Sodium

Introduction

Sodium (Na) is a vital electrolyte and mineral, fundamental for numerous physiological processes in the human body. It plays a critical role in maintaining fluid balance, nerve impulse transmission, and muscle contraction. Sodium is predominantly found in extracellular fluids, such as blood plasma, and its concentration is tightly regulated to ensure proper cellular function.

Biological Basis

The body’s sodium levels are primarily regulated by the kidneys, influenced by hormones like aldosterone and antidiuretic hormone (ADH). These regulatory mechanisms ensure that sodium intake and excretion are balanced, which is crucial for maintaining blood volume and pressure. Genetic variations can influence how an individual’s body handles sodium. For instance, research has identified a single nucleotide polymorphism (SNP),rs6035310 , located upstream of the PDYNgene, which is associated with urinary sodium levels. ThePDYNgene encodes prodynorphin, a precursor to opioid neuropeptides that are ligands for kappa opioid receptors. These receptors have been shown to play a role in regulating urinary sodium and water excretion, suggesting a potential genetic pathway influencing sodium balance.^[1]

Clinical Relevance

Imbalances in sodium levels, such as hyponatremia (low sodium) or hypernatremia (high sodium), can lead to severe health complications affecting neurological, cardiovascular, and renal systems. High dietary sodium intake is a well-established risk factor for hypertension (high blood pressure).^[1]Hypertension, in turn, is a major contributor to cardiovascular diseases. The mechanisms linking sodium and hypertension can involve enhanced renin release from the kidney, leading to vasoconstriction and increased sodium retention.^[1]Understanding an individual’s genetic predisposition to sodium handling can offer insights into their susceptibility to these conditions and inform personalized health strategies.

Social Importance

Given its widespread presence in the food supply and its strong link to public health concerns like hypertension and cardiovascular disease, sodium holds significant social importance. Public health initiatives often focus on educating the population about recommended sodium intake and encouraging reduced consumption of high-sodium foods. These efforts aim to mitigate the burden of diet-related chronic diseases. As genetic research advances, the potential for personalized dietary recommendations based on an individual’s genetic profile for sodium metabolism may become increasingly relevant in public health strategies.

Generalizability and Phenotypic Measurement Considerations

A significant limitation in understanding the genetic influences on sodium levels stems from the characteristics of the study populations. Many investigations have utilized samples such as adolescent twins and their siblings, or adult female monozygotic twins.^[2] While powerful for genetic discovery, findings from twin cohorts may not always be directly generalizable to the broader, non-twin population.^[2] Furthermore, studies frequently rely on volunteer participants, which introduces a potential selection bias that could impact the representativeness of the sample compared to the general population.^[2] The ethnic homogeneity of some cohorts, such as those predominantly of white European ancestry, also limits the applicability of findings to diverse populations and makes it uncertain how results would translate to other ethnic groups.^[3] Phenotypic measurements themselves can introduce variability and limitations. For instance, serum markers of iron status, which can be related to broader metabolic health, are known to be influenced by factors such as the time of day blood is collected and menopausal status.^[2] While some studies attempt to control for these variables, inconsistencies in collection protocols across different cohorts can introduce noise or confounding effects.^[2]Moreover, the focus on multivariable models in some analyses might inadvertently overlook important bivariate associations between single nucleotide polymorphisms (SNPs) and specific measures, potentially obscuring direct genetic effects.^[3]

Methodological and Statistical Constraints

The scope of genome-wide association studies (GWAS) is often constrained by the density and coverage of the SNP arrays used. Older generations of SNP chips, such as the 100K arrays, may not provide sufficient coverage of all gene regions, potentially leading to missed associations or an incomplete understanding of genetic influences.^[4] This limited coverage also impacts the ability to comprehensively study candidate genes or fully replicate previously reported findings, as different studies may identify associations with different SNPs within the same gene region due to varying linkage disequilibrium patterns or the presence of multiple causal variants.^[5]Statistical power is another critical limitation, particularly when aiming to detect genetic effects of modest size, given the extensive multiple testing inherent in GWAS.^[6] Associations with moderate statistical support may represent false-positive results, underscoring the necessity for independent replication.^[6] The estimation of genetic variance explained by SNPs also relies on the accuracy of phenotypic variance and heritability estimates, meaning any inaccuracies in these foundational assumptions can propagate into the reported effect sizes.^[2] Furthermore, the use of mean observations in certain study designs, such as monozygotic twin pairs, requires careful consideration and adjustment when translating findings to individual-level effects in the general population.^[2]

