Diuretic Use
Introduction
Section titled “Introduction”Diuretics are a class of medications designed to increase the excretion of water and salts from the body, primarily through their action on the kidneys. This process, known as diuresis, helps to reduce fluid volume in the body. Diuretics are widely prescribed for various medical conditions, most notably hypertension (high blood pressure) and edema (fluid retention) associated with conditions like heart failure, liver disease, and kidney disease.
Biological Basis
Section titled “Biological Basis”The primary biological basis for diuretic action involves targeting specific transporters in the renal tubules, which are responsible for reabsorbing sodium and other electrolytes back into the bloodstream. By inhibiting these renal sodium transport systems, diuretics prevent the reabsorption of sodium, leading to its increased excretion in urine. Water follows sodium, resulting in increased urine output and a reduction in overall body fluid volume.[1]Thiazide diuretics, for example, act on the distal convoluted tubule to inhibit sodium-chloride symporters. Genetic variations in an individual’s physiology, including components of the renin-angiotensin-aldosterone system or the renal sodium transport systems, can influence the effectiveness and side effects of diuretic therapy.[1] For instance, poor responders to diuretic therapy have been observed to have significantly greater mean 24-hour urinary excretion of aldosterone.[1]
Clinical Relevance
Section titled “Clinical Relevance”Diuretics, particularly thiazide diuretics, are a cornerstone of antihypertensive therapy and are often recommended as initial treatment for many patients.[1] However, their efficacy can vary significantly among individuals; for example, when used as monotherapy, blood pressure is controlled in only approximately 50% of patients.[1] This variability in response is a significant clinical challenge, as it necessitates a “trial-and-error” approach to find the most effective treatment for each patient.[1]Established predictors of greater blood pressure responses to diuretics include black race, older age, and lower activity of the renin-angiotensin-aldosterone system.[1] Research into pharmacogenomics aims to identify genetic variants that influence these responses, with the potential to personalize treatment strategies. Studies have identified genetic associations with diuretic response, such as a region on chromosome 12q15, defined by haplotypes from rs317689 , rs315135 , and rs7297610 , that was significantly associated with diastolic blood pressure response to hydrochlorothiazide, particularly in black subjects.[1] Genes in or near this region include LYZ, YEATS4, and FRS2.[1]Additionally, diuretic use, specifically thiazides, is a known confounder for serum urate levels.[2] and common genetic variations in genes like GLUT9(associated with serum uric acid levels, e.g., viars7442295 ) have been identified.[2] Provisional associations between SNPs near the PDYNgene on chromosome 12 and urinary sodium have also been noted.[2]
Social Importance
Section titled “Social Importance”The widespread prevalence of hypertension and other conditions treated with diuretics underscores the social importance of optimizing diuretic therapy. Moving beyond a conventional trial-and-error approach to antihypertensive therapy through pharmacogenomic insights has the potential to improve patient outcomes, reduce the burden of adverse drug reactions, and enhance the overall efficiency of healthcare. Understanding the genetic factors contributing to individual variability in diuretic response can lead to more precise prescribing, ultimately improving public health by ensuring more effective management of chronic conditions. The recognition of differing genetic influences across diverse populations, such as the observed locus on chromosome 12q15 in black subjects, highlights the importance of inclusive genomic research to address health disparities.[1]
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Studies often face limitations due to moderate cohort sizes, which can lead to insufficient statistical power to detect genetic associations of modest effect.[3] This lack of power increases the risk of false negative findings, where true associations might be overlooked.[3] Conversely, the extensive multiple statistical testing inherent in genome-wide association studies (GWAS) can inflate the likelihood of false positive findings, requiring rigorous replication in independent cohorts for validation.[4] The provisional nature of initial findings underscores the critical need for external replication to confirm true genetic associations.[4] Without such validation, many reported p-values may not represent genuine biological relationships.[4] Furthermore, specific analytical choices, such as focusing solely on multivariable-adjusted models, may inadvertently obscure important bivariate associations between genetic variants and traits.[4] While imputation methods are used to infer missing genotypes, they introduce an estimated error rate, which can range from 1.46% to 2.14% per allele, potentially affecting the accuracy of genetic associations.[5]
Phenotypic Assessment and Generalizability
