Angiotensin Converting Enzyme Activity Attribute
Introduction
Angiotensin-converting enzyme (ACE) activity refers to the functional level of the ACE enzyme, a critical component of the Renin-Angiotensin-Aldosterone System (RAAS). This complex hormonal system plays a fundamental role in regulating blood pressure, fluid balance, and electrolyte homeostasis in the body. The ACE gene, located on chromosome 17q23.3, encodes the ACE enzyme. [1] Biologically, ACE converts angiotensin I into angiotensin II, a potent vasoconstrictor, and also degrades bradykinin, a peptide that promotes vasodilation. Variations in the activity of this enzyme can significantly impact these physiological processes. [2] Genetic polymorphisms, such as rs4343 in the ACE gene, have been strongly associated with individual differences in ACE activity levels. [2]
The clinical relevance of ACE activity is extensive, particularly in cardiovascular medicine and neurology. In the context of hypertension, ACE is a primary target for several classes of antihypertensive drugs, including ACE inhibitors and Angiotensin II Receptor Blockers (ARBs). [3] Genetic variations influencing ACE activity can significantly predict an individual's blood pressure response to these medications. [4] For example, specific ACE gene polymorphisms have been shown to influence how effectively a patient's blood pressure is lowered by angiotensin II receptor type 1 antagonist treatment. [4] Furthermore, ACE activity is implicated in neurodegenerative diseases such as Alzheimer's disease (AD). Studies indicate that ACE can degrade amyloid-beta (Aβ) peptides and inhibit their aggregation, suggesting a role in AD pathogenesis. [1] Genetic variants influencing ACE levels in cerebrospinal fluid and plasma, including rs4968782 and rs4343, have been associated with AD candidate proteins. [1]
The social importance of understanding ACE activity attributes lies in its potential to advance personalized medicine and public health. By identifying genetic markers that predict how an individual will respond to specific antihypertensive drugs, healthcare providers can tailor treatment plans, leading to more effective outcomes and potentially reducing adverse drug reactions. [5] For instance, variants in the KCNIP4 gene have been associated with ACE inhibitor-induced cough, a common side effect. [6] Such pharmacogenomic insights enable more precise drug selection and dosage optimization. Additionally, elucidating ACE's role in complex conditions like Alzheimer's disease could pave the way for novel therapeutic strategies and drug targets, offering new avenues for prevention and treatment. [5]
Methodological and Statistical Constraints
Genetic association studies, including those on angiotensin converting enzyme activity, often face inherent methodological and statistical limitations that can influence the robustness and generalizability of findings. Sample sizes, particularly in discovery cohorts or for specific sub-analyses, may limit the power to detect associations for variants with lower minor allele frequencies or weaker effect sizes, potentially leading to an underestimation of the full genetic architecture of the trait . The variant rs4343, located in exon 17 of the ACE gene, is a synonymous substitution that has shown a strong association with angiotensin-converting enzyme activity. [2] The minor "G" allele of rs4343 is consistently linked to increased plasma and cerebrospinal fluid (CSF) ACE levels, and is predicted to affect transcription factor binding, suggesting a regulatory role. [1] Furthermore, studies have indicated that the allele associated with higher ACE levels for rs4343 is also associated with a decreased risk for AD. [1]
Another variant within the ACE gene, rs4362, like other polymorphisms in this gene, may influence the efficiency of ACE production or enzyme activity, thereby affecting the overall function of the RAAS and contributing to individual differences in blood pressure regulation and cardiovascular health. Such variations can impact the body's response to physiological stress or pharmacological interventions like ACE inhibitors. The ABO gene, well-known for determining human blood groups, encodes glycosyltransferases responsible for synthesizing A and B antigens on cell surfaces, including red blood cells. While its primary role is in blood typing, variants within the ABO gene have been found to influence a range of other biological traits. Specifically, the rs495828 variant in the ABO gene has been significantly associated with angiotensin-converting enzyme activity, highlighting a connection between blood group genetics and RAAS regulation. [2] The presence of rs495828 as a quantitative trait locus for ACE activity suggests that ABO genetic variations may contribute to the variability in ACE levels observed across individuals, potentially impacting susceptibility to conditions influenced by ACE activity. [2]
Defining Angiotensin-Converting Enzyme Activity
Angiotensin-converting enzyme (ACE) activity refers to the precise quantifiable enzymatic function of the ACE protein, officially known as Angiotensin I-converting enzyme. [1] This enzyme is a pivotal component of the renin-angiotensin-aldosterone system (RAAS), a complex hormonal cascade essential for regulating blood pressure, fluid balance, and electrolyte homeostasis in the body. [5] The activity specifically measures the efficiency with which the ACE enzyme catalyzes the conversion of angiotensin I into the potent vasoconstrictor angiotensin II, while also degrading bradykinin, a substance that promotes vasodilation.
