Systolic Blood Pressure

Systolic blood pressure (SBP) represents the maximum pressure exerted by blood against the arterial walls during the heart’s contraction phase, known as systole. It is the first and higher number recorded in a blood pressure reading, typically measured in millimeters of mercury (mm Hg). SBP is a critical indicator of cardiovascular health, reflecting the force with which the heart pumps blood into the circulatory system.

Biological Basis

The biological basis of SBP involves the dynamic interplay between the heart’s pumping action (cardiac output) and the resistance of the arterial system (vascular resistance). During systole, the left ventricle contracts, ejecting blood into the aorta and subsequently into the peripheral arteries, creating a pressure wave that is measured as SBP. Factors such as arterial stiffness, a measure of how flexible the arteries are, significantly contribute to SBP levels and overall cardiovascular risk.^[1] Blood pressure, including SBP, is recognized as a highly heritable trait, with studies providing significant evidence for genetic contributions to its variation across human populations.^[2] Large-scale genome-wide association studies (GWAS) and meta-analyses have identified numerous genomic loci and specific genetic variants that influence SBP.^[2]

Clinical Relevance

Clinically, elevated SBP is a primary risk factor for a range of severe health conditions, including heart disease, stroke, kidney disease, and premature death.^[1]Hypertension, or high blood pressure, is frequently defined by a SBP of 140 mm Hg or higher, or by the use of anti-hypertensive medication.^[3] For individuals receiving blood pressure-lowering medication, researchers often adjust observed SBP values by adding a constant (e.g., 10 mm Hg or 15 mm Hg) to account for treatment effects and improve statistical power in analyses.^[3]Understanding the genetic architecture of SBP is crucial because it measures partly distinct physiological features like cardiac output, vascular resistance, and arterial stiffness, all of which are important for determining a cardiovascular risk profile.^[1]

Social Importance

Systolic blood pressure’s social importance stems from the high prevalence of hypertension, affecting approximately one-quarter of adults, and its substantial public health burden worldwide.^[1]The widespread impact of hypertension on morbidity and mortality underscores the critical need for effective prevention, diagnosis, and management strategies. Research into the genetic underpinnings of SBP, particularly across diverse ancestral populations, is vital for defining pathophysiological mechanisms, identifying individuals at increased risk, and ultimately informing personalized approaches to treatment and prevention.^[2]

Methodological and Statistical Considerations

The detection of genetic associations with systolic blood pressure (SBP) often relies on meta-analyses of multiple genome-wide association studies (GWAS), which can introduce methodological complexities. Variations in genotyping platforms, quality control filters, imputation software, and reference genomes used across different studies can contribute to heterogeneity in results and impact the consistency of findings.^{[4], [5]} Furthermore, while large sample sizes are crucial for identifying genetic variants with small effect sizes, individual studies or specific subgroups within meta-analyses may have insufficient power, especially when analyzing rare variants or stratifying by factors like age.^{[6], [7]} The process of Winsorization or exclusion of extreme outlier blood pressure values, typically defined as those exceeding four standard deviations from the mean, is applied in some studies to normalize data, but this manipulation can alter the original distribution and potentially influence effect estimates.^{[4], [7]}Statistical challenges also include the “winner’s curse,” where initial effect size estimates for newly discovered variants may be inflated; efforts are often made to mitigate this bias.^[1] Replication of findings across independent cohorts is essential for validating genetic associations, yet some variants, particularly those with very low minor allele frequencies or borderline significance, may fail to replicate consistently, highlighting the need for robust validation studies.^[8] These statistical nuances underscore the importance of careful interpretation of reported effect sizes and the need for continued research to refine discovery methods and validate genetic associations.

Phenotypic Variability and Measurement Limitations

Systolic blood pressure is a highly dynamic physiological trait, influenced by numerous factors and exhibiting inherent variability, which poses challenges for precise phenotyping in genetic studies. Although estimates of test-retest reliability for blood pressure measurements are moderate, typically ranging from 0.65 to 0.75, this inherent variability means that single measurements may not fully capture an individual’s true long-term blood pressure status.^[6] To address this, many studies utilize long-term average SBP or incorporate multiple measurements over time, which has been shown to reduce phenotype variability and enhance the power to detect genetic effects, implying that studies relying on fewer measurements might have reduced accuracy.^{[7], [8]} A common practice in SBP studies involves adjusting blood pressure values for individuals taking antihypertensive medication, typically by adding a fixed constant (e.g., 10-15 mmHg for SBP) to their measured values.^{[4], [5], [7]} While this adjustment aims to account for treatment effects and increase statistical power, it relies on an imputation method that introduces an assumption about the medication’s impact, which may not perfectly reflect individual physiological responses. Additionally, some studies report genetic effects in terms of Z-scores, which are standardized units, rather than absolute mmHg values; while useful for cross-study comparisons, this can make direct clinical interpretation of the magnitude of genetic influence on SBP less intuitive.^[9]

Generalizability and Unexplained Influences

A significant limitation in the generalizability of SBP genetic findings stems from the predominant ancestral composition of many large-scale GWAS. Numerous studies have focused on specific populations, such as East Asians, Chinese, or African-ancestry populations, meaning that genetic variants identified in one group may not have the same effect sizes, allele frequencies, or even be present in other diverse ancestral backgrounds.^{[7], [10], [11]} This highlights the need for more inclusive trans-ancestry studies to ensure that genetic insights are broadly applicable.