Section titled “Phenotypic Assessment and Generalizability”The accuracy of phenotypic assessment is a key limitation in genetic studies. For instance, kidney function evaluated by a single serum creatinine measure can lead to misclassification, and the use of equations like MDRD to estimate GFR may underestimate true GFR in healthy individuals, introducing further inaccuracies into trait definitions.[4]Similarly, while cystatin C is used as a kidney function marker, its potential to also reflect cardiovascular disease risk independently of kidney function complicates its interpretation.[4]For endocrine traits, reliance on markers like TSH without comprehensive measures of free thyroxine or reliable assessments of thyroid disease can limit the depth of understanding of thyroid function.[4] A significant limitation is the generalizability of findings, particularly when studies are conducted in cohorts that are not ethnically diverse or nationally representative.[4] For example, studies predominantly involving individuals of White European ancestry may not accurately reflect genetic associations or drug responses in other ethnic groups.[6] This is further highlighted by observations that genetic effects on drug response, such as to thiazide diuretics, can differ markedly between Black and White subjects, suggesting race-specific mechanisms that influence treatment outcomes.[1]
Complex Genetic Architecture and Unexplained Variation
Section titled “Complex Genetic Architecture and Unexplained Variation”The genetic contribution to complex traits like antihypertensive drug responses is likely polygenic, involving numerous genes with modest individual effects, rather than a few strong loci.[1] This complex genetic architecture, coupled with potentially modest overall heritability, means that even after accounting for identified genetic variants and established predictors, a substantial portion of the interindividual variation in drug responses often remains unexplained.[1] This “missing heritability” points to the need for more comprehensive approaches to capture the full spectrum of genetic and environmental influences.
While studies may adjust for known confounders such as serum creatinine, alcohol consumption, blood pressure, and sex, the potential for unmeasured environmental factors or intricate gene–environment interactions to influence traits remains a challenge.[2] The current understanding of the biological mechanisms underlying observed genetic associations, particularly concerning drug responses, often requires further investigation to fully elucidate the pathways involved.[1] Addressing these gaps will require continued research into both genetic and environmental contributions, as well as their complex interplay.
Variants
Section titled “Variants”Genetic variations play a crucial role in individual differences in physiological processes, including kidney function, blood pressure regulation, and metabolic health, which can influence the effectiveness and side effects of diuretic medications. Variants in genes like KCNK3 and NOS3are particularly relevant due to their direct involvement in cardiovascular and renal physiology. Thers1275988 variant within or near KCNK3(Potassium Channel Subfamily K Member 3) may affect the activity of potassium channels, which are vital for maintaining cellular membrane potential and regulating vascular tone, thereby impacting blood pressure. Similarly, thers3918226 variant in NOS3 (Nitric Oxide Synthase 3), also known as endothelial nitric oxide synthase, could alter nitric oxide production, a key vasodilator that regulates blood pressure and renal blood flow. Alterations in these pathways can influence a person’s baseline blood pressure and fluid balance, potentially modifying their response to diuretics, which aim to reduce fluid retention and lower blood pressure.[1], [4] Other genetic loci contribute to broader biological pathways that indirectly impact kidney health and diuretic response. Variants such as rs10857147 and rs12509595 associated with PRDM8 (PR/SET Domain 8) and FGF5 (Fibroblast Growth Factor 5) may influence transcriptional regulation and growth factor signaling, pathways critical for cellular development and tissue maintenance. The HOXA11-AS and HOXA13 genes, with the associated variant rs916880 , are part of the Homeobox A cluster, essential for embryonic development, including kidney and urogenital system formation, which could predispose individuals to certain renal characteristics. Likewise, the CASZ1 (Castor Zinc Finger 1) gene, linked to rs880315 , functions as a transcription factor involved in neurogenesis and tumor suppression, while RSPO3 (R-Spondin 3), with variants rs9398819 and rs9375459 , is a Wnt signaling pathway potentiator, crucial for tissue repair and regeneration. These genes collectively highlight the complex genetic architecture underlying organ function and its potential modulation of drug efficacy.[3], [4] Beyond direct physiological regulators, genes involved in immune response and metabolism also play a role. LSP1 (Lymphocyte-Specific Protein 1), with variants rs569550 and rs562434 , is active in immune cells, and variations might influence inflammatory responses that can affect kidney function or drug metabolism. The FTO(Fat Mass and Obesity Associated) gene, containing variantsrs62048402 and rs56094641 , is strongly associated with obesity and metabolic traits. Given that obesity is a significant risk factor for hypertension and kidney disease, conditions often managed with diuretics,FTOvariants could indirectly modify diuretic effectiveness by influencing body weight and metabolic status. Additionally, several pseudogenes such asRPL37P11, RPS4XP9, TBX3-AS1 (an antisense RNA), UBA52P7, UBA52P4, and RNU1-96P (with variants like rs35441 , rs35436 , rs664223 , rs591668 ) are present in the human genome. While pseudogenes do not typically encode functional proteins, they can exert regulatory roles on their protein-coding counterparts or other genes, thus potentially influencing diverse biological processes including those relevant to drug response and disease susceptibility.[2]