The terminology surrounding this attribute is straightforward, with the enzyme commonly referred to as ACE and its corresponding gene symbol also being ACE. [1] Variations in the ACE gene, such as polymorphisms, are known to influence the levels of its enzymatic activity, thereby impacting individual physiological responses. [5] The "angiotensin converting enzyme activity attribute" is therefore an operational definition representing a measurable characteristic of this enzymatic function, routinely assessed in biological samples like plasma for research and clinical purposes. [2]
Measurement and Diagnostic Approaches
Measurement of angiotensin-converting enzyme (ACE) activity typically involves biochemical assays designed to quantify the rate of substrate conversion by the enzyme in a given biological specimen. [2] These quantitative measurements are critical for establishing operational definitions of ACE activity, allowing researchers to categorize individuals based on their enzyme levels and correlate these levels with genetic variations or clinical phenotypes. [2] The ability to precisely measure this activity is fundamental for its application as a biomarker in various research contexts, including genome-wide association studies (GWAS) aimed at identifying genetic determinants of ACE activity. [2]
In a diagnostic and research context, ACE activity levels serve as a crucial biomarker, where specific thresholds or cut-off values can be employed to stratify individuals. [2] This is particularly relevant in pharmacogenomic research, where the identification of genetic loci influencing ACE activity carries significant implications for predicting an individual's response to ACE inhibitors. [2] Such predictive criteria are vital for understanding how genetic predispositions to certain ACE activity levels might influence the efficacy of antihypertensive treatments, including angiotensin II receptor blockers. [5]
Clinical Significance and Therapeutic Implications
The clinical significance of angiotensin-converting enzyme (ACE) activity is profound, largely stemming from its central role in blood pressure regulation and its direct impact on cardiovascular health. [5] Dysregulation of ACE activity can contribute to the pathophysiology of conditions such as hypertension, solidifying its status as a key target for pharmacological intervention. Consequently, understanding individual variations in ACE activity is not merely an academic exercise but holds direct relevance for tailoring patient management strategies, especially in the context of antihypertensive pharmacotherapy. [5]
While ACE activity is inherently a continuous, dimensional trait, its quantification allows for the development of categorical classifications related to therapeutic response to medications. Individuals exhibiting particular ACE activity profiles, often influenced by genetic polymorphisms, may demonstrate distinct responses to ACE inhibitors or angiotensin II receptor blockers. [5] This capacity enables a form of pharmacogenomic classification, where patients can be stratified based on their anticipated efficacy or potential side effect profiles for these essential cardiovascular drugs. [2] Such classifications represent a significant step towards personalized medicine, optimizing treatment regimens based on an individual's unique biological attributes.