Environmental Confounders and Remaining Knowledge Gaps

Genetic variants do not operate in isolation; their influence on phenotypes can be highly context-specific and modulated by environmental factors.^[6]For instance, associations between genes and cardiovascular traits have been shown to vary with dietary salt intake, highlighting the potential for significant gene-environment interactions.^[6] However, many studies do not explicitly undertake comprehensive investigations of these complex interactions, which can lead to an incomplete picture of genetic susceptibility and phenotypic expression.^[6] Despite the advancements in GWAS, there remains a substantial portion of heritability for many complex traits that is yet to be explained by identified common genetic variants. This “missing heritability” suggests that current approaches may not fully capture the genetic architecture, potentially due to the influence of rare variants, structural variations, or more complex gene-gene and gene-environment interactions.^[7] Furthermore, some genetic effects might be sex-specific and could go undetected in studies that perform only sex-pooled analyses.^[4] Continued research with larger, more diverse cohorts, denser genotyping arrays, and improved statistical methods for gene-environment interaction analysis will be crucial for bridging these knowledge gaps.

Variants

Genetic variants play a significant role in modulating various physiological processes, including the intricate balance of sodium and overall fluid homeostasis in the human body. These variations can impact gene function, protein activity, and downstream pathways, leading to subtle or pronounced effects on an individual’s health. The genes discussed here contribute to diverse biological functions, from osmoregulation and metabolic control to neural signaling and basic cellular processes, all of which can indirectly or directly influence the body’s sodium regulation.

Central to sodium balance and osmoregulation are genes likeNFAT5 and SLC4A10. NFAT5, also known as TonEBP, is a crucial transcription factor that enables cells to adapt to changes in osmotic pressure, particularly in high-salt environments. It orchestrates the expression of genes vital for maintaining cellular volume and function under hypertonic stress, which is highly relevant to how the body handles sodium and maintains fluid balance. Variants such asrs17298067 , rs72783110 , and rs39999 in NFAT5, or rs564381127 located near NFAT5 and NQO1(NAD(P)H Quinone Dehydrogenase 1, involved in detoxification), could influence this critical osmotic stress response, thereby impacting how the body processes sodium and maintains overall electrolyte equilibrium.SLC4A10(Solute Carrier Family 4 Member 10), also known as NBCn2, encodes a sodium bicarbonate cotransporter that significantly contributes to pH regulation and sodium transport, particularly in the brain and kidney. Genetic variations, includingrs62188151 and rs62188153 in SLC4A10, may alter the efficiency of this transporter, affecting cellular sodium and bicarbonate levels, which in turn can influence blood pressure regulation and broader electrolyte homeostasis.^[1]Other genes contribute to metabolic and systemic processes that indirectly impact sodium-related traits.TCF7L2 (Transcription Factor 7 Like 2) is a key component of the Wnt signaling pathway and is strongly associated with the risk of type 2 diabetes. Variants such as rs7903146 and rs34872471 in TCF7L2can affect insulin secretion and glucose metabolism. WhileTCF7L2’s primary role is not direct sodium handling, disruptions in glucose metabolism can lead to kidney complications, such as diabetic nephropathy, which significantly impact sodium and fluid balance, making these variants relevant to overall metabolic health and its downstream effects on electrolytes.HBB(Hemoglobin Subunit Beta) is essential for oxygen transport in red blood cells, and the variantrs334 is notably linked to sickle cell trait. Although HBB’s direct involvement in sodium transport is limited, conditions affecting red blood cell function, like sickle cell disease, can lead to renal complications such as impaired urine concentrating ability and electrolyte imbalances, including altered sodium excretion. Thus, genetic variations inHBBcan have systemic effects that indirectly influence kidney function and sodium regulation.^[8] Beyond direct metabolic and osmoregulatory roles, several genes involved in neural, regulatory, and general cellular processes can also exert an influence. SYT1(Synaptotagmin 1) plays a critical role in neurotransmitter release, mediating the fusion of synaptic vesicles, and while its direct link to systemic sodium balance is not immediate, central nervous system regulation of fluid and electrolyte homeostasis is vital for maintaining sodium levels. Long intergenic non-coding RNAs (lncRNAs), such as LINC02424, LINC00332, and LINC00598, with the variantrs9549089 , are known to regulate gene expression and can indirectly influence various physiological processes, potentially including those related to sodium handling or associated traits. Genes likeCSE1L (Chromosome Segregation 1 Like), involved in nuclear transport and cell cycle progression, and MAST2(Microtubule Associated Serine/Threonine Kinase 2), a signaling kinase, have broad cellular functions. Variants such asrs79186842 in CSE1L and rs6666743 in MAST2may affect cell proliferation, protein trafficking, or signal transduction pathways, which can have systemic consequences that indirectly affect sodium-related physiological traits. Pseudogenes, includingPSMA2P1 and RNU6-1135P, with variants rs2375030 and rs7113624 , are typically non-coding but can exert regulatory effects on functional genes, potentially contributing to the complex genetic landscape influencing sodium homeostasis.^{[9], [10]}