Furthermore, environmental factors known to profoundly influence SBP, such as dietary sodium and potassium intake or alcohol consumption, are often not comprehensively measured or adjusted for across all cohorts included in meta-analyses.^[6] The omission of these key confounders, even if assumed not to systematically alter blood pressure by genotype, can potentially reduce statistical power and obscure the full picture of gene-environment interactions. The complex interplay between genes and environmental factors, including gene-age interactions, is still being actively investigated, and current models may not fully capture these intricate relationships, representing a remaining knowledge gap.^[4]Finally, inferring direct causality between genetic variants, SBP, and downstream cardiovascular outcomes remains challenging. Mendelian randomization approaches, while powerful, rely on assumptions that genetic effects are mediated solely through blood pressure and not via alternative causal pathways, which can be difficult to definitively establish.^[1]

Variants

Variants across several genes and intergenic regions contribute to the complex genetic architecture underlying systolic blood pressure regulation. These genetic markers often influence distinct biological pathways, including calcium signaling, lipid metabolism, growth factor activity, ion channel function, and gene expression regulation, all of which play roles in maintaining cardiovascular homeostasis.

The ATP2B1gene encodes a plasma membrane calcium ATPase, a critical enzyme responsible for pumping calcium ions out of cells. This function is essential for maintaining cellular calcium balance and regulating the contraction of vascular smooth muscle, directly impacting vascular tone. Variants inATP2B1, including rs12230074 , rs12579302 , and rs11105354 , have been consistently linked to both systolic and diastolic blood pressure levels, as well as the overall risk of hypertension.^[12] These associations highlight ATP2B1’s significant role in blood pressure regulation, possibly by influencing peripheral vascular resistance. Nearby loci, such as those associated with the chloride channel gene CLCN6, also show relevance to blood pressure phenotypes, with CLCN6 being identified as an expressed gene in the context of blood pressure.^[12] CLCN6is involved in chloride transport, which contributes to cell volume regulation and excitability, processes that can indirectly affect cardiovascular function and blood pressure.

Regions encompassing HERPUD1 and CETP, including the rs247617 variant, may influence blood pressure through pathways related to lipid metabolism. CETP(cholesteryl ester transfer protein) plays a key role in transferring cholesteryl esters and triglycerides among lipoproteins, affecting cholesterol levels that are broadly linked to cardiovascular health and hypertension risk.^[1] Similarly, variants near PRDM8 and FGF5, such as rs13125101 , rs12509595 , and rs16998073 , have been associated with blood pressure.^[9] FGF5 (Fibroblast Growth Factor 5) is involved in various biological processes, and its influence on blood pressure could stem from roles in vascular development or metabolic regulation. The NT5C2gene, involved in nucleotide metabolism, andZPR1, which plays a role in cell proliferation, also contain variants (rs11191580 , rs79780963 , rs12412038 for NT5C2 and rs964184 for ZPR1) that may contribute to the complex genetics of systolic blood pressure by affecting cellular energy states or vascular remodeling.^[13] Genetic variations in regions involving long non-coding RNAs, such as LINC02577 (rs13225723 , rs35267491 , rs11770800 ) and LINC02120, often play regulatory roles in gene expression, potentially influencing pathways critical for blood pressure homeostasis. The intergenic region of CCDC71L and LINC02577 contains variants like rs62481856 , rs12705390 , and rs17477177 , suggesting a role in complex regulatory networks affecting cardiovascular traits.^[14] The NPR3gene (Natriuretic Peptide Receptor 3) is a crucial regulator of blood pressure by binding and clearing natriuretic peptides, which are hormones that lower blood pressure by promoting vasodilation and sodium excretion. Variants in theNPR3 - LINC02120 region, including rs1173727 , rs13154066 , and rs12656497 , may therefore impact this critical pathway.^[15] Additionally, variants in the RPL37P11 - KCNK3 region, such as rs1275988 , rs1275985 , and rs1275984 , relate to KCNK3(Potassium Two Pore Domain Channel Subfamily K Member 3), a potassium channel known to regulate vascular smooth muscle tone and pulmonary vascular resistance, thereby influencing systemic blood pressure.

