Agents Acting On The Renin Angiotensin System
Introduction
Section titled “Introduction”The Renin-Angiotensin System (RAS) is a vital hormonal cascade that plays a fundamental role in regulating blood pressure, fluid balance, and electrolyte homeostasis in the body. This intricate system is comprised of several key components, including the enzyme renin, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II, which collectively influence vascular tone, renal function, and cardiac remodeling. Given its central role in cardiovascular and renal physiology, the RAS is a significant target for pharmacological interventions designed to manage conditions like hypertension, heart failure, and chronic kidney disease.
Biological Basis
Section titled “Biological Basis”The RAS initiates when the enzyme renin, primarily secreted by the kidneys, cleaves angiotensinogen (a protein produced by the liver) to form angiotensin I. Angiotensin I is then converted into the highly active peptide angiotensin II by the angiotensin-converting enzyme (ACE), which is predominantly found in the endothelial cells of blood vessels, particularly in the lungs. Angiotensin II exerts its effects by binding to specific receptors, primarily the AT1 receptor, leading to vasoconstriction, increased aldosterone secretion from the adrenal glands, and subsequent sodium and water retention. These actions collectively contribute to an elevation in blood pressure.
Genetic variations, or polymorphisms, within the genes encoding components of the RAS can influence the activity and efficiency of this system. For instance, polymorphisms in the ACEgene, such as the insertion/deletion (I/D) polymorphism, have been investigated for their association with various physiological responses. These include effects on cardiovascular hemodynamics and the acute blood pressure response to aerobic exercise in individuals with hypertension.[1] Furthermore, genetic variations in RAS genes have been linked to endothelium-dependent vasodilation.[2]and left ventricular mass, an important indicator of cardiac health.[3]Beyond its direct cardiovascular actions, angiotensin II has also been shown to influence cellular signaling pathways, such as increasing phosphodiesterase 5A expression in vascular smooth muscle cells, which can antagonize cGMP signaling.[4]
Clinical Relevance
Section titled “Clinical Relevance”Pharmacological agents targeting the RAS are among the most widely prescribed medications for cardiovascular and renal diseases. These include ACE inhibitors, which prevent the conversion of angiotensin I to angiotensin II, and angiotensin receptor blockers (ARBs), which block the binding of angiotensin II to its receptors. Understanding genetic variations that influence the RAS is clinically relevant because these variations can impact an individual’s susceptibility to diseases regulated by the RAS and their responsiveness to RAS-modulating therapies. For example, specific RAS polymorphisms have been observed to alter the acute blood pressure response to aerobic exercise in men with hypertension.[1]The study of these genetic influences, often through large-scale investigations like those conducted within the Framingham Heart Study, helps to elucidate the complex interplay between genetics and cardiovascular health.[5]
Social Importance
Section titled “Social Importance”The widespread prevalence of hypertension, heart failure, and chronic kidney disease underscores the significant social importance of understanding the RAS and the agents that act upon it. Genetic insights into how individuals respond to RAS-modulating drugs offer the potential for personalized medicine, allowing clinicians to tailor treatments based on an individual’s genetic profile. This approach aims to optimize therapeutic efficacy, minimize adverse drug reactions, and ultimately improve patient outcomes. By identifying genetic markers associated with differential responses, public health efforts can be better directed towards preventing and managing these common, debilitating conditions, thereby reducing the global burden of cardiovascular and renal diseases. Large cohort studies, such as the Framingham Heart Study, provide valuable data for uncovering these genetic associations in the general population.[6]
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The studies often face limitations in statistical power due to moderate sample sizes, which can hinder the detection of genetic effects, especially for complex traits with small effect sizes.[5] The extensive multiple testing inherent in genome-wide association studies further exacerbates this issue, increasing the risk of false positive findings if associations do not reach genome-wide significance thresholds.[5] Consequently, while some associations may not meet stringent statistical criteria, their potential biological relevance cannot be entirely dismissed.