Key Variants

RS ID	Gene	Related Traits
rs11109717 rs12581220 rs11109811	LINC02424 - SYT1	urate measurement glomerular filtration rate uric acid measurement sodium measurement
rs2375030 rs7113624	PSMA2P1 - RNU6-1135P	chloride amount glomerular filtration rate sodium measurement
rs17298067 rs72783110 rs39999	NFAT5	gout sodium measurement
rs334	HBB	glomerular filtration rate urinary albumin to creatinine ratio HbA1c measurement hemolysis urate measurement
rs7903146 rs34872471	TCF7L2	insulin measurement clinical laboratory measurement, glucose measurement body mass index type 2 diabetes mellitus type 2 diabetes mellitus, metabolic syndrome
rs79186842	CSE1L	body fat percentage sodium measurement
rs564381127	NFAT5 - NQO1	sodium measurement
rs62188151 rs62188153	SLC4A10	sodium measurement
rs6666743	MAST2	sodium measurement
rs9549089	LINC00332, LINC00598	sodium measurement

Definition and Physiological Significance

Sodium, an essential electrolyte, is crucial for numerous biological processes, including the maintenance of fluid balance, blood pressure regulation, and proper nerve and muscle function.^[1]Its physiological importance extends to complex regulatory mechanisms within the body, where its retention or excretion directly impacts systemic hemodynamics. For instance, enhanced renin release from the kidney can lead to vasoconstriction and sodium retention, a process with significant implications for cardiovascular health.^[1]The conceptual framework for understanding sodium’s role also encompasses its intricate regulation by various systems. The balance of sodium within the body, particularly its excretion via urine, is influenced by neuroendocrine pathways. Specifically, kappa opioid receptors have been demonstrated to play a role in regulating both urinary sodium and water excretion, highlighting a sophisticated control mechanism over electrolyte homeostasis.^[1]

Measurement and Reference Ranges

The assessment of sodium levels is a standard component of clinical diagnostics, providing insights into an individual’s electrolyte status. A common approach for quantifying sodium excretion involves collecting 24-hour urine samples, which yields a comprehensive measure of urinary sodium.^[1]These measurements are typically performed by specialized clinical biochemistry units using standardized protocols to ensure accuracy and consistency. While some serum biochemistry measures may be performed on nonfasting samples, the reliability of 24-hour urinary sodium requires complete urine collections.^[1]Diagnostic and research criteria for sodium levels often rely on established reference ranges to identify deviations from normal physiological function. For 24-hour urinary sodium, a typical normal range is between 40.00 and 222.00 mmol/24 hr.^[1]Values outside this range can indicate imbalances such as sodium retention or excessive loss, which may necessitate clinical intervention or further investigation into underlying causes. In genetic association studies, sodium is treated as a quantitative trait, with analyses often adjusting for factors like age, sex, and body mass index to isolate genetic effects.^[1]