Key Variants

RS ID	Gene	Related Traits
rs12230074 rs12579302 rs11105354	ATP2B1	systolic blood pressure
rs247617	HERPUD1 - CETP	low density lipoprotein cholesterol measurement metabolic syndrome high density lipoprotein cholesterol measurement systolic blood pressure level of phosphatidylcholine
rs13125101 rs12509595 rs16998073	PRDM8 - FGF5	mean arterial pressure, alcohol drinking diastolic blood pressure systolic blood pressure atrial fibrillation erythrocyte count
rs55857306 rs17037452 rs17037427	CLCN6	diastolic blood pressure systolic blood pressure serum alanine aminotransferase amount hypertension pulse pressure measurement
rs62481856 rs12705390 rs17477177	CCDC71L - LINC02577	pulse pressure measurement, alcohol consumption quality systolic blood pressure hypertension pulse pressure measurement
rs11191580 rs79780963 rs12412038	NT5C2	body mass index attention deficit hyperactivity disorder, bipolar disorder, autism spectrum disorder, schizophrenia, major depressive disorder schizophrenia systolic blood pressure diastolic blood pressure
rs964184	ZPR1	very long-chain saturated fatty acid measurement coronary artery calcification vitamin K measurement total cholesterol measurement triglyceride measurement
rs1173727 rs13154066 rs12656497	NPR3 - LINC02120	body height mean arterial pressure systolic blood pressure hypertension BMI-adjusted hip circumference
rs13225723 rs35267491 rs11770800	LINC02577	systolic blood pressure carotid artery thickness blood urea nitrogen amount hypertension, Antihypertensive use measurement diastolic blood pressure
rs1275988 rs1275985 rs1275984	RPL37P11 - KCNK3	diastolic blood pressure pulse pressure measurement systolic blood pressure mean arterial pressure hypertension

Defining Systolic Blood Pressure and Its Measurement

Systolic blood pressure (SBP) represents the maximum pressure exerted on arterial walls during the heart’s contraction phase, known as systole. It is considered a highly heritable physiological trait.^[2] SBP is routinely measured using various methods, including manual techniques with mercury sphygmomanometers and the auscultation of Korotkoff sounds, typically the first sound, or through automated oscillometric devices.^[2] Standardized protocols often involve measurements taken after a rest period, sometimes averaging multiple readings from both arms, or by trained and certified observers using random zero sphygmomanometers.^[3]

Clinical Classification and Diagnostic Criteria

Systolic blood pressure plays a critical role in the clinical classification and diagnosis of hypertension. According to established criteria, hypertension is commonly defined by an SBP of 140 mm Hg or higher, or by the self-report of taking anti-hypertensive medication.^[3] Conversely, normotensive individuals are typically characterized by an SBP of 120 mm Hg or less and not receiving anti-hypertensive treatment.^[3] For individuals undergoing anti-hypertensive treatment, SBP values are often adjusted in studies by adding a constant, commonly 10 mm Hg, to account for the medication’s effect on measured pressure.^[3]

Research Operationalization and Related Blood Pressure Indices

In research, SBP is frequently analyzed as a continuous quantitative trait, allowing for the examination of inter-individual variation and genetic influences.^[2]Its operationalization in studies often involves using raw SBP values, or more commonly, residuals derived from regression models that adjust for covariates such as age, sex, and body mass index (BMI).^[3]Beyond SBP itself, related hemodynamic indices are also derived, including pulse pressure (PP), calculated as the difference between SBP and diastolic blood pressure (DBP), and mean arterial pressure (MAP), computed as SBP/3 + 2DBP/3.^[1]These derived measures provide additional insights into cardiovascular function and are often analyzed independently alongside SBP.^[1]

Clinical Measurement and Assessment

Systolic blood pressure (SBP) is primarily assessed through objective measurement rather than subjective signs or symptoms, serving as a key physiological phenotype. Standardized protocols for its determination typically involve the use of a mercury column sphygmomanometer in a clinical setting, with measurements taken after a participant has been seated for at least five minutes.^[14] SBP is often identified by the first Korotkoff sound, and multiple readings are commonly averaged to ensure accuracy, such as one nurse/technician reading and two physician readings.^[2] For individuals undergoing antihypertensive treatment, adjustments are frequently applied to their raw SBP values, often by adding 10 or 15 mmHg to account for the medication’s effect and derive a medication-adjusted SBP for research analyses.^[3] The consistency of SBP measurements is crucial, with some studies collecting at least two measurements over a year apart in a clinical environment using established methods.^[3] While most assessments occur in a clinical setting with trained personnel and bias-free instrumentation, some data may also be extracted from electronic medical records (EMR).^[3] Beyond single-point measurements, “long-term average SBP” is also utilized as a phenotype in research, reflecting a more stable representation of an individual’s blood pressure status over time.^[2]This objective approach underscores SBP as a measurable trait fundamental to cardiovascular health assessment.