A critical limitation across these studies is the frequent absence of independent replication for observed genetic associations.[7] Without external validation in diverse cohorts, many statistically significant p-values could represent spurious findings, complicating the prioritization of single nucleotide polymorphisms (SNPs) for further functional investigation.[7] Although some research endeavors provide unfiltered aggregate data to facilitate in silico replication, the ultimate confirmation of these genetic links requires empirical validation in distinct populations.[5]
Generalizability and Phenotype Assessment Challenges
Section titled “Generalizability and Phenotype Assessment Challenges”The generalizability of findings is often limited by the demographic characteristics of study cohorts, which may not be ethnically diverse or nationally representative.[7] This lack of diversity raises uncertainty about the applicability of genetic associations to broader populations, especially given documented “racial differences” in drug response and the “haplotype diversity” observed across different groups.[8] Such population-specific genetic architectures underscore the need for more inclusive study designs to ensure broader relevance of research outcomes.
Challenges in phenotype assessment also introduce limitations, as the chosen biomarkers may not perfectly capture the intended physiological function or may reflect broader health risks.[7]For instance, while cystatin C is used as a kidney function marker, it may also indicate cardiovascular disease risk independently, complicating the interpretation of its genetic associations.[7]Similarly, relying on thyroid stimulating hormone (TSH) as a proxy for thyroid function without direct measures of free thyroxine or comprehensive thyroid disease assessment can limit the precision of findings.[7]Furthermore, the reliance on estimated measures, such as glomerular filtration rate derived from equations like the Modification of Diet in Renal Disease Study equation, or the inherent “error” in certain collection methods like 24-hour urine specimens, can introduce variability and potential bias into analyses.[7]
Complex Trait Architecture and Environmental Influences
Section titled “Complex Trait Architecture and Environmental Influences”The complex polygenic nature of many physiological traits means that the “specific genes contributing to variability” of most biomarkers are still “incompletely understood,” pointing to significant “missing heritability”.[9] Current genome-wide association studies, while powerful, may not fully capture the intricate interplay of numerous common and rare genetic variants, along with epigenetic factors, that collectively influence a phenotype. This suggests that the “lack of genome-wide significance” for many associations does not negate the existence of genetic influences, but rather highlights the limitations in detecting them with current methodologies.[5] Furthermore, the influence of environmental factors and gene-environment interactions on trait expression presents a substantial challenge. The interplay between “environmental and genetic factors contributing to interindividual variability in systemic biomarker concentrations” is complex and not fully elucidated.[9] While studies often adjust for known covariates, unmeasured or unacknowledged environmental confounders can obscure true genetic signals or introduce spurious associations. The focused use of multivariable models, while important for controlling confounders, might also inadvertently “miss important bivariate associations” between individual SNPs and trait measures, underscoring the ongoing need for comprehensive analytical approaches to fully unravel the genetic and environmental architecture of complex traits.[7]
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing an individual’s cardiovascular and renal health, thereby affecting the efficacy and necessity of agents acting on the renin-angiotensin system (RAS). Variants within genes likeNOS3 and KCNK3 are particularly relevant due to their direct involvement in vascular function. For instance, the NOS3 gene encodes endothelial nitric oxide synthase, an enzyme critical for producing nitric oxide (NO), a powerful vasodilator. Common genetic variations at the NOS3 locus, such as rs3918226 , have been studied for their relationship to brachial artery vasodilator function, highlighting their impact on blood vessel relaxation and overall blood pressure regulation.[5]Alterations in NO production can influence vascular tone and the body’s response to blood pressure-regulating mechanisms, including the RAS, and polymorphisms in the renin-angiotensin system are known to affect endothelium-dependent vasodilation.[2] Similarly, variants like rs1275982 , rs1731243 , and rs13394970 in the KCNK3gene, which codes for a potassium channel (TASK-1) involved in regulating cellular excitability and vascular tone, particularly in pulmonary circulation, can also impact cardiovascular function and potentially modulate how the body responds to RAS-targeting therapies.