Key Variants
Section titled “Key Variants”Operational Definitions and Measurement of Antihypertensive Response
Section titled “Operational Definitions and Measurement of Antihypertensive Response”Diuretic use, particularly thiazide diuretics like hydrochlorothiazide, is a common therapeutic approach for hypertension, with a standard regimen often involving a daily oral dose, such as 25 mg, administered over a specific period, typically four weeks.[1] The primary measure of antihypertensive drug response is operationally defined as the difference in blood pressure (BP) readings taken before and after the treatment period.[1] Specifically, this involves calculating the change in the average of repeated diastolic BP measurements from a drug-free baseline to the end of the diuretic treatment.[1]To ensure accurate and consistent measurements, BP readings are typically obtained by trained personnel using a standardized sphygmomanometer after participants have been seated quietly for several minutes, and subjects may be instructed to adhere to a standard dietary sodium intake and discontinue other antihypertensive medications prior to the study.[1]
Categorization of Diuretic Response
Section titled “Categorization of Diuretic Response”The response to diuretic therapy is often categorized to differentiate individuals based on treatment efficacy, a classification crucial for understanding inter-individual variability in drug response.[1] This typically involves classifying subjects into “good responders” and “poor responders,” often achieved by sampling individuals from opposite tertiles of the distribution of their diastolic BP response.[1] This categorical approach, which prioritizes diastolic BP as the primary measure, is particularly useful in genetic association studies to maximize statistical power for identifying genomic loci influencing drug efficacy.[1]Such classifications acknowledge that while thiazide diuretics are widely recommended, they control BP in only approximately 50% of patients when used as monotherapy, highlighting the heterogeneity of pathophysiologic mechanisms contributing to hypertension.[1]
Associated Physiological and Biochemical Markers
Section titled “Associated Physiological and Biochemical Markers”Inter-individual variation in response to diuretic therapy is associated with several physiological and biochemical markers, which serve as important indicators and potential predictors of treatment outcome. Poor responders to diuretic therapy have been observed to exhibit significantly greater mean 24-hour urinary excretion of aldosterone.[1]In certain populations, such as Black subjects, poor responders also demonstrate significantly greater mean duration of diagnosed hypertension, waist circumference, baseline systolic BP, plasma renin activity, and serum aldosterone, coupled with a greater increase in 24-hour urinary excretion of sodium and lower mean serum potassium.[1]Other related biochemical traits frequently assessed in cardiovascular and renal health contexts, which can be influenced by or predictive of diuretic action, include glomerular filtration rate (GFR), measured using equations like the simplified Modification of Diet in Renal Disease Study equation, and urinary albumin/creatinine ratio (UACR), a reliable measure of albumin excretion.[4]Additionally, serum uric acid levels, which can be affected by diuretic use, are measured using enzymatic-colorimetric methods, with hyperuricemia defined by specific concentration thresholds.[2]
Evolution of Diuretic Therapy and Understanding of Response
Section titled “Evolution of Diuretic Therapy and Understanding of Response”The use of diuretics, particularly thiazide diuretics, has long been a cornerstone in the management of hypertension, establishing themselves as a recommended initial and preferred therapy for many patients.[1] This widespread adoption reflects a historical understanding of their efficacy in blood pressure control. However, scientific understanding has evolved beyond general efficacy to acknowledge significant variability in patient response, with approximately half of patients achieving controlled blood pressure with monotherapy.[1]This recognition has spurred deeper investigation into the heterogeneous pathophysiologic mechanisms underlying hypertension and individual drug responses, moving the field towards a more nuanced and personalized approach to diuretic therapy.[1]
Demographic and Physiological Determinants of Diuretic Efficacy
Section titled “Demographic and Physiological Determinants of Diuretic Efficacy”Epidemiological studies have illuminated distinct demographic and physiological patterns influencing the effectiveness of diuretic treatment. Research indicates that certain groups, such as black individuals and older patients, tend to exhibit a more pronounced antihypertensive response to diuretics.[1]Beyond age and ancestry, an individual’s physiological profile plays a critical role; those with lower activity in the renin-angiotensin-aldosterone system generally respond more favorably.[1]Conversely, poor responders to thiazide diuretics, particularly within black populations, are characterized by higher mean 24-hour urinary excretion of aldosterone, elevated plasma renin activity, and increased serum aldosterone, alongside a greater duration of diagnosed hypertension, higher baseline systolic blood pressure, increased waist circumference, and lower serum potassium levels.[1] These findings underscore the complex interplay of genetic, physiological, and anthropometric factors that dictate diuretic efficacy across diverse populations.