Variability and Influencing Factors

Systolic blood pressure exhibits significant variability and heterogeneity across individuals and populations, influenced by a complex interplay of genetic and environmental factors. Blood pressure, including SBP, is recognized as a highly heritable trait, with studies of familial aggregation providing substantial evidence for this genetic component.^[2]Inter-individual variation in SBP is a well-documented phenomenon, which is further shaped by demographic factors such as age, sex, and body mass index (BMI), which are consistently included as covariates in SBP analyses to account for their effects.^[16] Phenotypic diversity in SBP is also observed across different human populations, with research involving individuals of European, East Asian, South Asian, and African descents highlighting the broad scope of this variation.^[2] This underscores the need to consider population stratification and ancestry when studying SBP, as genetic variants influencing blood pressure may vary in their prevalence and effect across these groups.^[2] The inclusion of age-squared as a covariate in some models further refines the understanding of age-related changes in SBP.^[16]

Diagnostic Thresholds and Clinical Significance

The measurement of systolic blood pressure holds significant diagnostic and prognostic value, primarily in the identification and management of hypertension and associated health risks. Hypertension is clinically defined by specific SBP thresholds, often alongside diastolic blood pressure (DBP) levels or the use of antihypertensive medication.^[3]For instance, SBP ≥ 140 mm Hg (or DBP ≥ 90 mm Hg) or self-reported medication use typically indicates hypertension.^[3] Conversely, normotensive individuals are generally characterized by SBP ≤ 120 mm Hg and DBP ≤ 85 mm Hg without medication.^[3] More stringent definitions for hypertensive cases might include SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg for untreated subjects, or being on chronic antihypertensive treatments, often with an age of onset criterion.^[3]The diagnostic significance of SBP extends beyond hypertension itself, as it can serve as a prognostic indicator for other conditions. For example, SBP values may help define pathophysiological mechanisms and identify patients at an increased risk for Silent Cerebral Infarction (SCI).^[2]These established thresholds and clinical correlations highlight SBP as a critical objective measure for assessing cardiovascular health and predicting future health outcomes.

Causes

The regulation of systolic blood pressure (SBP) is a complex physiological process influenced by a multitude of interacting factors, ranging from an individual’s genetic makeup to environmental exposures and developmental experiences. Understanding these diverse causal pathways is crucial for comprehending the etiology of SBP variation and related cardiovascular conditions.

Genetic Architecture and Heritability

Systolic blood pressure is recognized as a highly heritable trait, with familial aggregation studies providing significant evidence for genetic influence on its variation.^[3] Heritability estimates have been derived using variance-component methods, underscoring the substantial genetic contribution to SBP levels.^[3] Modern genomic research, particularly through genome-wide association studies (GWAS), has identified numerous genetic loci associated with blood pressure traits, including SBP, across diverse populations.^[3]These large-scale studies have pinpointed many novel single nucleotide polymorphisms (SNPs) and genomic regions implicated in SBP regulation, although collectively they explain only a fraction of the estimated heritability, suggesting a complex polygenic architecture and the presence of “missing heritability”.^[3] Specific genetic variants and candidate genes have been linked to SBP regulation. For instance, multi-trait GWAS analyses have identified loci such as EVX1/HOXA, ULK4, TCF21, IGFBP3, CDH17, and ZNF746 as influencing blood pressure traits.^[3]Beyond common variants, the genetic basis of Mendelian forms of hypertension has highlighted the critical role of genes involved in renal sodium handling, demonstrating how specific genetic defects can profoundly impact SBP through altered kidney function.^[3]Furthermore, genes within the renin-angiotensin-aldosterone pathway are considered strong candidate genes due to their established roles in hypertension and vascular properties.^[3]

Environmental and Lifestyle Factors

Various environmental and lifestyle factors significantly contribute to systolic blood pressure levels and the risk of hypertension. Dietary sodium intake is a well-established environmental determinant, with its impact on blood pressure varying considerably among individuals and populations.^[3]Lifestyle choices such as alcohol consumption and smoking habits (quantified by pack-years) also exert a measurable influence, with studies showing their associations with SBP.^[3]Broader environmental and socioeconomic contexts further modulate SBP. Factors such as age, ethnicity, education level, socioeconomic status, and geographic location have been identified as contributors to blood pressure variation.^[3]Body mass index (BMI) is another crucial lifestyle-related factor, consistently adjusted as a covariate in studies investigating SBP due to its strong association with blood pressure levels.^[3]

