Calcium-phosphorus Metabolism And The Risk Of Cardiovascular Disease
Eric N Taylor
Brigham And Women´s Hospital
Grant 1R01HL092947-01A1 from National Heart, Lung, And Blood Institute IRG: CASE
Abstract: The goal of this application is to answer clinically and scientifically important questions about the role of calcium-phosphorus homeostasis in the development of cardiovascular disease. First, we will determine the associations between parathyroid hormone (PTH) and the development of coronary heart disease (CHD) and hypertension. By direct or indirect actions on bone, kidney, and intestine, PTH plays a central role in calcium and phosphorus balance. However, the PTH receptor also is expressed in vascular smooth muscle and the endothelium, and PTH increases the endothelial expression of factors implicated in endothelial dysfunction and atherosclerosis, such as endothelin-1, the receptor of advanced glycation end products, and IL-6. Second, we will clarify the independent associations between plasma levels of 25-hydroxyvitamin D (25[OH]D), calcium, phosphorus, PTH, creatinine and incident CHD. Previous prospective studies of calcium-phosphorus metabolism and CHD risk did not simultaneously measure these interrelated factors. Finally, we aim to resolve existing controversies about supplemental calcium use, phosphorus intake and the risk of incident CHD. We plan to conduct prospective nested case-control studies of the independent associations between plasma levels of intact PTH, 25(OH)D, calcium, and phosphorus and the risk of CHD and hypertension in the Health Professionals Follow-up Study (HPFS; N=51,529 men) and the Nurses´ Health Study (NHS; N=121,700 women). We also plan to conduct prospective cohort studies examining the relations between supplemental calcium use, phosphorus intake, and incident CHD. Because previous data suggest an association between PTH and hypertension in men but not pre-menopausal women, we will determine whether the impact of PTH on the risk of hypertension in post-menopausal women varies by use of post-menopausal hormones. This application represents the first large-scale prospective effort to examine the impact of PTH on CHD risk in individuals without primary hyperparathyroidism or chronic kidney disease. The unique strengths of this application include 1) updated, detailed exposure information accumulated prospectively over long periods, 2) archived plasma, and 3) large sample sizes providing high statistical power. We expect our studies of calcium and phosphorus metabolism to provide new insights into the development of cardiovascular disease and to identify several novel and modifiable coronary heart disease risk factors. Our findings may stimulate future research that eventually allows factors regulating calcium- phosphorus balance to serve as targets for the prevention of coronary heart disease and hypertension
Project start date: 2009-06-15
Project end date: 2012-04-30
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Eric N Taylor
CALCIUM-PHOSPHORUS METABOLISM AND THE RISK OF CARDIOVASCULAR DISEASE
Eric N Taylor
Brigham And Women´s Hospital, Research Administration, Boston, Ma 02115
Grant 5R01HL092947-02 from National Heart, Lung, And Blood Institute
Abstract: The goal of this application is to answer clinically and scientifically important questions about the role of calcium-phosphorus homeostasis in the development of cardiovascular disease. First, we will determine the associations between parathyroid hormone (PTH) and the development of coronary heart disease (CHD) and hypertension. By direct or indirect actions on bone, kidney, and intestine, PTH plays a central role in calcium and phosphorus balance. However, the PTH receptor also is expressed in vascular smooth muscle and the endothelium, and PTH increases the endothelial expression of factors implicated in endothelial dysfunction and atherosclerosis, such as endothelin-1, the receptor of advanced glycation end products, and IL-6. Second, we will clarify the independent associations between plasma levels of 25-hydroxyvitamin D (25[OH]D), calcium, phosphorus, PTH, creatinine and incident CHD. Previous prospective studies of calcium-phosphorus metabolism and CHD risk did not simultaneously measure these interrelated factors. Finally, we aim to resolve existing controversies about supplemental calcium use, phosphorus intake and the risk of incident CHD. We plan to conduct prospective nested case-control studies of the independent associations between plasma levels of intact PTH, 25(OH)D, calcium, and phosphorus and the risk of CHD and hypertension in the Health Professionals Follow-up Study (HPFS; N=51,529 men) and the Nurses´ Health Study (NHS; N=121,700 women). We also plan to conduct prospective cohort studies examining the relations between supplemental calcium use, phosphorus intake, and incident CHD. Because previous data suggest an association between PTH and hypertension in men but not pre-menopausal women, we will determine whether the impact of PTH on the risk of hypertension in post-menopausal