Myeloperoxidase

Background

Myeloperoxidase (MPO) is a lysosomal enzyme primarily stored within the azurophilic granules of circulating neutrophils, monocytes, and tissue macrophages.^[1] It is released into the extracellular space and phagosomes when these white blood cells become activated.^[1]

Biological Basis

The primary biological role of MPO is in innate immunity, where it generates various reactive oxidants and free radicals to effectively kill invading parasites and pathogens.^[1] However, these same MPO-derived oxidants can also have detrimental effects within the body. They have been implicated in processes such as the formation of atherogenic low-density lipoprotein particles, the development of dysfunctional high-density lipoprotein (HDL) particles, the catalytic consumption of nitric oxide, vascular endothelial injury, and the progression of atherosclerotic plaque and its associated clinical conditions.^[2]

Clinical Relevance

Circulating MPO levels, which can be measured in serum, plasma, or leukocytes, serve as a significant biomarker in clinical practice. Elevated MPOlevels are associated with an increased risk of coronary artery disease (CAD).^[3]and are predictive of major adverse cardiac events in both healthy individuals and patients diagnosed with CAD or heart failure.^[4] Studies have shown a positive correlation between MPOlevels and several traditional and inflammatory CAD risk factors, including age, sex, blood pressure, body mass index, cigarette smoking, glucose, white blood cell count, and C-reactive protein levels.^[5] Hereditary MPO deficiency has been characterized biochemically and molecularly.^[6] with research exploring its potential consequences.^[7] Genetic variations, such as polymorphisms in the MPO gene, have been linked to plasma MPOlevels and the severity of coronary artery disease.^[8]and even to cardiovascular events in individuals with CAD.^[9] Specific coding sequence variants like rs28730837 and rs35897051 have been associated with serum MPO levels.^[3] Furthermore, MPO has been implicated in the etiology of acute promyelocytic leukemia.^[10]and its activity can lead to the oxidation and functional impairment of apolipoprotein A-I in individuals with cardiovascular disease.^[11] The CardioMPO assay is an FDA and EU cleared in vitro diagnostic test used in patient care.^[3]

Social Importance

Given its dual role in essential immune defense and the pathogenesis of widespread conditions like cardiovascular disease, myeloperoxidase is a focus of significant medical research and clinical interest. The ability to measureMPOlevels provides valuable information for risk stratification and disease management, potentially aiding in the early identification of individuals at higher risk for cardiac events. Understanding the genetic factors influencingMPOlevels, through studies like genome-wide association studies (GWAS), contributes to a deeper comprehension of disease susceptibility and could inform the development of more personalized preventive and therapeutic strategies.^[3] The availability of FDA and EU cleared diagnostic tests underscores its established utility in public health and patient care.^[3]

Methodological and Statistical Considerations

The comprehensive analyses of myeloperoxidase levels, while yielding significant insights, are subject to several methodological and statistical constraints that warrant careful consideration in interpreting the findings. The meta-analysis integrated data from multiple studies employing diverse genotyping platforms and imputation methodologies, which, despite efforts towards standardization, can introduce inherent variability and potential biases across the combined cohorts.^[3]This analytical heterogeneity, coupled with the difficulties in harmonizing myeloperoxidase assays—influenced by factors such as sample storage conditions or acute minor infections at blood collection—necessitated the use of a sample-weighted Z-score meta-analysis, a method that combines results but does not fully eliminate underlying differences.^[3] Consequently, some genetic associations that did not achieve genome-wide significance in combined analyses might represent true but smaller effects that the studies were underpowered to detect, potentially leading to an incomplete understanding of the trait’s genetic architecture.