Gene-Environment Interactions

The complex nature of systolic blood pressure means that genetic predispositions often interact with environmental triggers to manifest their effects. Traditional single-marker genetic analyses may overlook the marginal effects of variants that are significantly modified by environmental factors.^[3] Consequently, analyzing gene-environment interactions is a powerful approach to uncover additional genetic factors influencing blood pressure regulation.^[3]A notable example is the interaction between genes and dietary sodium intake, where specific genetic backgrounds can modify an individual’s blood pressure response to sodium.^[3]This interplay is particularly relevant given that many genes implicated in Mendelian hypertension exert their effects via renal sodium handling.^[3] Similarly, gene-alcohol interactions have led to the identification of novel blood pressure loci, including a promising locus near SLC16A9.^[3] Furthermore, gene-smoking interactions, particularly with cumulative smoking exposure (pack-years), have revealed genome-wide significant associations for SBP, highlighting SNPs like rs12149862 within CYB5B and rs2268365 intronic to LRP2.^[3]

Developmental and Epigenetic Influences

The role of epigenetic mechanisms, particularly DNA methylation, has been implicated in blood pressure regulation.^[3]Epigenetic modifications represent changes in gene expression that do not involve alterations to the underlying DNA sequence, yet can have lasting effects on physiological traits. DNA methylation is a key epigenetic mark, and its influence suggests that molecular mechanisms beyond genetic sequence variation contribute to the long-term control and variability of SBP.^[3]

Age, Comorbidities, and Pharmacological Modulators

Age is a prominent factor influencing systolic blood pressure, with both SBP and diastolic blood pressure (DBP) generally increasing with advancing age.^[3]However, DBP tends to plateau and may even decline in individuals over 60-65 years, leading to an increase in pulse pressure (SBP-DBP) with age.^[3] The study of gene-age interactions further explores how genetic effects on blood pressure can change across the lifespan.^[3]Comorbidities can also significantly impact SBP. For example, studies have investigated SBP in children with sickle cell disease, indicating that specific health conditions can modulate blood pressure profiles.^[3] Moreover, the use of antihypertensive medications is a critical consideration in SBP research, as these treatments directly alter blood pressure levels. To account for the effects of medication and reduce bias in genetic and epidemiological studies, observed SBP values are often statistically adjusted by adding a constant (e.g., 10 mm Hg or 15 mm Hg) for individuals on antihypertensive therapy.^[3] Such adjustments are vital to reveal underlying familial and genetic contributions to SBP variation, which can otherwise be obscured by treatment.^[3]

Genetic Basis of Systolic Blood Pressure

Systolic blood pressure (SBP) is recognized as a highly heritable trait, with familial aggregation studies providing significant evidence for a strong genetic contribution to its variation.^[2] Large-scale genome-wide association studies (GWAS) involving hundreds of thousands of individuals have identified numerous genomic loci associated with SBP in both adult and pediatric populations.^[2] While these studies have pinpointed many novel genetic variants, including approximately 50 loci, the identified genetic factors collectively explain a relatively small proportion, less than 2.5%, of the total variance in blood pressure.^[13] suggesting a complex polygenic architecture and the influence of other factors.

The genetic regulation of SBP involves intricate interactions between genes and environmental factors. For instance, gene-age and gene-alcohol interactions have been shown to influence blood pressure regulation, leading to the identification of novel loci such as one near SLC16A9.^[13]Similarly, gene-sodium interactions are critical, particularly involving genes that regulate renal sodium handling, which are fundamental to blood pressure control.^[17]Beyond sequence variation, epigenetic modifications like DNA methylation and gene transcription are increasingly recognized as mechanisms that explain the relationship between genetic variants and blood pressure phenotypes.^[3] Many of these polymorphic variants are distributed across different continental ancestries, suggesting their functional effects predate human continental differentiation.^[15]Candidate gene analyses have also focused on specific genes within pathways like the renin-angiotensin-aldosterone system, implicating them in hypertension.^[1] with examples including ATP2B1, CSK, MTHFR, CYP17A1, STK39, and FGF5.^[18]

Molecular and Cellular Regulation of Blood Pressure

At the molecular level, systolic blood pressure is largely regulated by complex signaling pathways, with the renin-angiotensin-aldosterone system (RAAS) being a central mediator.^[1]This pathway involves critical proteins and enzymes that control vasoconstriction, fluid balance, and electrolyte homeostasis. Furthermore, genes responsible for Mendelian forms of hypertension often exert their effects through proteins that regulate renal sodium handling, underscoring the kidney’s pivotal role in maintaining salt-water balance and, consequently, blood pressure.^[17]These proteins and their regulatory networks are crucial for maintaining cardiovascular homeostasis.