women varies by use of post-menopausal hormones. This application represents the first large-scale prospective effort to examine the impact of PTH on CHD risk in individuals without primary hyperparathyroidism or chronic kidney disease. The unique strengths of this application include 1) updated, detailed exposure information accumulated prospectively over long periods, 2) archived plasma, and 3) large sample sizes providing high statistical power. We expect our studies of calcium and phosphorus metabolism to provide new insights into the development of cardiovascular disease and to identify several novel and modifiable coronary heart disease risk factors. Our findings may stimulate future research that eventually allows factors regulating calcium- phosphorus balance to serve as targets for the prevention of coronary heart disease and hypertension
Keywords: 25-hydroxyvitamin D; 4H-Imidazol-4-one, 2-amino-1, 5-dihydro-1-methyl-; Address; Advanced Glycosylation End Products; Angiotensin-Forming Enzyme; Angiotensinogenase; Archives; Arterial Fatty Streak; Atheroma; Atheromatous; Atheromatous degeneration; Atheromatous plaque; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; Autoregulation; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Blood Coagulation Factor IV; Blood Plasma; Blood Pressure; Blood Pressure, High; Bone; Bone and Bones; Bones and Bone Tissue; CREA; Ca++ element; Calcium; Cardiac infarction; Cardiovascular Diseases; Cessation of life; Chemotherapy-Hormones/Steroids; Chronic; Chronic Kidney Failure; Chronic Renal Disease; Coagulation Factor IV; Cohort Studies; Concurrent Studies; Coronary Disease; Coronary heart disease; Creatinine; Data; Death; Development; Differentiation Factor, B-Cell; Dysfunction; Endocrine Gland Secretion; Endothelin A Receptor; Endothelium; Equilibrium; Estrogenic Agents; Estrogenic Compounds; Estrogens; Factor IV; Follow-Up Studies; Followup Studies; Functional disorder; Future; Glycation End Products, Advanced; Glycosylation End Products, Advanced; Goals; HPGF; Health Care Professional; Health Professional; Health profession; Healthcare professional; Healthcare worker; Hepatocyte-Stimulating Factor; Homeostasis; Hormones; Hybridoma Growth Factor; Hyperparathyroidism; Hypertension; IFN-beta 2; IFNB2; IL-6; IL6 Protein; INFLM; Individual; Inflammation; Infusion; Infusion procedures; Intake; Interleukin 6 (Interferon, Beta 2); Interleukin-6; Intestinal; Intestines; Kidney; Kidney Failure, Chronic; Ligands; MGI-2; Measures; Mediating; Muscle, Smooth, Vascular; Myeloid Differentiation-Inducing Protein; Myocardial Infarct; Myocardial Infarction; Nested Case-Control Study; Nuclear; Nurses` Health Study; ODF; OPGL; Organ; P element; PTH (1-84); PTH protein, human; PTH-PTHrP Receptor; PTH-Related Peptide Receptor; PTH-Related Protein Receptor; PTHLP Receptor; PTHrP Receptor; Parathyroid Hormone; Parathyroid Hormone (1-84); Parathyroid Hormone Receptor; Parathyroid Hormone Receptor 1; Parathyroid Hormone Receptor Type I; Parathyroid Hormone Receptors; Parathyroid Hormone-Related Peptide Receptor; Parathyroid Hormones; Phosphorus; Physiological Homeostasis; Physiopathology; Plasma; Plasmacytoma Growth Factor; Play; Population; Post-Menopause; Post-menopausal Period; Postmenopausal Period; Postmenopause; Pre-Menopause; Pre-menopausal Period; Premenopausal; Premenopausal Period; Premenopause; Prevention; Prospective Studies; RANKL; Receptor Protein; Receptor, Endothelin A; Receptor, Endothelin-1; Receptor, Parathyroid Hormone, Type 1; Receptor, Parathyroid Hormone-Like Peptide; Renal Failure, Chronic; Renin; Reporting; Research; Resistance; Reticuloendothelial System, Serum, Plasma; Risk; Risk Factors; Role; Rupture; Sample Size; Serum, Plasma; Skeleton; Stimulus; Streaks, Arterial Fatty; TNFSF11; TNFSF11 gene; Therapeutic Estrogen; Therapeutic Hormone; Update; Urinary System, Kidney; Variant; Variation; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Vascular calcification; Woman; advanced glycation endproduct; atheromatosis; atherosclerosis plaque; atherosclerotic lesions; atherosclerotic plaque; atherosclerotic vascular disease; balance; balance function; bone; bone turnover; bowel; cardiac disease risk; cardiac disorder risk; cardiac hypertension; cardiac infarct; cardiovascular disease risk; cardiovascular disorder; cardiovascular disorder risk; chronic kidney disease; coronary attack; coronary disorder; coronary infarct; coronary infarction; cytokine; hPTH(1-84); hRANKL2; heart attack; heart disease hypertension; heart disease risk; heart disorder hypertension; heart disorder risk; heart hypertension; heart infarct; heart infarction; high risk; human PTH protein; hyperpiesia; hyperpiesis; hypertensive cardiomyopathy; hypertensive disease; hypertensive heart disease; hypertensive heart disorder; insight; interferon beta 2; men; men`s; novel; parathormone; parathyroid hormone, human; pathophysiology; phosphorus metabolism; post-menopausal; postmenopausal; pre-menopausal; prospective; public health relevance; receptor; renal; resistant; sOdf; social role; vulnerable plaque