The Renin-Angiotensin-Aldosterone System and ACE's Central Role
Angiotensin-converting enzyme (ACE) is a critical component of the Renin-Angiotensin-Aldosterone System (RAAS), a complex endocrine system fundamental to cardiovascular and renal physiology. Within this intricate pathway, the liver-derived protein angiotensinogen is initially converted into angiotensin I through the enzymatic action of renin. Subsequently, ACE catalyzes the transformation of angiotensin I into angiotensin II, which stands as the primary effector molecule of the RAAS. [7] Angiotensin II exerts a wide array of biological effects across various tissues, including the kidneys, heart, and vasculature, mediating both local and systemic responses. It is a potent vasoconstrictor, directly elevating blood pressure, and significantly influences cardiac and vascular remodeling processes. [7]
Beyond its direct effects on blood vessels, angiotensin II also stimulates the adrenal glands to produce aldosterone, a hormone that plays a crucial role in fluid and electrolyte homeostasis by enhancing sodium and water reabsorption in the kidneys. [7] Thus, the RAAS, with ACE at its enzymatic core, is a major determinant of blood pressure regulation, fluid balance, and the structural integrity of the cardiovascular system. Dysregulation of ACE activity and the broader RAAS pathway is intimately linked to the development and progression of cardiovascular diseases, making pharmacological modulation of this system, such as through ACE inhibitors, a key therapeutic strategy for improving patient outcomes. [7]
Genetic Regulation of ACE Activity and Expression
ACE activity, a widely implicated factor in various biological systems, is subject to significant genetic regulation. The ACE gene, located on chromosome 17q23.3, encodes the angiotensin-converting enzyme itself. [1] Numerous single nucleotide polymorphisms (SNPs) within and near the ACE gene have been identified as quantitative trait loci influencing ACE activity levels. For instance, the SNP rs4343, located in exon 17 close to the well-known insertion/deletion polymorphism, exhibits a strong association with ACE activity. [2]
Research indicates that specific genetic variants can significantly impact ACE protein levels in bodily fluids. The minor allele of rs4968782, for example, is associated with elevated ACE protein levels in cerebrospinal fluid (CSF), accounting for approximately 11% of the variance in CSF ACE levels. [1] This SNP, and other highly linked synonymous substitutions like rs4343 and rs4316, demonstrate consistent associations with ACE levels in both CSF and plasma, highlighting the systemic influence of these genetic variations on enzyme expression and activity. [1] Furthermore, SNPs in other genes, such as rs495828 and rs8176746 in the ABO gene, have also been found to be significantly associated with ACE activity, suggesting complex regulatory networks extending beyond the ACE gene itself. [2]
ACE Activity in Cardiovascular Health and Pharmacogenomics
Given ACE's central role in the RAAS, its activity is a critical determinant of cardiovascular health, particularly in the context of blood pressure regulation. Variations in ACE activity can lead to homeostatic disruptions, contributing to conditions like hypertension. Pharmacological inhibitors of ACE (ACE inhibitors) are a cornerstone of antihypertensive therapy, working by reducing the production of the potent vasoconstrictor angiotensin II. [3] The effectiveness of these therapies, however, can vary significantly among individuals, a phenomenon partly explained by pharmacogenetic differences. [5]
Genetic polymorphisms in genes of the RAAS, including the ACE gene itself, have been shown to predict an individual's blood pressure response to various antihypertensive treatments. For example, specific ACE gene polymorphisms influence the response to angiotensin II receptor type 1 antagonists and diuretics like hydrochlorothiazide. [4] The ACE insertion/deletion polymorphism, in particular, has been associated with blood pressure and cardiovascular risk in relation to antihypertensive treatment. [8] Understanding these gene-drug interactions allows for the identification of genetic markers that predict drug response, potentially enabling more individualized and effective antihypertensive drug therapy by matching specific treatments to a patient's genetic profile. [9]
ACE's Multifaceted Role in Alzheimer's Disease Pathogenesis
Beyond its well-established cardiovascular functions, ACE activity has been significantly implicated in the pathogenesis of Alzheimer's disease (AD). Studies indicate that ACE possesses the enzymatic capability to degrade Alzheimer amyloid beta-peptide (Aβ), a key component in the formation of amyloid plaques characteristic of AD. [10] This degradation process by ACE not only retards Aβ aggregation, deposition, and fibril formation but also inhibits its cytotoxicity, suggesting a protective role for ACE activity in the brain. [10]
A critical mechanism involves ACE's ability to convert the highly amyloidogenic Aβ42 peptide into the less stable Aβ40 peptide. [11] Evidence from in vivo models demonstrates that inhibiting ACE activity promotes Aβ42 deposition in the hippocampus of AD mouse models, reinforcing its role in amyloid clearance. [11] The enzyme's degrading action on Aβ is a two-step process, first cleaving Aβ42 to Aβ40, followed by further degradation of Aβ40. [1] Furthermore, genetic associations between ACE gene variants and the risk for late-onset AD have been observed, with some common variants contributing to variable age-at-onset of the disease and influencing brain Aβ levels. [12]