Genetic and Population-Based Epidemiological Trends
Section titled “Genetic and Population-Based Epidemiological Trends”Contemporary epidemiological trends are increasingly shaped by advances in genomic research, with genome-wide association studies (GWAS) identifying genetic variants that influence diuretic response. A significant landmark study pinpointed a region on chromosome 12q15, characterized by haplotypes derived from rs317689 , rs315135 , and rs7297610 , as being strongly associated with diastolic blood pressure response to thiazide diuretics, especially in black subjects.[1]This discovery contributes to understanding the genetic underpinnings of observed demographic differences in drug efficacy, building upon earlier efforts to map human loci for essential hypertension.[7] Furthermore, large-scale population-based cohorts, including the Framingham Heart Study.[4] the UK-based GRAPHIC study and TwinsUK registry.[2] the NHANES I Epidemiologic Follow-up Study.[2] the Rotterdam Study.[8] and studies in Sardinia and Chianti.[2]have been crucial for understanding hypertension, kidney function, and serum uric acid levels—conditions frequently managed with diuretics. These studies often consider diuretic administration as a potential confounder when investigating biomarkers like serum urate, highlighting the widespread use of these medications in general populations and their broad impact on physiological parameters.[2] The continued analysis of such extensive cohorts is vital for projecting future trends in the personalized application of diuretic therapy.
Renal Physiology and Diuretic Action
Section titled “Renal Physiology and Diuretic Action”Diuretics, particularly thiazide diuretics, exert their therapeutic effects primarily by influencing the kidney’s crucial role in maintaining fluid and electrolyte balance and regulating blood pressure. These medications target specific molecular and cellular pathways within the renal tubules, particularly the distal convoluted tubule, where they inhibit the reabsorption of sodium and chloride ions.[1]This inhibition leads to increased excretion of sodium and water in the urine, thereby reducing intravascular volume and subsequently lowering blood pressure. The precise interaction involves key biomolecules, such as sodium-chloride co-transporters, which are integral membrane proteins responsible for moving these ions across renal cell membranes.
The systemic consequences of diuretic action extend beyond direct fluid removal. By altering sodium balance, diuretics impact overall vascular tone and peripheral resistance, contributing to their antihypertensive effect. However, these physiological changes can also disrupt normal homeostatic mechanisms, leading to compensatory responses. For instance, increased sodium excretion can sometimes be accompanied by altered potassium balance, potentially resulting in lower serum potassium levels.[1] Understanding these intricate tissue-level interactions within the kidney and their broader systemic implications is fundamental to comprehending the variability in diuretic response among individuals.