Relevance: /Relevance: We expect our studies of calcium and phosphorus metabolism to provide new insights into the development of cardiovascular disease and to identify several novel and modifiable coronary heart disease risk factors. Our findings may stimulate future research that eventually allows factors regulating calcium- phosphorus balance to serve as targets for the prevention of coronary heart disease and hypertension
Project start date: 2009-06-15
Project end date: 2012-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: PA-07-070
5R01HL092947-02 (2010): $530766
ACID-BASE STATUS AND THE DEVELOPMENT OF HYPERTENSION AND DIABETES
Eric N Taylor
Brigham And Women´s Hospital, Research Administration, Boston, Ma 02115
Grant 5R01DK084019-02 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Recent data suggest that small changes in acid-base status may play an important role in the development of hypertension and type 2 diabetes. Lower pH may result in higher blood pressure by promoting renal salt- retention and may lead to insulin resistance by inhibiting binding of insulin to its receptors. In healthy participants of the National Health and Nutrition Examination Survey who had blood pressure, fasting glucose, and plasma bicarbonate in ranges considered normal, lower bicarbonate was associated with higher blood pressure and greater insulin resistance, independent of body size and kidney function. Because bicarbonate is the primary buffer in extra-cellular fluid, lower plasma bicarbonate generally reflects lower extra-cellular pH. As part of the compensatory response to acid production, the kidney decreases the amount of citrate lost in the urine - and we previously reported lower 24-hour urinary citrate in Nurses Health Study (NHS) participants with hypertension. High alkali diets (such as the DASH diet) reduce blood pressure, and observational studies report that higher dietary potassium (a marker of alkali intake) is associated with a lower risk of diabetes. Because previous human studies examining the relations between acid-base status, hypertension, and diabetes were cross-sectional, it is unknown whether low-grade metabolic acidosis is a cause or a consequence of these diseases. To determine the independent associations between acid-base status and the subsequent risk of hypertension and type 2 diabetes, we propose the following prospective studies of women in NHS I and II 1) a nested case-control study of the association between plasma bicarbonate and risk of incident hypertension (N = 1500), 2) a cohort study of the association between 24-hour urinary citrate and risk of incident hypertension (N = 2000), 3) a cohort study of the association between plasma bicarbonate and changes in insulin resistance in women without diabetes (N = 750), and 4) a nested case-control study of the relation between plasma bicarbonate and risk of incident diabetes (N = 1500). This application represents the first large-scale prospective effort to examine the impact of acid-base status on the risk of developing hypertension, insulin resistance, and type 2 diabetes. The unique strengths of this application include 1) updated, detailed exposure information accumulated prospectively over long periods, 2) archived plasma, and 3) large sample sizes providing high statistical power. We propose to conduct the first prospective studies of the impact of acid-base status on the risk of hypertension and diabetes. We expect our study to provide novel insights into the development of hypertension and diabetes and to suggest new strategies, such as alkali therapy, to prevent these diseases.
Keywords: Acids; Active Follow-up; Affect; Alkalies; Animals; Archives; Baking Soda; Bicarbonates; Binding; Binding (Molecular Function); Blood Plasma; Blood Pressure; Blood Pressure, High; Body Size; Buffers; Carbonic Acid Monosodium Salt; Cardiovascular Diseases; Cause of Death; Chronic Kidney Failure; Chronic Renal Disease; Citrates; Cohort Studies; Common Rat Strains; Concurrent Studies; Cross Sectional Analysis; Cross-Sectional Analyses; Cross-Sectional Studies; Cross-Sectional Survey; DASH diet; Data; Development; Diabetes Mellitus; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Diet; Dietary Potassium; Disease; Disease Frequency Surveys; Disorder; Excretory function; Fasting; Goals; HCO3; History; Hour; Human; Human, General; Humulin R; Hydrogen Carbonates; Hypertension; Individual; Insulin; Insulin (ox), 8A-L-threonine-10A-L-isoleucine-30B-L-threonine-; Insulin Resistance; Insulin, Regular; Intake; Kidney; Kidney Failure; Kidney Failure, Chronic; Kidney Insufficiency; Lead; Liquid substance; MODY; Mammals, Rats; Man (Taxonomy); Man, Modern; Maturity-Onset Diabetes Mellitus; Metabolic acidosis; Modeling; Molecular Interaction; NHANES; NIDDM; National Health and Nutrition Examination Survey; Nested Case-Control Study; Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; Novolin R; Nurses` Health Study; Observational Study; Oral; Participant; Pb element; Plasma; Play; Potassium, Dietary; Preventive