Other variants, including rs12509595 and rs13125101 in the PRDM8-FGF5 region, rs604723 in ARHGAP42, rs1894400 in _FES*, rs35429 , rs35441 , and rs192267 within the TBX3-AS1-UBA52P7 locus, rs880315 in CASZ1, and *rs57541197 * near LINC02625 and CABCOCO1, contribute to a broader spectrum of cellular processes that indirectly influence cardiovascular and renal health.ARHGAP42 is involved in regulating Rho GTPases, which are key players in cell signaling and cytoskeletal organization, fundamental processes for vascular integrity. FES is a tyrosine kinase proto-oncogene that participates in cell growth and differentiation pathways, while CASZ1 is a transcription factor with roles in development. The TBX3-AS1-UBA52P7 region encompasses non-coding RNAs and pseudogenes that can regulate gene expression, and similar regulatory roles are attributed to LINC02625 and CABCOCO1. These genes, through their diverse cellular functions, can subtly influence the underlying physiology of blood pressure and kidney function, potentially affecting an individual’s susceptibility to conditions requiring RAS intervention or their response to such treatments.
The FTO gene, with variants such as rs55872725 and rs72805611 , is widely recognized for its strong association with obesity and metabolic traits. Obesity is a significant risk factor for hypertension, kidney disease, and other cardiovascular conditions, all of which are often managed with agents that modulate the renin-angiotensin system. Therefore, genetic predispositions to obesity throughFTO variants can indirectly influence an individual’s need for, or the effectiveness of, RAS-acting medications by impacting overall metabolic health.[6] Similarly, variants like rs7938342 and rs1973765 in the LSP1gene, involved in leukocyte adhesion and migration, highlight the role of inflammatory processes in cardiovascular and renal disease progression. Chronic inflammation is a known contributor to these conditions, and by influencing immune cell function,LSP1 variants could indirectly affect the severity of diseases targeted by RAS inhibition.
Key Variants
Section titled “Key Variants”Conceptual Framework and Terminology of the Renin-Angiotensin System
Section titled “Conceptual Framework and Terminology of the Renin-Angiotensin System”The Renin-Angiotensin System (RAS) is a complex hormonal cascade fundamental to the physiological regulation of blood pressure, fluid balance, and electrolyte homeostasis. This system involves key components such as renin, angiotensinogen, angiotensin I, and angiotensin II, with the angiotensin-converting enzyme (ACE) playing a central role in converting angiotensin I to the potent vasoconstrictor angiotensin II.[3] Genetic variations within RAS components, such as the ACEgene I/D polymorphism, have been investigated for their associations with cardiovascular phenotypes like left ventricular mass in individuals with systemic hypertension.[3]The intricate signaling of the RAS significantly influences vascular tone and overall cardiovascular health.
“Agents acting on the renin-angiotensin system” primarily refers to pharmacological interventions designed to modulate this pathway, serving as a cornerstone for the treatment of hypertension and various cardiovascular diseases. These therapeutic agents are broadly encompassed by the terms “hypertension treatment” (HTN Rx) or “blood pressure medication” in clinical and research contexts.[9] Beyond pharmacotherapy, the term also extends to the study of endogenous factors and genetic polymorphisms within the RAS that influence its activity and downstream effects, impacting physiological processes such as endothelium-dependent vasodilation.[2] Precise terminology is essential for accurate classification of both therapeutic interventions and intrinsic genetic influences on blood pressure regulation.
Classification and Operational Definitions of RAS Modulation
Section titled “Classification and Operational Definitions of RAS Modulation”The classification of the use of agents acting on the renin-angiotensin system in research studies typically involves categorizing individuals based on their therapeutic status. This often translates into a binary classification indicating the presence or absence of “hypertension treatment” (HTN Rx) or “blood pressure medication”.[9] Such a categorical approach is crucial for researchers to account for the confounding effects of pharmacotherapy when analyzing physiological traits, particularly blood pressure, where medication status directly influences observed values. These operational definitions provide a standardized framework for integrating treatment effects into genetic and epidemiological studies.
For detailed analyses, specific adjustments are often applied to physiological measurements for individuals on medication to approximate their unmedicated state or to standardize comparisons. For instance, in studies measuring blood pressure, an operational definition may involve adding 15 mmHg to systolic blood pressure (SBP) and 10 mmHg to diastolic blood pressure (DBP) for subjects currently receiving blood pressure medication.[10]This methodological adjustment aims to mitigate the impact of active treatment on measured phenotypes, allowing for a more accurate assessment of underlying genetic or environmental associations with metabolic and cardiovascular traits.