Cellular functions critical to blood pressure include the modulation of calcium channels, such as by the CaVbeta2 subunit on the CaV1.2channel, which impacts vascular smooth muscle contraction.^[19]Angiotensin II also plays a significant role in vascular smooth muscle cell proliferation through signaling pathways involvingc-Src and the Shc/Grb2/ERK2 cascade.^[20] The renal endothelin system is another key regulatory network, influencing renal function and vascular tone.^[21] Moreover, the genes NPPA and NPPBare associated with circulating natriuretic peptides, which are hormones involved in blood pressure reduction and cardiovascular homeostasis.^[6] Genetic studies have also highlighted the enrichment of regulatory elements for gene expression in vascular endothelial cells, indicating their widespread influence on blood pressure across various tissues and organs.^[15]

Organ Systems and Systemic Homeostasis

The regulation of systolic blood pressure is fundamentally intertwined with the function of several key organ systems, particularly the kidneys and the vascular network. The kidney’s ability to regulate sodium excretion and its subsequent impact on extracellular volume is considered a primary pathway determining intra-arterial pressure, a concept supported by studies on proteins regulating salt-water balance.^[15] Disruptions in these renal homeostatic mechanisms, often involving rare deleterious mutations in proteins that regulate salt-water balance, can significantly alter blood pressure.^[15]Beyond the kidneys, the vascular system plays a crucial role, with increased arterial stiffness identified as a key factor in the pathogenesis of systolic hypertension and cardiovascular disease.^[1] The broad distribution of vascular endothelial cells, which line both large and small vessels across all tissues and organs, suggests that regulatory elements affecting these cells have a systemic impact on blood pressure.^[15]The systemic consequences of dysregulated blood pressure are profound, contributing to an increased risk for heart disease, stroke, and kidney disease, highlighting the interconnectedness of these organ systems in maintaining overall cardiovascular health.^[1]

Pathophysiological Implications of Blood Pressure Dysregulation

Dysregulation of systolic blood pressure (SBP) is a major public health concern, contributing significantly to cardiovascular and cerebrovascular diseases, which are leading causes of death and functional disabilities worldwide.^[1]Hypertension is clinically defined by a systolic blood pressure greater than 140 mm Hg or the use of anti-hypertensive medication.^[3]Even within the normal range, increases in SBP have a continuous and graded impact on cardiovascular disease risk.^[6] underscoring the importance of maintaining optimal blood pressure levels.

Various lifestyle factors contribute to the risk of elevated SBP, including high dietary sodium intake, excessive alcohol consumption, elevated body mass index, and insufficient physical activity.^[6] In research settings, it is crucial to account for these influences and treatment effects; for instance, statistical adjustments are often made by adding constants to SBP values for individuals taking blood pressure-lowering medication.^[3]Understanding SBP’s pathophysiological mechanisms is also critical in specific populations, such as children with sickle cell disease, where SBP may help identify those at increased risk for silent cerebral infarct.^[2]

Vascular Tone and Ion Channel Signaling

The precise regulation of vascular tone is central to maintaining systolic blood pressure, involving intricate signaling pathways that control the contraction and relaxation of vascular smooth muscle cells. Key among these are calcium-dependent mechanisms, such as the modulation of theCaV1.2 calcium channel by its CaVbeta2subunit, which directly influences cellular calcium dynamics essential for muscle contraction.^[22]Similarly, the angiotensin II-dependent proliferation of vascular smooth muscle cells (VSMCs) is critically mediated by thec-Src and Shc/Grb2/ERK2 signaling pathway, highlighting a major regulatory axis in vascular remodeling and blood pressure control.^[3] The renal endothelin system also plays a significant role, contributing to vasoconstriction and blood pressure elevation.^[21] Counteracting vasoconstrictive forces, natriuretic peptides, encoded by genes like NPPA and NPPB, influence circulating peptide levels and blood pressure, promoting vasodilation and fluid balance.^[3] Furthermore, the plasma membrane calcium/calmodulin-dependent ATPase, ATP2B1 (also known as PMCA1), is expressed in vascular endothelium and actively pumps calcium out of the cytosol to the extracellular compartment. Dysregulation, such as elevated PMCA1 mRNA levels observed in spontaneously hypertensive rats, underscores its critical role in blood pressure regulation.^[3] The inorganic cation anion solute carrier (SLC) transporter pathway is also significantly enriched with hypertension-associated genes, emphasizing the importance of ion transport and cellular homeostasis in maintaining normal blood pressure.^[3]