Intervention; Production; Prospective Studies; Public Health; Rat; Rattus; Receptor Protein; Recording of previous events; Renal Failure; Renal Failure, Chronic; Renal Insufficiency; Renal function; Reporting; Reticuloendothelial System, Serum, Plasma; Risk; Risk Factors; Role; Sample Size; Serum, Plasma; Sodium Bicarbonate; Sodium Chloride; Sodium Hydrogen Carbonate; Sodium chloride (NaCl); Study, Nested Case-Control; T2D; T2DM; Triacylglycerol; Triglycerides; Type 2 diabetes; Type II diabetes; United States; Update; Urinary System, Kidney; Urinary System, Urine; Urine; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Woman; adult onset diabetes; base; cardiovascular disorder; chronic kidney disease; diabetes; diabetes risk; disease/disorder; excretion; fasted; fasting plasma glucose; fasts; fluid; follow-up; heavy metal Pb; heavy metal lead; high risk; hyperpiesia; hyperpiesis; hypertensive disease; improved; insight; insulin resistant; insulin sensitivity; ketosis resistant diabetes; kidney function; liquid; maturity onset diabetes; modifiable risk; new therapeutics; next generation therapeutics; novel; novel therapeutics; prevent; preventing; preventional intervention strategy; prospective; public health medicine (field); public health relevance; receptor; renal; response; salt; social role; urinary
Relevance: We propose to conduct the first prospective studies of the impact of acid-base status on the risk of hypertension and diabetes. We expect our study to provide novel insights into the development of hypertension and diabetes and to suggest new strategies, such as alkali therapy, to prevent these diseases.
Project start date: 2009-07-15
Project end date: 2013-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: PA-07-070
5R01DK084019-02 (2010): $362639
Novel Risk Factors For Kidney Stone Formation
Eric N Taylor
Brigham And Women´s Hospital
research Administration
boston, Ma 02115
Grant 5K08DK073381-04 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: Dr. Eric N. Taylor hopes to become a physician-scientist who will make substantial, lasting contributions to the care of patients with renal disease. A mentored career development award will allow Dr. Taylor to develop the following prerequisites for a successful career as an independent clinical investigator 1) advanced skills in biostatistics and epidemiology; 2) protected time to pursue a focused research program; and 3) close, long-term mentorship by experienced, successful clinical investigators. Dr. Taylor´s research interest is nephrolithiasis, which is a common, costly, and painful disease. The goals of this proposal are to resolve controversies in the field of nutrition and nephrolithiasis and to identify novel lifestyle, hormonal, and genetic risk factors for kidney stone formation. Using a prospective study design, he will examine the association between specific dietary and lifestyle factors and the risk of symptomatic kidney stone formation in three large cohorts the Health Professionals Follow-up Study (N=51,000 men), the Nurses´ Health Study I (N= 121,000 older women), and the Nurses´ Health Study II (N=116,000 younger women). These factors include the dietary intake of oxalate, non-dairy calcium, and phytate, and the use of non-steroidal anti-inflammatory drugs (NSAIDs). In addition, he will study the relation between insulin resistance, as assessed by fasting levels of plasma insulin, and the risk of kidney stone formation using a nested case-control design (N=1500). He also will examine the association between specific polymorphisms of the vitamin D receptor and the calcium-sensing receptor genes and the risk of incident nephrolithiasis (N=3000). Finally, he will examine the effect of these genetic polymorphisms on the 24-hour urinary excretion of calcium (N=1500). Overall, Dr. Taylor anticipates that his research will result in better strategies to prevent stone disease. In addition to providing Dr. Taylor a unique opportunity to develop experience and expertise in the study of risk factors for kidney stone formation, the career development award will allow him to become proficient with advanced epidemiologic and analytic techniques. At the completion of this career development award, Dr. Taylor will have a unique combination of skills and experience that will enable him to succeed as an independent clinical investigator
Keywords: disease /disorder proneness /risk, nephrolithiasis age difference, calcium, calcium metabolism, diet, dietary constituent, gender difference, genetic polymorphism, genetic susceptibility, hormone regulation /control mechanism, inositol phosphate, insulin sensitivity /resistance, lifestyle, nonsteroidal antiinflammatory agent, oxalate, vitamin D receptor clinical research, female, human middle age (35-64), human old age (65+), human subject, male, nutrition related tag, urinalysis, young adult human (21-34)
Project start date: 2005-09-30
Project end date: 2010-08-31
5K08DK073381-04 (2008): $133920
5K08DK073381-03 (2007): $133920
5K08DK073381-02 (2006): $133920
1K08DK073381-01 (2005): $133920