Approaches and Clinical Relevance
Section titled “Approaches and Clinical Relevance”approaches for agents acting on the renin-angiotensin system involve both the direct assessment of medication use and the quantification of its physiological consequences and related biomarkers. Blood pressure, a primary indicator of RAS activity and its modulation, is typically measured using standardized protocols, such as mercury sphygmomanometers, with duplicate measures taken after a period of rest to ensure accuracy.[10]Beyond blood pressure, echocardiographic dimensions like left ventricular mass (LV mass) and left atrial size (LA size) serve as crucial indicators of chronic RAS-mediated effects and are often adjusted for covariates including SBP and HTN Rx in analyses.[9] These comprehensive measurements provide insights into the long-term impact of RAS activity and its therapeutic control.
The clinical relevance of understanding agents acting on the RAS is profound due to its central role in the pathogenesis and management of hypertension and cardiovascular disease. Genetic polymorphisms, such as theACEgene I/D variant, have been shown to correlate with left ventricular mass, underscoring a genetic predisposition to systemic hypertension and its structural cardiac consequences.[3]Furthermore, natriuretic peptides, including N-terminal pro-atrial natriuretic peptide and B-type natriuretic peptide, serve as important biomarkers that are counter-regulatory to the RAS; their levels are measured and adjusted for various factors, including age, sex, BMI, SBP, and HTN Rx, highlighting the intricate interplay of these systems in maintaining cardiovascular homeostasis.[9]These measurements are indispensable for accurate disease diagnosis, risk stratification, and guiding personalized therapeutic strategies.
Foundations of RAS Management: Lifestyle and Primary Prevention
Section titled “Foundations of RAS Management: Lifestyle and Primary Prevention”Lifestyle interventions are crucial for primary prevention and managing conditions affected by the renin-angiotensin system (RAS), such as hypertension and chronic kidney disease. Regular physical activity, including aerobic exercise, can influence blood pressure responses, although genetic polymorphisms in the RAAS might modulate these effects -Organ Function
Beyond the core RAS components, genetic variations in related signaling pathways and end-organ function can modify the overall pharmacodynamic effects of RAS agents. For instance, common genetic variation at the endothelial nitric oxide synthase (NOS3) locus has been linked to brachial artery vasodilator function, indicating that genetic differences in nitric oxide production, a critical modulator of vascular tone, can influence cardiovascular responses.[11] Angiotensin II itself can increase PDE5Aexpression in vascular smooth muscle cells, thereby antagonizing cGMP signaling, a pathway that can be modulated by RAS agents.[4]Additionally, genetic variants influencing kidney function biomarkers, such as estimated glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UAE), have been identified in genes likeLRP1B, ADRBK2, APOB, CCL3, CCL4, CCL18, SCARB1, NFKB1, TGFB1, PPARG, and ANGPT1.[7] Since RAS agents are critical for kidney protection, understanding these genetic influences on renal function can provide insights into differential therapeutic outcomes and potential for adverse effects.
Impact of Genetic Variation on Metabolic Phenotypes and Drug Disposition
Section titled “Impact of Genetic Variation on Metabolic Phenotypes and Drug Disposition”Pharmacogenetic considerations extend to the broader metabolic landscape, where genetic variations can influence metabolic phenotypes that may indirectly affect drug disposition or overall physiological response. The field of metabolomics has demonstrated how genetics can meet metabolite profiles in human serum, revealing evidence of different metabolic phenotypes in humans that are influenced by genetic variants.[12] The concept of genetically determined metabolic profiles and drug toxicity is established.[13] For example, the SLC2A9 (GLUT9) gene, a transporter, is associated with serum uric acid levels, and a common nonsynonymous variant inGLUT9has been linked to uric acid concentrations with pronounced sex-specific effects.[14]Furthermore, single nucleotide polymorphisms (SNPs) near thePDYNgene, related to opioid neuropeptide precursors, are associated with urinary sodium, which is relevant given the role of kappa opioid receptors in regulating urinary sodium and water excretion.[15] These examples illustrate how genetic variations in transporters and metabolic pathways can affect physiological parameters often impacted by RAS agents, suggesting potential indirect pharmacogenetic influences on their overall effectiveness and tolerability.