The Renin-Angiotensin-Aldosterone System (RAAS) Cascade
Angiotensin Converting Enzyme (ACE) activity is a pivotal component of the Renin-Angiotensin-Aldosterone System (RAAS), a complex enzymatic cascade central to cardiovascular and renal physiology. This system initiates with the liver-derived protein angiotensinogen, which is converted to angiotensin I through the catalytic action of renin. Subsequently, ACE mediates the crucial transformation of angiotensin I into angiotensin II, which serves as the primary effector molecule of the entire RAAS. [7] Angiotensin II then exerts its widespread biological effects in various tissues, including the kidneys, heart, and vasculature, by binding to its specific receptors. [7] This leads to potent vasoconstriction, adverse impacts on cardiac and vascular remodeling, and the stimulation of aldosterone production in the adrenal glands, which in turn enhances sodium and water reabsorption in the kidneys. [7] The integrated actions of Angiotensin II thus critically determine fluid and electrolyte hemostasis, regulate blood pressure, and influence cardiovascular remodeling. [7]
Molecular Regulation of ACE Activity
The activity of ACE is subject to intricate molecular regulation, significantly influenced by genetic factors. Polymorphisms within the ACE gene, located on chromosome 17q23.3, have been identified as key determinants of circulating ACE levels and activity. [1] For instance, specific single nucleotide polymorphisms (SNPs) such as rs4968782 and rs4343 are strongly associated with varying ACE protein levels in both cerebrospinal fluid (CSF) and plasma, with the minor allele of rs4968782 correlating with higher ACE CSF protein levels. [1] These genetic variations can impact the efficiency of ACE's enzymatic function, thereby influencing the rate of angiotensin II production and the overall tone of the RAAS. The precise genetic architecture of ACE activity also carries significant implications for pharmacogenomics, as these variations can predict an individual's response to ACE inhibitors, a class of drugs designed to modulate this enzyme's function. [2]
Systemic Integration and Pathway Crosstalk
ACE activity plays a critical role in integrating multiple physiological systems and exhibits significant crosstalk with other molecular pathways beyond its canonical role in RAAS. The RAAS itself is a major determinant of systemic blood pressure and fluid balance, with its dysregulation contributing to cardiovascular and renal morbidity. [7] Furthermore, genetic variants affecting components of the renin-angiotensin system can reciprocally interact with renal sodium transport systems, highlighting complex network interactions that maintain blood pressure homeostasis. [5] Notably, ACE also participates in the processing of amyloid beta (Aβ) peptides, which are implicated in Alzheimer's disease pathogenesis. ACE has been shown to degrade Aβ, retard its aggregation and fibril formation, and convert the highly amyloidogenic Aβ(1-42) peptide into the more stable Aβ(1-40) form, thereby inhibiting Aβ cytotoxicity. [10], [11] This dual role underscores ACE's broader biological significance, linking cardiovascular regulation with neurodegenerative processes.
Disease Pathogenesis and Therapeutic Implications
Dysregulation of ACE activity and the broader RAAS is directly implicated in the pathogenesis of various diseases, offering crucial therapeutic targets. Elevated or uncontrolled RAAS activity contributes significantly to the development and progression of cardiovascular diseases, necessitating pharmacological intervention. [7] ACE inhibitors are a cornerstone of antihypertensive therapy, acting by reducing angiotensin II production and subsequently lowering blood pressure. [5] Genetic polymorphisms, such as those in the ACE gene, can predict individual responses to these treatments, as well as to angiotensin II receptor blockers (ARBs) and diuretics, paving the way for personalized medicine approaches. [4], [13], [14], [15] Beyond cardiovascular health, ACE activity is also relevant in neurodegenerative conditions, particularly Alzheimer's disease. Studies indicate that ACE inhibition can enhance brain Aβ deposition, suggesting that maintaining optimal ACE activity is crucial for Aβ clearance and preventing amyloid pathology. [11] Therefore, understanding the intricate pathways and regulatory mechanisms of ACE activity is vital for developing targeted therapies and improving patient outcomes across a spectrum of diseases.
Pharmacogenetics of Angiotensin Converting Enzyme Activity
Angiotensin converting enzyme (ACE) activity plays a crucial role in regulating blood pressure through the renin-angiotensin-aldosterone system (RAAS). Genetic variations influencing ACE activity, as well as the metabolism and targets of drugs acting on this pathway, can significantly impact the efficacy and safety of antihypertensive treatments, particularly ACE inhibitors and angiotensin II receptor blockers (ARBs). Pharmacogenetics aims to leverage this genetic variability to personalize prescribing and optimize patient outcomes.
