.  Genetic Traits Related to Hypertension and Electrolyte Metabolism , 1991, Hypertension.

[47]  C. Maser-Gluth,et al.  Rapid screening test for primary hyperaldosteronism: ratio of plasma aldosterone to renin concentration determined by fully automated chemiluminescence immunoassays. , 2004, Clinical chemistry.

[48]  A. Weyman,et al.  Cardiovascular and Humoral Responses to Extremes of Sodium Intake in Normal Black and White Men , 1979, Circulation.

[49]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[50]  P. Weidmann,et al.  Interrelations among blood pressure, blood volume, plasma renin activity and urinary catecholamines in benign essential hypertension. , 1977, The American journal of medicine.

[51]  M. G. Crane,et al.  Effect of aging on renin activity and aldosterone excretion. , 1976, The Journal of laboratory and clinical medicine.

[52]  J. Hall,et al.  The renin-angiotensin system and long-term regulation of arterial pressure. , 1986, Journal of hypertension.

[53]  B. Egan,et al.  Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans. , 1995, Hypertension.

[54]  R. Weinshilboum,et al.  The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. , 1997, Archives of internal medicine.

[55]  Z. Kamenov,et al.  Ambulatory blood pressure monitoring and active renin in menopausal women treated with amlodipine and hormone replacement therapy , 2004, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[56]  L. Hansson,et al.  Remikiren (Ro 42-5892)--an orally active renin inhibitor in essential hypertension. Effects on blood pressure and the renin-angiotensin-aldosterone system. , 1996, American journal of hypertension.

[57]  S. Zacharieva,et al.  Effect of different hormone replacement therapy regimens on circadian blood pressure profile and active renin in postmenopausal women , 2002, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[58]  Daniel Levy,et al.  Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study , 2001, The Lancet.

[59]  T. MacDonald,et al.  The current epidemic of primary aldosteronism: causes and consequences. , 2004, Journal of hypertension.

[60]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[61]  J. Laragh,et al.  Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. , 1991, The New England journal of medicine.

[62]  J. Laragh,et al.  Essential hypertension: renin and aldosterone, heart attack and stroke. , 1972, The New England journal of medicine.

[63]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[64]  C. Stratakis,et al.  A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22) , 2000, Journal of medical genetics.

[65]  T. MacDonald,et al.  Primary aldosteronism, diagnosed by the aldosterone to renin ratio, is a common cause of hypertension , 2003, Clinical endocrinology.

[66]  M. Weinberger,et al.  Plasma renin activity and aldosterone secretion in hypertensive patients during high and low sodium intake and administration of diuretic. , 1968, The Journal of clinical endocrinology and metabolism.

[67]  G. Stevenson.  Immunotherapy of non-metastatic complication of malignant disease , 1999, The Lancet.

[68]  M. Stowasser,et al.  HIGH INCIDENCE OF PRIMARY ALDOSTERONISM IN 199 PATIENTS REFERRED WITH HYPERTENSION , 1994, Clinical and experimental pharmacology & physiology.