Clinical Considerations for Personalized Renin-Angiotensin System Use
Section titled “Clinical Considerations for Personalized Renin-Angiotensin System Use”The growing understanding of pharmacogenetic influences on the renin-angiotensin system and related physiological pathways holds significant promise for personalized medicine. While specific dosing recommendations or drug selection algorithms based on genetic profiles are not universally implemented, the existence of “context-dependent genetic effects in hypertension” emphasizes the need for individualized approaches.[16] Common genetic variations are known to influence biochemical parameters measured in everyday clinical care, suggesting that integrating genetic information could lead to more tailored therapeutic strategies.[15]For instance, predicting an individual’s acute blood pressure response based on genetic polymorphisms could optimize treatment selection for hypertension.[5]As the evidence base strengthens, pharmacogenetic testing could potentially aid in guiding drug selection, predicting efficacy, and anticipating adverse reactions, thereby enhancing the precision and effectiveness of agents acting on the renin-angiotensin system.
Frequently Asked Questions About Agents Acting On The Renin Angiotensin System Use
Section titled “Frequently Asked Questions About Agents Acting On The Renin Angiotensin System Use”These questions address the most important and specific aspects of agents acting on the renin angiotensin system use based on current genetic research.
1. Why does my blood pressure stay high even if I exercise a lot?
Section titled “1. Why does my blood pressure stay high even if I exercise a lot?”It’s possible your genetics play a role in how your body responds to exercise. Specific variations in genes related to the Renin-Angiotensin System (RAS), like theACEgene, can influence how much your blood pressure lowers after aerobic exercise. Some people with certain genetic profiles might not see as significant a drop in blood pressure from exercise compared to others, even with consistent effort. This doesn’t mean exercise isn’t beneficial, but your genetic makeup can affect thedegree of blood pressure response.
2. Why do my blood pressure pills not work as well for me?
Section titled “2. Why do my blood pressure pills not work as well for me?”Your genetic makeup can influence how effectively certain blood pressure medications work for you. Medications targeting the Renin-Angiotensin System (RAS), such as ACE inhibitors or ARBs, interact with proteins in your body that are encoded by your genes. Variations in these RAS genes can alter how your body processes the drug or how your receptors respond to it, leading to different levels of effectiveness for different individuals. This is why personalized medicine, considering your genetic profile, is gaining importance.
3. Could a DNA test help pick my best blood pressure medicine?
Section titled “3. Could a DNA test help pick my best blood pressure medicine?”Yes, a DNA test could potentially help guide the choice of your blood pressure medication. Genetic variations in the Renin-Angiotensin System (RAS) can predict how you might respond to specific drugs like ACE inhibitors or ARBs. By understanding your genetic profile, doctors might be able to select a medication that is more likely to be effective for you and potentially minimize side effects, moving towards more personalized treatment.
4. My family has high blood pressure, am I doomed?
Section titled “4. My family has high blood pressure, am I doomed?”Not necessarily, but you may have a higher genetic predisposition. While a strong family history of high blood pressure suggests you’ve inherited certain genetic variations that increase your risk, it doesn’t mean it’s inevitable. Many genes, including those in the Renin-Angiotensin System (RAS), contribute to blood pressure regulation, and their effects interact with lifestyle factors. Healthy habits can significantly mitigate genetic risks.
5. Will my blood pressure medicine work differently because of my ancestry?
Section titled “5. Will my blood pressure medicine work differently because of my ancestry?”Yes, your ancestry can play a role in how your blood pressure medicine works. Genetic variations in the Renin-Angiotensin System (RAS) and other drug-metabolizing pathways can differ significantly across various ethnic and racial groups. These differences can lead to variations in how effectively certain medications are processed by your body or how your body responds to them. This is why some drug responses are observed to have “racial differences” and “haplotype diversity.”
6. Can my genes make my heart work harder than it should?
Section titled “6. Can my genes make my heart work harder than it should?”Yes, genetic variations can influence factors that make your heart work harder. The Renin-Angiotensin System (RAS) plays a key role in cardiac remodeling, which includes changes to the heart’s structure, like left ventricular mass. Variations in RAS genes, such as theACEgene, have been linked to an increased left ventricular mass, which can indicate that your heart is working harder to pump blood, especially in conditions like hypertension.