Genetic Influences on Renin-Angiotensin System Drug Efficacy
Polymorphisms within the ACE gene itself are a primary focus for pharmacogenetic studies related to antihypertensive response. The ACE insertion/deletion (I/D) polymorphism, for instance, has been associated with varying blood pressure and cardiovascular risk in individuals receiving antihypertensive treatment, including ACE inhibitor monotherapy. [8] This polymorphism can influence the circulating levels of ACE, thereby modulating the effectiveness of ACE inhibitors which directly target the enzyme. Furthermore, the ACE gene polymorphism has been shown to predict blood pressure response to angiotensin II receptor type 1 antagonist (ARB) treatment in hypertensive patients. [4] Research has also identified novel genetic loci influencing ACE activity, suggesting potential interactions between ACE and ABO blood group polymorphisms that impact blood pressure response to ACE inhibitors. [2]
Beyond ACE, variants in other genes within the RAAS pathway, such as CYP11B2 (aldosterone synthase), also contribute to differential drug responses. The CYP11B2 -344 C/T polymorphism has been linked to variations in antihypertensive response. [4] Specific variants of the CYP11B2 gene can predict an individual's response to ARBs like candesartan. [14] These genetic variations affect the downstream production of aldosterone, influencing the overall RAAS activity and thus modifying the therapeutic outcomes of drugs that modulate this complex system. Moreover, interactions between ACE and CYP11B2 gene polymorphisms have been observed to affect blood pressure response to other antihypertensive agents, such as hydrochlorothiazide. [16]
Pharmacokinetic Modulation and Variable Drug Response
Genetic variations in drug-metabolizing enzymes can significantly alter the pharmacokinetics and pharmacodynamics of antihypertensive medications, leading to variable therapeutic responses. For example, the cytochrome P450 enzyme CYP2C9 is critical for the metabolism of several ARBs. Polymorphisms in CYP2C9 can affect how quickly these drugs are processed and eliminated from the body. Studies have demonstrated that the CYP2C9 genotype predicts the blood pressure response to irbesartan. [17]
Specifically, the presence of the CYP2C9*3 allele can alter the pharmacokinetics and pharmacodynamics of losartan in healthy individuals. Carriers of this allele may exhibit different drug exposure levels, potentially influencing the drug's efficacy and the likelihood of adverse events. [15] Understanding these metabolic phenotypes is crucial for predicting how an individual will absorb, distribute, metabolize, and excrete ARBs, thereby providing insights into expected drug efficacy and the potential for dose-dependent effects or adverse reactions.
Genomic Insights into Adverse Reactions and Personalized Treatment Strategies
Pharmacogenetic insights extend beyond efficacy to include the prediction and mitigation of adverse drug reactions. A notable example is the association between variants in the KCNIP4 gene and the occurrence of ACE inhibitor-induced cough. [6] Identifying such genetic predispositions allows clinicians to anticipate and potentially prevent this common adverse effect by selecting alternative antihypertensive therapies for at-risk patients. This represents a direct application of pharmacogenomics in improving patient tolerability and adherence to treatment.
The utility of pharmacogenetics in clinical implementation is further highlighted by the ability of certain genetic markers to predict directionally opposite blood pressure responses to different classes of antihypertensive drugs. For instance, single nucleotide polymorphisms (SNPs) associated with blood pressure response to an ARB like candesartan have been shown to have opposite directional associations with blood pressure response to a diuretic like hydrochlorothiazide. [5] Such predictors hold significant promise for individualizing antihypertensive drug therapy by guiding drug selection. This personalized prescribing approach considers an individual's unique genetic profile, including race-specific differences in marker SNP frequencies and linkage disequilibrium, to optimize drug efficacy and minimize adverse reactions, ultimately leading to more effective and tailored treatment strategies. [5]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs4343 rs4362 |
ACE | angiotensin converting enzyme activity attribute serum metabolite level aspartylphenylalanine-to-X-14450--phenylalanylleucine ratio glycylphenylalanine measurement level of Gly-Trp in blood |
| rs495828 | ABO - Y_RNA | hemoglobin measurement erythrocyte count hematocrit venous thromboembolism alkaline phosphatase measurement |
Frequently Asked Questions About Angiotensin Converting Enzyme Activity Attribute
These questions address the most important and specific aspects of angiotensin converting enzyme activity attribute based on current genetic research.