The Renin-Angiotensin-Aldosterone System (RAAS) and Hypertension
Section titled “The Renin-Angiotensin-Aldosterone System (RAAS) and Hypertension”The Renin-Angiotensin-Aldosterone System (RAAS) is a critical neurohormonal regulatory network deeply involved in blood pressure control, fluid balance, and electrolyte homeostasis. In hypertension, dysregulation of the RAAS often contributes to elevated blood pressure through mechanisms such as increased vascular constriction and enhanced sodium and water retention. Key biomolecules like renin, angiotensinogen, angiotensin-converting enzyme (ACE), and aldosterone are central to this pathway, with aldosterone, in particular, promoting sodium reabsorption and potassium excretion in the kidneys.[1]Patients who respond poorly to diuretic therapy frequently exhibit significantly higher activity of the RAAS, as evidenced by elevated plasma renin activity, serum aldosterone, and 24-hour urinary excretion of aldosterone.[1]This suggests that a highly active RAAS can counteract the effects of diuretics, which aim to reduce fluid volume, by promoting compensatory sodium and water retention. Genetic variations in genes encoding components of the RAAS have been explored as potential predictors of antihypertensive responses, highlighting the complex interplay between genetic predisposition and pathophysiological processes in determining treatment efficacy.[1]
Genetic Influences on Diuretic Response
Section titled “Genetic Influences on Diuretic Response”Individual responses to thiazide diuretics exhibit significant variability, with only about 50% of patients achieving blood pressure control with monotherapy, indicating a strong genetic component influencing drug efficacy.[1] Genome-wide association studies have begun to uncover specific genetic mechanisms that contribute to this heterogeneity. For example, a locus on chromosome 12q15, defined by haplotypes constructed from *rs317689 *, *rs315135 *, and *rs7297610 *, has been significantly associated with diastolic blood pressure response to hydrochlorothiazide, particularly in Black subjects.[1] This region contains genes such as LYZ, YEATS4, and FRS2, though the specific biological mechanism by which these genes influence diuretic response remains to be fully elucidated.[1] The genetic contribution to antihypertensive response is likely polygenic, involving multiple genes with small effects, similar to the genetic architecture of blood pressure itself.[1] Beyond specific loci, regulatory elements and epigenetic modifications may also play a role in modulating gene expression patterns that affect drug metabolism, transport, or target pathways. These genetic insights are crucial for moving beyond a trial-and-error approach to antihypertensive therapy, potentially enabling personalized medicine strategies based on an individual’s genetic profile.[1]
Uric Acid Metabolism and Diuretic Interactions
Section titled “Uric Acid Metabolism and Diuretic Interactions”Uric acid, the end product of purine metabolism, plays a complex role in human physiology and pathophysiology, with elevated serum levels (hyperuricemia) being linked to hypertension, cardiovascular disease, and metabolic syndrome.[9]Diuretic use, particularly thiazide diuretics, can influence uric acid levels, often contributing to hyperuricemia, which may confound or exacerbate existing conditions.[9]This interaction involves molecular and cellular pathways regulating uric acid production and, critically, its renal excretion.
Key biomolecules involved in uric acid transport include the glucose transporter-like protein 9 (GLUT9, also known as SLC2A9) and the urate-anion exchanger (SLC22A12).[10] GLUT9is highly expressed in the liver and kidney and plays a significant role in determining serum uric acid levels, with alternative splicing altering its trafficking and function.[11]Disruptions in the function of these transporters, whether due to genetic variants or drug interactions, can impair the kidney’s ability to excrete uric acid, contributing to higher serum concentrations and potentially influencing the overall efficacy and side-effect profile of diuretic therapy.[10]
Renal Sodium Transport and Fluid Homeostasis
Section titled “Renal Sodium Transport and Fluid Homeostasis”Diuretics exert their primary therapeutic effects by modulating renal sodium transport systems, thereby influencing fluid balance and blood pressure (BP) control. Thiazide diuretics, for instance, are a common initial treatment for hypertension, acting on specific transporters within the kidney tubules to inhibit sodium reabsorption.[1]This inhibition leads to increased sodium and water excretion, reducing extracellular fluid volume and consequently lowering BP. However, the efficacy of diuretic monotherapy varies significantly among individuals, with BP controlled in approximately 50% of patients, suggesting a complex interplay of underlying pathophysiological mechanisms and compensatory responses.[1]Poor responders to diuretic therapy often exhibit distinct physiological profiles, including significantly greater mean 24-hour urinary excretion of aldosterone, indicating increased activity of the renin-angiotensin-aldosterone system (RAAS).[1]This heightened aldosterone level can act as a compensatory mechanism, promoting sodium retention and counteracting the diuretic’s intended effect, particularly in certain demographic groups such as black subjects who also show higher plasma renin activity and serum aldosterone.[1] Understanding these compensatory pathways is crucial for optimizing therapeutic strategies and overcoming drug resistance.
Genetic Determinants of Diuretic Response
Section titled “Genetic Determinants of Diuretic Response”The observed heterogeneity in antihypertensive responses to diuretics is influenced by genetic factors, suggesting a polygenic contribution to drug efficacy.[1] Knowledge of specific genetic variants has the potential to move beyond trial-and-error approaches in therapy. For example, a genome-wide association study identified a significant locus on chromosome 12q15 in black subjects that was strongly associated with diastolic BP response to thiazide diuretics.[1]This region is defined by haplotypes constructed from single nucleotide polymorphisms (SNPs)rs317689 , rs315135 , and rs7297610 , highlighting specific genetic markers that influence drug response.[1]While candidate genes encoding components of the RAAS or renal sodium transport systems have been explored, the majority of interindividual variation in BP responses remains unexplained, underscoring the complexity of genetic interactions.[1] Although the FRS2 gene is located within the chromosome 12q15 region, evidence of its direct association with BP response was found to be weak.[1] These findings suggest that multiple genes, possibly with context-dependent effects, contribute to the overall response to diuretic therapy, necessitating further investigation to elucidate the complete genetic architecture.