Genetic Terminology and Associated Pathways

Genetic studies have begun to unravel the molecular underpinnings of sodium regulation, identifying specific genes and pathways involved. Key terminology in this field includes thePDYNgene, which is located upstream of prodynorphin and has been associated with urinary sodium levels through variants likers6035310 .^[1] PDYN itself is classified as a preproprotein within the opioid neuropeptide precursor family, undergoing proteolytic processing to generate secreted opioid peptides.^[1] The significance of the PDYNgene in sodium regulation stems from its downstream products. The opioid peptides derived fromPDYNserve as ligands for the kappa type of opioid receptor, which has a known role in modulating urinary sodium and water excretion.^[1]This genetic association suggests a direct molecular link between the opioid system and renal sodium handling, offering a potential biological pathway for understanding individual differences in sodium balance and its implications for conditions where sodium regulation is critical.

Clinical Assessment of Sodium Status

Sodium levels are routinely assessed in clinical practice through both serum and urine biochemistry. Serum sodium measurements are typically performed on nonfasting samples, with a median concentration observed at 139.04 mmol/L within a normal reference range of 135.00–144.00 mmol/L.^[1]This objective measure provides a snapshot of the body’s overall sodium balance and is a fundamental component of electrolyte panels. Deviations from this established normal range can serve as critical indicators of electrolyte disturbance, prompting further clinical investigation.

Beyond serum, 24-hour urine collections are utilized to quantify urinary sodium excretion, reflecting renal handling of this essential electrolyte. The median 24-hour urinary sodium is reported as 140.93 mmol/24 hr, with a broad normal range spanning 40.00–222.00 mmol/24 hr.^[1]This comprehensive collection method allows for the assessment of daily sodium output, offering insights into dietary intake, fluid status, and kidney function. Both serum and urine sodium measurements are considered standard diagnostic tools, routinely employed in everyday clinical care to monitor physiological parameters.^[1]

Genetic Influences on Sodium Homeostasis

Genetic variation plays a role in influencing biochemical parameters, including sodium levels, and contributes to inter-individual heterogeneity.^[1]Specifically, a notable association has been identified between urinary sodium levels and single nucleotide polymorphisms (SNPs) located close to thePDYN gene, such as rs6035310 .^[1] The PDYN gene is upstream of prodynorphin, a preproprotein that undergoes proteolytic processing to form secreted opioid peptides.^[1]These opioid peptides are known ligands for the kappa type of opioid receptor, which has been implicated in the regulation of urinary sodium and water excretion.^[1]This genetic link suggests a potential biological pathway through which inherited factors can influence the body’s sodium balance and excretion patterns, although these associations are considered provisional until replicated in further studies.^[1]

Diagnostic Significance of Sodium Measurements

The measurement of serum and urine sodium holds significant diagnostic value, serving as crucial biomarkers in various clinical contexts. These biochemical parameters are routinely used to define comorbid traits and assess overall physiological function.^[1]For instance, serum sodium provides an objective measure of hydration status and osmotic balance, while urinary sodium excretion helps in evaluating renal tubular function and response to diuretic therapy. The diagnostic utility extends to identifying genetic influences on these quantitative traits, which might serve as risk factors for common diseases or their associated complications.^[1]Understanding the variability in sodium levels, whether due to genetic predispositions or other factors, is essential for accurate diagnosis, differential diagnosis of electrolyte disorders, and tailoring appropriate management strategies in patient care.

Inherited Genetic Variants

Research indicates that common genetic variations can significantly influence biochemical parameters, including urinary sodium levels. A genome-wide association study identified a specific single nucleotide polymorphism (SNP),rs6035310 , located upstream of the PDYNgene, as being associated with urinary sodium.^[1]This finding suggests a genetic predisposition influencing an individual’s excretion of sodium. However, these initial associations are considered provisional and require replication in further studies to confirm their definitive role.^[1]