Genetic and Epigenetic Regulation of Blood Pressure

The genetic landscape of systolic blood pressure involves complex regulatory mechanisms, including gene expression and chromatin dynamics. A transcription and chromatin modification network, enriched with genes encoding histones such asHIST1H4C, HIST1H2AC, HIST1H2BC, and HIST1H1T, suggests that epigenetic regulation plays a substantial role in blood pressure control.^[3]These modifications, which alter chromatin structure, can influence gene accessibility and transcription factor binding, thereby modulating the expression of genes critical for cardiovascular function.^[23] Beyond chromatin, specific genes demonstrate direct regulatory impact. For instance, the SF3A3gene, involved in pre-mRNA splicing, shows an association between its expression in human VSMCs and increased pulse pressure, indicating a role in post-transcriptional gene regulation relevant to vascular stiffness.^[3] Additionally, the MECOM–MDS1–EVI1 complex, an oncoprotein, may be involved in the regulation of apoptosis stimulated by DNA damage, a process that can contribute to cellular turnover and tissue remodeling within the vascular system.^[3] Other candidate genes identified through expression-associated SNPs, such as JARID1A, SLC6A12, and CLCN6, further highlight the diverse genetic regulatory elements influencing blood pressure.^[3]

Metabolic Processes and Oxidative Stress

Metabolic pathways and oxidative stress mechanisms significantly contribute to the regulation of systolic blood pressure. Cytochrome P450 enzymes are integral to vascular homeostasis, participating in the metabolism of various compounds and the synthesis of crucial biomolecules. For example,CYB5B, a mitochondrial cytochrome P450 enzyme, is involved in the synthesis of steroid sex hormones by the adrenal glands, which are known regulators of fluid and electrolyte balance and, consequently, blood pressure.^[14] Another enzyme, CYP2A6, is implicated in the c-oxidation of nicotine, suggesting roles in xenobiotic metabolism that can indirectly affect vascular health.^[3]Oxidative stress pathways, characterized by the production of reactive oxygen species (ROS), also have a direct impact on cardiovascular function. TheNOX4locus, for instance, has been associated with lower diastolic blood pressure, indicating its role in modulating vascular tone through redox signaling.^[3] Furthermore, an oxidative stress-driven (ROS/NADPH) pathway is enriched among cardiac development pathways, suggesting its involvement in the long-term structural and functional integrity of the heart, which is intimately linked to blood pressure regulation.^[3]While common inherited variations in mitochondrial genes have not been found to be enriched for associations with type 2 diabetes or related glycemic traits, the broader interplay of energy metabolism and cellular redox balance remains critical for maintaining cardiovascular health.^[3]

Systems-Level Integration and Disease Crosstalk

The regulation of systolic blood pressure is an emergent property of complex interactions across multiple physiological systems, involving extensive pathway crosstalk and network interactions. Functional association network analysis, employing tools like Cytoscape and the GeneMANIA plugin, has been instrumental in combining candidate gene sets and identifying enriched functional terms, revealing the interconnectedness of various biological processes.^[3] This systems-level approach has highlighted the enrichment of pathways such as inflammation signaling and blood vessel development, indicating their broad influence on vascular tone and blood pressure.^[3] Moreover, the intricate connections between blood pressure regulation and other conditions are evident through pathway overlaps. Cardiac development pathways, including those driven by oxidative stress and the Wnt/β-catenin/integrin signaling, include genes like MYH6, MYH7, and TBX2, revealing a potential overlap with cardiomyopathies and suggesting shared underlying biological mechanisms.^[3] The pleiotropic effects of genetic variants are further exemplified by a gain-of-function mutation in TBX5, which is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation, demonstrating how developmental genes can impact cardiovascular function.^[3] Genes like ADAMTS7, which is associated with lower diastolic blood pressure and has strong biological support from mouse knockout phenotypes, represent potential therapeutic targets for systemic anti-hypertensive therapy, underscoring the translational significance of understanding these integrated pathways.^[15]

Diagnostic and Prognostic Significance

Systolic blood pressure (SBP) is a fundamental physiological parameter with critical diagnostic utility in identifying hypertension, typically defined as SBP ≥140 mm Hg, while normotensive individuals are often characterized by SBP ≤120 mm Hg.^[3] Its measurement follows standardized protocols, including rest periods and bias-free instrumentation, although data can also be extracted from electronic medical records.^[3] When patients are undergoing antihypertensive treatment, observed SBP values are commonly adjusted by adding a constant to accurately reflect the underlying blood pressure status.^[3] The long-term average of SBP measurements serves as a robust phenotype in genetic research, enhancing the accuracy of studies aimed at uncovering its biological mechanisms.^[8]Beyond diagnosis, SBP carries significant prognostic value, particularly in vulnerable populations such as children with sickle cell disease, where specific SBP patterns may indicate underlying pathophysiological processes and heighten the risk for complications like silent cerebral infarct.^[2] This highlights SBP’s role not just in current health status but also in predicting future health outcomes.

Genetic Risk Assessment and Personalized Medicine

Systolic blood pressure is recognized as a highly heritable trait, with extensive genome-wide association studies (GWAS) having identified numerous genetic loci that contribute to its variation across diverse human populations.^[2]Genetic risk scores (GRS), which aggregate the effects of multiple single nucleotide polymorphisms (SNPs) associated with SBP, have proven effective in predicting the onset of hypertension, with their predictive power increasing as more relevant SNPs are incorporated.^[8]These genetic insights pave the way for personalized medicine, enabling the early identification of individuals with a heightened genetic predisposition to hypertension.