1. Why do my blood pressure pills work differently for me than my friend?
Your genetic makeup, specifically variations in the ACE gene, can influence how effectively your body processes blood pressure medications like ACE inhibitors or Angiotensin II Receptor Blockers (ARBs). This means the same drug might have a different impact on your blood pressure compared to someone else, leading to varied responses.
2. Why do certain blood pressure medicines make me cough?
Specific genetic variations, such as those in the KCNIP4 gene, have been associated with an increased risk of developing a cough when taking ACE inhibitor medications. Your genetics can influence how your body reacts to these drugs, leading to common side effects.
3. Does my family history of Alzheimer's mean I'm more at risk?
Yes, your genetic background, including variations that affect ACE activity, can play a role in your risk for conditions like Alzheimer's disease. ACE is involved in degrading amyloid-beta peptides in the brain, and differences in its activity could influence disease development.
4. Could a DNA test help my doctor pick the best blood pressure medicine for me?
Yes, understanding your genetic markers, particularly those influencing ACE activity, can help your doctor tailor your treatment. This personalized approach, based on pharmacogenomic insights, can lead to more effective blood pressure control and potentially reduce adverse drug reactions.
5. Why do some people seem to handle stress better without high blood pressure?
Differences in your genetic makeup, including variations in the ACE gene, can influence how your body regulates blood pressure in response to various factors like stress. Some individuals might be genetically predisposed to maintain healthier blood pressure levels even under similar stressors due to their enzyme activity.
6. Can exercise help overcome my family history of high blood pressure?
Yes, exercise is a powerful tool. Even if you have genetic variations that predispose you to higher blood pressure by influencing ACE activity, lifestyle changes like regular exercise can significantly help in managing and lowering your blood pressure. It's about working with your genetics to support your health.
7. Could a special test tell me my personal risk for high blood pressure?
Knowing your genetic profile, particularly variants associated with ACE activity, could offer insights into your individual risk for conditions like hypertension. This information can help your doctor create a more personalized prevention or treatment plan tailored to your specific genetic predispositions.
8. Can my genetics influence my brain health as I age?
Yes, your genetics can play a role in your brain health. Variations that affect your ACE activity, for instance, have been linked to how your brain processes certain proteins involved in conditions like Alzheimer's disease, potentially influencing your risk for neurodegenerative issues over time.
9. Why might one type of blood pressure medicine work better for me than another?
Your genetic makeup, specifically variations in genes like ACE, influences how your body responds to different classes of blood pressure medications. This means one type of drug, such as an ACE inhibitor, might be more effective or cause fewer side effects for you compared to another, guiding your doctor's choice.
10. Does my ethnic background change how blood pressure medicine affects me?
While the article doesn't specifically detail ethnic differences for ACE activity, genetic variations influencing medication response can vary across populations. This highlights the importance of considering individual genetic profiles, which can sometimes correlate with ethnic background, for personalized treatment.
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
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[10] Hu, J., et al. "Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity." J Biol Chem, 2001.
[11] Zou, K., et al. "Angiotensin-converting enzyme converts amyloid beta-protein 1–42 (Abeta(1–42)) to Abeta(1–40), and its inhibition enhances brain Abeta deposition." J Neurosci, 2007.
[12] Ning, M., et al. "Amyloid-beta-Related Genes SORL1 and ACE are Genetically Associated With Risk for Late-onset Alzheimer Disease in the Chinese Population." Alzheimer disease and associated disorders, 2010.
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[14] Ortlepp, J. R. et al. "Variants of the cyp11b2 gene predict response to therapy with candesartan." European Journal of Pharmacology, vol. 445, no. 1-2, 2002, pp. 151-152.
[15] Sekino, K. et al. "Effect of the single cyp2c9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy japanese subjects." European Journal of Clinical Pharmacology, vol. 59, no. 8-9, 2003, pp. 589-592.
[16] Wu, S. L. et al. "[Association of polymorphisms in ace and cyp11b2 genes with antihypertensive effects of hydrochlorothiazide]." Zhonghua Xin Xue Guan Bing Za Zhi, vol. 33, no. 8, 2005, pp. 595-598.
[17] Hallberg, P. et al. "The cyp2c9 genotype predicts the blood pressure response to irbesartan: Results from the swedish irbesartan left ventricular hypertrophy investigation vs atenolol (silvhia) trial." Journal of Hypertension, vol. 20, no. 10, 2002, pp. 2089-2093.