Molecular Pathways of Sodium Regulation

The PDYNgene, implicated in urinary sodium regulation, encodes prodynorphin, a preproprotein belonging to the opioid neuropeptide precursor family.^[1] Prodynorphin undergoes proteolytic processing to yield secreted opioid peptides, which function as ligands for the kappa type of opioid receptor.^[1]These kappa opioid receptors are known to play a crucial role in the physiological regulation of both urinary sodium and water excretion, thereby providing a plausible molecular mechanism for the observed genetic association with sodium levels.^[1]

Polygenic Influence on Biochemical Parameters

Beyond specific single-gene associations, the overall levels of many routinely measured biochemical traits, such as sodium, are understood to be under substantial genetic control.^[1] Genome-wide association studies (GWAS) aim to uncover how common genetic variation influences the inheritance of these heritable quantitative traits, which can serve as important biomarkers or risk factors for various common diseases.^[1] This approach highlights the polygenic nature of complex traits, where numerous genetic variants, each with a small effect, collectively contribute to an individual’s unique biochemical profile.^[1]

Genetic Architecture of Sodium Regulation

A specific genetic variant, rs6035310 , has been identified upstream of the PDYNgene (MIM 131340) and associated with variations in urinary sodium levels.^[1] The PDYN gene, belonging to the opioid neuropeptide precursor family, is responsible for encoding prodynorphin.^[1] Prodynorphin functions as a preproprotein that undergoes proteolytic processing to yield secreted opioid peptides, which are crucial for cellular communication.^[1]This genetic link suggests a significant role for the opioid system in the complex regulatory network governing sodium balance within the body.^[1]

Molecular and Cellular Pathways of Sodium Excretion

The secreted opioid peptides, generated through the processing of prodynorphin, act as specific ligands for the kappa type of opioid receptor.^[1]The binding of these peptides to kappa opioid receptors initiates signaling pathways that have been demonstrated to play a direct role in regulating the excretion of both sodium and water by the kidneys.^[1] This intricate molecular mechanism highlights how neuropeptide signaling at the cellular level precisely controls renal tubular function, thereby maintaining vital electrolyte and fluid homeostasis.^[1]

Renal and Systemic Sodium Homeostasis

The kidneys are paramount in orchestrating the body’s sodium balance, which is fundamental for maintaining overall fluid volume and blood pressure. Disruptions in this delicate homeostatic process can trigger significant compensatory responses, such as enhanced renin release from the kidneys.^[1]This release leads to a cascade that includes vasoconstriction and subsequent sodium retention, a critical mechanism for blood pressure regulation.^[1]Furthermore, angiotensin II, a potent vasoconstrictor, can influence vascular smooth muscle cells, suggesting a broader systemic impact on sodium-related pathways.^[11]

Sodium Retention and Cardiovascular Pathophysiology

Sodium retention is a well-established pathophysiological process contributing to the development and progression of conditions like hypertension and cardiovascular disease.^[1]Factors such as elevated uric acid levels can exacerbate this by promoting enhanced renin release, which in turn leads to increased vasoconstriction and sodium retention, contributing to higher blood pressure.^[1]This disruption of sodium homeostasis contributes to broader systemic consequences including endothelial dysfunction and suppression of nitric oxide production, intensifying the risk for cardiovascular complications.^[1]The interplay between genetic predispositions and environmental factors can also lead to context-dependent genetic effects in hypertension, further complicating the clinical picture.^[12]

Neuroendocrine Regulation of Electrolyte Balance

The intricate balance of urinary sodium excretion is significantly influenced by neuroendocrine pathways. ThePDYN gene, identified through a common genetic variant (rs6035310 ) associated with urinary sodium levels, plays a crucial role in this regulatory process.^[1] This gene encodes prodynorphin, a precursor protein that undergoes proteolytic processing to generate various secreted opioid peptides. These opioid peptides then function as ligands, initiating specific signaling cascades upon binding to their respective receptors.^[1]

Receptor-Mediated Control of Renal Function

The opioid peptides derived from prodynorphin primarily exert their effects by interacting with kappa opioid receptors. These receptors are integral components of the signaling pathway that modulates renal function, with a direct impact on the excretion of both sodium and water.^[1]The binding of these neuropeptides to kappa opioid receptors can influence the cellular mechanisms within the kidneys, which are responsible for maintaining overall fluid and electrolyte balance. This receptor activation represents a critical regulatory mechanism that contributes to the body’s sodium homeostasis.^[1]