Hormonal and Intracellular Signaling Integration
Section titled “Hormonal and Intracellular Signaling Integration”The renin-angiotensin-aldosterone system (RAAS) plays a central role in blood pressure regulation and significantly modulates the response to diuretics. Diuretics, by reducing fluid volume, can activate the RAAS, leading to increased renin release and subsequent production of angiotensin II and aldosterone. Higher baseline activity of the RAAS and elevated aldosterone levels are established predictors of a lesser BP response to diuretics, as seen in poor responders who exhibit elevated urinary aldosterone excretion.[1] This hormonal feedback loop represents a critical regulatory mechanism that can diminish diuretic efficacy.
Beyond direct RAAS effects, angiotensin II has broader intracellular signaling implications, including increasing phosphodiesterase 5A expression in vascular smooth muscle cells.[12] This action antagonizes cGMP signaling, which is crucial for vasodilation, thereby contributing to vasoconstriction and elevated BP.[12]Such pathway crosstalk demonstrates how diuretic-induced changes in fluid balance can trigger complex hormonal and intracellular signaling cascades that influence vascular tone and overall cardiovascular function.
Metabolic Dysregulation and Urate Pathways
Section titled “Metabolic Dysregulation and Urate Pathways”Diuretic use can impact metabolic pathways, notably affecting serum uric acid levels, which is a disease-relevant mechanism associated with cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus.[9]The renal handling of urate is primarily mediated by specific transport proteins, includingSLC2A9 (also known as GLUT9) and SLC22A12.[10] SLC2A9is a facilitative glucose transporter family member with alternative splicing variants, and genetic variants within this gene have been strongly associated with serum uric acid concentrations and urate excretion, with pronounced sex-specific effects.[11]Dysregulation of these urate transport pathways, potentially exacerbated by diuretics, can lead to hyperuricemia. Furthermore, metabolic factors such as fructose consumption are known to induce hyperuricemia, providing an additional layer of complexity to urate metabolism.[13]The interplay between diuretic action, genetic predispositions in urate transporters, and dietary influences highlights how therapeutic interventions can interact with underlying metabolic pathways, potentially leading to adverse outcomes like hyperuricemia, and identifies these transporters as therapeutic targets for managing such conditions.[14]
Genetic Influences on Antihypertensive Response
Section titled “Genetic Influences on Antihypertensive Response”Interindividual variability in blood pressure (BP) response to thiazide diuretics, such as hydrochlorothiazide, is a significant clinical challenge, with approximately half of patients failing to achieve BP control with monotherapy. This variation is largely attributed to pharmacodynamic differences in drug action rather than pharmacokinetic variations in drug levels, suggesting a heterogeneity in the underlying pathophysiologic mechanisms of hypertension.[1] Genetic factors play a crucial role in this differential response. A genome-wide association study identified a significant locus on chromosome 12q15, defined by haplotypes constructed from *rs317689 *, *rs315135 *, and *rs7297610 *, that was strongly associated with diastolic BP response to hydrochlorothiazide, particularly in non-Hispanic black individuals.[1] This region is in proximity to genes such as LYZ, YEATS4, and FRS2, with subsequent genotyping corroborating associations for LYZ and YEATS4 with diastolic BP response in both black and white subjects.[1]These genetic variants are thought to influence the efficacy of diuretics by modulating pathways involved in BP regulation. Poor responders to diuretic therapy, especially among black subjects, have been observed to exhibit characteristics such as significantly greater 24-hour urinary excretion of aldosterone, higher plasma renin activity, and increased baseline systolic BP.[1]This suggests that genetic variations affecting the renin-angiotensin-aldosterone system or renal sodium transport mechanisms, which are the therapeutic targets of diuretics, may contribute to the observed interindividual differences in treatment outcomes.[1] While candidate gene studies have previously explored polymorphisms in these systems, genome-wide approaches are beginning to uncover novel genetic loci that provide a more comprehensive understanding of diuretic pharmacodynamics.[1]
Pharmacodynamic and Electrolyte Homeostasis Effects