Specific genetic variants, such as rs3184504 within the SH2B3 gene and rs267561 in ITGA9, have been linked to the regulation of blood pressure and an individual’s risk for hypertension.^[1] The integration of these genetic markers with conventional clinical measurements allows for more precise risk stratification, facilitating the development of targeted prevention strategies and earlier therapeutic interventions for high-risk individuals, including those identified in pediatric cohorts.^[2]

Associations with Comorbidities and Target Organ Damage

Elevated systolic blood pressure is a major contributing factor to the development and progression of a broad spectrum of cardiovascular and renal comorbidities. A multi-BP SNP score, which reflects an individual’s genetic susceptibility to higher SBP, has been shown to predict the risk of various forms of hypertensive target organ damage.^[15]These complications include significant conditions such as heart failure, an increase in left ventricular wall thickness, and detrimental changes in kidney function as indicated by markers like eGFR, creatinine levels, and microalbuminuria.^[15]Moreover, this genetic risk score also predicts cerebrovascular events, encompassing both general stroke subtypes and specifically ischemic stroke, as well as microvascular complications such as mild retinopathy and alterations in central retinal artery caliber.^[15]Recognizing these extensive associations is fundamental for delivering comprehensive patient care, informing appropriate screening protocols, and guiding management strategies aimed at mitigating the systemic and long-term consequences of uncontrolled systolic blood pressure.

Frequently Asked Questions About Systolic Blood Pressure

These questions address the most important and specific aspects of systolic blood pressure based on current genetic research.

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1. My parents have high SBP; will I definitely get it too?

Not necessarily “definitely,” but SBP is a highly heritable trait, meaning genetics play a significant role. If your parents have it, you have an increased genetic predisposition. However, lifestyle factors like diet and exercise can still greatly influence whether you develop high SBP.

2. Why is my SBP high when I eat well, but my friend’s is low despite bad habits?

This difference can often be attributed to your unique genetic makeup. While diet is important, some individuals have genetic variants that predispose them to higher SBP regardless of seemingly healthy habits. Your friend might have protective genetic factors influencing their cardiovascular system.

3. Can exercise really overcome my family’s high SBP history?

Yes, absolutely. While you may have a genetic predisposition due to family history, lifestyle choices like regular exercise are powerful tools. Engaging in physical activity can help manage your SBP and mitigate the impact of your genetic risk factors, contributing to better cardiovascular health.

4. Does my ethnic background affect my SBP risk?

Yes, your ancestral background can influence your SBP risk. Research shows that genetic risk factors for SBP can vary across diverse ancestral populations. Studying these differences is vital for understanding why certain ethnic groups may have higher rates of hypertension and for developing more personalized prevention strategies.

5. If I take SBP meds, does that hide my actual genetic risk?

When you’re on medication, your measured SBP is lower than it would be without treatment. For genetic studies, researchers often adjust for this by adding a constant to account for the medication’s effect, trying to estimate your underlying SBP. This adjustment helps reveal your genetic predisposition, but it is an estimation based on assumptions.

6. My SBP readings vary a lot; is that normal for me?

SBP is a very dynamic trait, and it’s normal for readings to fluctuate. Factors like stress, activity levels, or even the time of day can cause variability. While some fluctuations are expected, consistently high variability might warrant further investigation to ensure your long-term cardiovascular health is being accurately assessed.

7. Is one SBP reading enough to know my long-term risk?

No, a single SBP measurement may not fully capture your true long-term blood pressure status. Due to inherent variability, studies often use multiple measurements over time or long-term averages to get a more accurate picture. Relying on just one reading might lead to a less accurate assessment of your risk.

8. Does high SBP mean my arteries are already stiffening?

High SBP can certainly be an indicator of increased arterial stiffness. Arterial stiffness is a key factor contributing to SBP levels and overall cardiovascular risk, as it affects how flexibly your arteries respond to blood flow. Understanding this connection is important for assessing your cardiovascular health profile.

9. Why do some people just seem to have naturally low SBP?

Some individuals are genetically predisposed to naturally lower SBP. Just as some genetic variants contribute to higher SBP, others can contribute to a more efficient cardiovascular system, leading to lower baseline pressures. This highlights the broad range of genetic influences on blood pressure variation across the population.

10. Does stress really impact my SBP, or is that a myth?

Stress can absolutely impact your SBP. While genetics and physical mechanisms are key, SBP is a highly dynamic trait influenced by numerous factors, and stress is a known physiological factor that can temporarily elevate blood pressure. Managing stress is an important part of a holistic approach to maintaining healthy SBP levels.

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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.

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