Systems-Level Integration in Fluid Homeostasis

The pathway involving the PDYN gene and kappa opioid receptors exemplifies a systems-level integration where the neuroendocrine system directly influences renal physiology. This particular axis contributes to the complex network interactions that govern fluid and electrolyte homeostasis, showcasing how neuropeptide signaling can hierarchically regulate vital organ functions.^[1] The interplay between opioid peptides and their receptors underscores a broader principle of pathway crosstalk, where signals originating from the nervous system are effectively translated into specific physiological responses within peripheral organs, thereby ensuring systemic equilibrium.

Clinical Significance and Disease Relevance

Dysregulation within the PDYN-kappa opioid receptor pathway can carry significant disease-relevant implications, particularly in conditions characterized by altered sodium and water balance. Given its established role in regulating urinary sodium excretion, variations or disruptions in this molecular mechanism could contribute to the pathogenesis of conditions such as hypertension or various renal disorders.^[1]A deeper understanding of these precise molecular interactions and their functional significance may reveal promising therapeutic targets for managing clinical conditions where sodium excretion is compromised or requires modulation.

Genetic Predisposition and Renal Sodium Handling

Research has identified a genetic association between urinary sodium levels and the single nucleotide polymorphism (SNP)rs6035310 , located upstream of the PDYN gene.^[1] The PDYNgene encodes prodynorphin, a precursor to opioid peptides that function as ligands for kappa opioid receptors, which are known to play a role in regulating urinary sodium and water excretion.^[1]While this association is currently provisional and requires replication in independent studies, it suggests a potential genetic influence on individual variations in renal sodium handling and overall fluid balance. Such genetic insights, once validated, could contribute to personalized risk assessment by identifying individuals potentially predisposed to altered sodium excretion, which may inform future prevention or management strategies for related health conditions.

Diagnostic and Monitoring Utility of Sodium Levels

Sodium levels, particularly 24-hour urinary sodium, are routinely measured biochemical parameters in clinical care.^[1]The typical normal range for 24-hour urinary sodium is between 40.00 and 222.00 mmol/24 hr, with a median of 140.93 mmol/24 hr reported in studies.^[1]Monitoring these levels offers significant diagnostic utility for evaluating renal excretory function, assessing dietary sodium intake, and managing conditions characterized by fluid and electrolyte imbalances. Consistent measurement allows clinicians to track a patient’s physiological response to therapeutic interventions and disease progression, thereby guiding necessary adjustments to maintain optimal sodium balance and support patient care.

Sodium Balance in Comorbidities and Risk Stratification

Maintaining appropriate sodium balance is paramount given its critical role in the pathophysiology of several comorbidities, including hypertension and cardiovascular disease. Sodium retention is a recognized mechanism that contributes to conditions like hypertension, potentially leading to enhanced renin release, vasoconstriction, and endothelial dysfunction.^[1]While the precise pathways linking specific biochemical markers and disease outcomes are intricate, understanding the involvement of sodium allows for improved risk stratification. Identifying individuals prone to sodium retention and implementing targeted interventions, such as dietary modifications or pharmacological management, is essential for preventing disease progression and optimizing long-term cardiovascular health outcomes.

References

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[2] Benyamin, Beben, et al. “Variants in TF and HFEexplain approximately 40% of genetic variation in serum-transferrin levels.”American Journal of Human Genetics, vol. 84, no. 1, 2009, pp. 60-65.

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[7] Kathiresan, Sekar, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nature Genetics, vol. 41, no. 1, 2008, pp. 56-65.

[8] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet, vol. 8, no. Suppl 1, 2007, p. S11.

[9] Wilk, J. B., et al. “Framingham Heart Study genome-wide association: results for pulmonary function measures.” BMC Med Genet, vol. 8, 2007, p. S8.

[10] Willer, C. J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161-9.

[11] 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.

[12] Kardia, S. L. “Context-Dependent Genetic Effects in Hypertension.”Curr Hypertens Rep, vol. 2, 2000, pp. 32-38.