Section titled “Pharmacodynamic and Electrolyte Homeostasis Effects”Genetic variants can profoundly influence the pharmacodynamic effects of diuretics, leading to varied therapeutic responses and potential adverse reactions. For instance, the PDYNgene, which encodes prodynorphin, a precursor to opioid peptides that interact with kappa opioid receptors, has been linked to urinary sodium excretion through the single nucleotide polymorphism*rs6035310 *.[4]Given that kappa opioid receptors play a role in regulating urinary sodium and water excretion, variations inPDYNcould modulate the renal handling of sodium, thereby affecting the efficacy of diuretics that primarily target sodium reabsorption.[4]Such genetic influences on electrolyte balance are critical, as poor responders to diuretics have been noted to have lower mean serum potassium levels, highlighting the importance of understanding the genetic underpinnings of diuretic-induced electrolyte disturbances.[1]Beyond direct sodium excretion, genetic factors also influence other key physiological processes affected by diuretic therapy. The impact of diuretics on uric acid levels, a common side effect, is also subject to genetic modulation. A prominent example is the*rs7442295 * polymorphism within the SLC2A9gene, which has been strongly associated with serum urate concentrations.[2] SLC2A9encodes a glucose transporter family member involved in uric acid transport, and variants in this gene can significantly influence uric acid concentrations, with notable sex-specific effects.[15]Understanding these genetic predispositions can help predict which patients may be at higher risk for hyperuricemia during diuretic treatment, informing clinical monitoring and management strategies.
Clinical Implementation and Personalized Prescribing
Section titled “Clinical Implementation and Personalized Prescribing”The identification of genetic variants influencing diuretic response holds significant potential for advancing personalized medicine in hypertension management, moving beyond the traditional trial-and-error approach.[1] Although current evidence suggests that the genetic contribution to antihypertensive response may be polygenic with many genes having small effects, the discovery of loci like those on chromosome 12q15 provides a foundation for future clinical guidelines.[1] For instance, in patients identified as potential poor responders based on genetic profiles, alternative antihypertensive agents or combination therapies could be considered earlier, optimizing therapeutic outcomes and reducing the time to achieve BP control.
While direct dosing recommendations based on diuretic pharmacogenetics are not yet standard clinical practice, these findings emphasize the utility of genomic information in predicting treatment efficacy and potential adverse effects. Personalized prescribing could involve using genetic markers to guide initial drug selection, particularly in patient populations with known differential responses, such as those of black race, where specific genetic associations have been more pronounced.[1] Further research is warranted to fully elucidate the biological mechanisms underlying these genetic associations and to translate these insights into actionable clinical guidelines that incorporate pharmacogenetic testing for diuretics, ultimately improving patient care.[1]
References
Section titled “References”[1] Turner, S. T., et al. “Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic.” Hypertension, 2008.
[2] Wallace, C., et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, vol. 82, no. 1, 2008, pp. 139–149.
[3] 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. S9.
[4] 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, 2007.
[5] Willer, C. J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nature Genetics, 2008.
[6] Melzer, D., et al. “A genome-wide association study identifies protein quantitative trait loci (pQTLs).” PLoS Genetics, 2008.
[7] Caulfield, M. et al. “Genome-wide mapping of human loci for essential hypertension.”Lancet, vol. 361, no. 9375, 2003, pp. 2118–2123.
[8] Dehghan, A., et al. “Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.”Lancet, vol. 372, no. 9654, 2008, pp. 1959-1965.
[9] Hayden, M. R., and S. C. Tyagi. “Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle.”Nutr Metab (Lond), vol. 1, 2004, p. 10.
[10] Li, S., et al. “The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.”PLoS Genet, 2007.
[11] Augustin, R., et al. “Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking.”J Biol Chem, vol. 279, no. 16, 2004, pp. 16229–16236.
[12] 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, no. 1, 2005, pp. 175-184.
[13] Perheentupa, J., and K. Raivio. “Fructose-induced hyperuricaemia.”Lancet, vol. 2, no. 7515, 1967, pp. 528–31.
[14] Dawson, J., et al. “Uric acid reduction: a new paradigm in the management of cardiovascular risk?”Curr Med Chem, vol. 14, no. 17, 2007, pp. 1879–1886.
[15] Gieger, C., et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genetics, 2008.