7. Why does eating salty food make me feel so bloated?
Section titled “7. Why does eating salty food make me feel so bloated?”Your body’s system for regulating fluid and salt, the Renin-Angiotensin System (RAS), might be particularly sensitive. When you consume salty foods, your body’s RAS responds by increasing aldosterone secretion, which leads to sodium and water retention. This mechanism helps regulate blood pressure, but some individuals may have a more pronounced response, causing them to retain more fluid and feel bloated after high-salt meals.
8. Can my genes make my blood vessels stiffer?
Section titled “8. Can my genes make my blood vessels stiffer?”Yes, your genetic makeup can influence the stiffness of your blood vessels. The Renin-Angiotensin System (RAS) is crucial for regulating vascular tone, meaning how constricted or relaxed your blood vessels are. Genetic variations within RAS components can affect this balance, potentially leading to increased vasoconstriction and reduced endothelium-dependent vasodilation, which contributes to stiffer blood vessels and higher blood pressure.
9. Can my healthy habits really overcome my family’s high blood pressure?
Section titled “9. Can my healthy habits really overcome my family’s high blood pressure?”Yes, healthy habits can significantly influence your risk, even with a family history of high blood pressure. While genetics contribute to your susceptibility through systems like the Renin-Angiotensin System (RAS), lifestyle choices like diet, exercise, and stress management play a huge role. These habits can modify how your genes are expressed and how your body functions, often mitigating inherited risks and helping to prevent or manage conditions like hypertension.
10. Is there a way to know my personal risk for high blood pressure?
Section titled “10. Is there a way to know my personal risk for high blood pressure?”Yes, combining family history, lifestyle, and genetic information can give you a clearer picture. Researchers study genetic variations, particularly in systems like the Renin-Angiotensin System (RAS), to identify markers associated with an increased susceptibility to high blood pressure. While a DNA test can reveal some of these genetic predispositions, a comprehensive assessment also considers your overall health, diet, and activity levels.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Blanchard, B. E., et al. “RAAS polymorphisms alter the acute blood pressure response to aerobic exercise among men with hypertension.”Eur J Appl Physiol, vol. 97, 2006, pp. 26-33.
[2] Kurland, L et al. “Polymorphisms in the renin-angiotensin system and endothelium-dependent vasodilation in normotensive subjects.”Clin Physiol, 2001.
[3] Celentano, A. et al. “Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension.”Am J Cardiol, vol. 83, 1999, pp. 1196-1200.
[4] Kim, D. et al. “Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling.”J Mol Cell Cardiol, vol. 38, 2005, pp. 175-184.
[5] Vasan, R. S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S2.
[6] McArdle, P. F., et al. “Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish.”Arthritis & Rheumatism, vol. 58, 2008, pp. 2194-2202.
[7] Hwang, S. J., et al. “A genome-wide association for kidney function and endocrine-related traits in the NHLBI’s Framingham Heart Study.” BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S10.
[8] Krauss, Ronald M., et al. “Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment.”Circulation, 2008.
[9] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, suppl. 1, 2007, p. S2.
[10] Sabatti, C. et al. “Loci related to metabolic-syndrome pathways including LEPR, HNF1A, IL6R, and GCKRassociate with plasma C-reactive protein: the Women’s Genome Health Study.”Am. J. Hum. Genet., vol. 82, 2008, pp. 1185–1192.
[11] Kathiresan, S. et al. “Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function in the community.” Circulation, vol. 112, 2005, pp. 1419-1427.
[12] Gieger, Christian, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genetics, vol. 4, no. 11, 2008, e1000282.
[13] Nicholson, J.K. et al. “Metabonomics: a platform for studying drug toxicity and gene function.” Nat Rev Drug Discov, vol. 1, 2002.
[14] Li, S. et al. “The GLUT9Gene Is Associated with Serum Uric Acid Levels in Sardinia and Chianti Cohorts.”PLoS Genet, vol. 3, no. 11, 2007, pp. e194.
[15] Wallace, C et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, 2008.
[16] Kardia, S. L. “Context-dependent Genetic Effects in Hypertension.”Curr Hypertens Rep, vol. 2, 2000, pp. 32-38.