Furthermore, the study design presents challenges related to effect size interpretation and the broader replicability of findings. While certain associations were successfully replicated across cohorts, the specific choice of GWAS method can influence replication rates, highlighting the importance of robust validation across various analytical approaches.^[12] A notable example is the strong association of rs2814778 with serum myeloperoxidase levels in African Americans, which was significantly attenuated after adjusting for white blood cell count, suggesting that the observed genetic effect was largely mediated by neutrophil count rather than a direct influence on myeloperoxidase itself.^[3]This observation underscores the need for thorough investigation of mediating factors, as initial associations might otherwise overstate the direct genetic contribution to myeloperoxidase levels.

Generalizability and Phenotypic Heterogeneity

A significant limitation revolves around the generalizability of the findings and the inherent heterogeneity in myeloperoxidase measurements across studies. The primary genome-wide association studies were predominantly conducted in cohorts of European ancestry, implying that the identified genetic associations might not fully translate or exert the same effect sizes in other global populations.^[3] Although replication efforts were extended to African American cohorts, these populations were represented by considerably smaller sample sizes, which limited the statistical power to detect novel associations or to definitively validate European-centric findings across diverse genetic backgrounds.^[3]This ethnic imbalance highlights the critical need for larger, ethnically diverse cohorts to comprehensively characterize the genetic determinants of myeloperoxidase levels across all human populations.^[13]Beyond population differences, the of circulating myeloperoxidase itself introduces challenges due to phenotypic heterogeneity. The various participating cohorts utilized different assays and sample types (e.g., serum versus plasma) for myeloperoxidase assessment.^[3] This variability in methodology can lead to intrinsic differences in reported biomarker values, complicating direct comparisons between studies and potentially obscuring genuine genetic effects. Such inconsistencies in biomarker assessment can introduce noise into the analyses, even with statistical adjustments, and may impact the overall reliability and interpretation of identified associations across different research efforts.^[3]

Unaccounted Confounders and Unexplained Variance

While the studies accounted for fundamental demographic covariates such as age and sex, they might not have fully captured the intricate interplay of environmental factors and gene-environment interactions that influence myeloperoxidase levels. Circulating myeloperoxidase concentrations are known to be modulated by a range of external factors, including acute minor infections at the time of blood collection or specific sample storage conditions, which can introduce variability independent of genetic predisposition.^[3]Moreover, systemic inflammatory biomarker concentrations, including myeloperoxidase, are influenced by a broad spectrum of genetic and environmental factors, some of which may not have been comprehensively assessed or adjusted for in the analyses.^[14]Despite the identification of significant genetic loci, a substantial portion of the heritability of myeloperoxidase levels may remain unexplained, indicating existing knowledge gaps. The genetic variants identified represent only a fraction of the total phenotypic variance, suggesting that other genetic factors, such as rarer variants or complex polygenic interactions, or non-genetic influences like epigenetic modifications (e.g., DNA methylation) or post-transcriptional regulation, also contribute to individual differences in myeloperoxidase levels.^[15]Furthermore, the studies primarily focused on blood-based measurements, and a more comprehensive analysis of myeloperoxidase expression or regulation in other relevant tissues might yield additional insights, as biomarkers are not always primarily expressed in blood cells.^[15]

Variants

Genetic variations play a significant role in influencing circulating myeloperoxidase (MPO) levels, a key inflammatory biomarker linked to cardiovascular health. The gene encoding myeloperoxidase,MPO, located on chromosome 17q22, is central to this process. MPOproduces an enzyme stored in immune cells like neutrophils and monocytes, which is released during inflammation to generate reactive oxidants for pathogen killing; however, these oxidants can also damage tissues and contribute to conditions like atherosclerosis. Several variants within or near theMPO gene have been linked to its circulating levels. For instance, the rare variant rs35897051 disrupts a splice junction in intron 11 of MPO, potentially altering enzyme production or function, and is significantly associated with serum MPO levels.^[3] Another MPO variant, rs28730837 , causes an Ala332Val amino acid substitution, also showing a strong association with serum MPO levels.^[3]Other single nucleotide polymorphisms (SNPs) in the 17q22 region, such asrs12940923 , rs6503905 , rs9911753 , and rs2680701 , are also significantly associated with plasma MPO levels, highlighting a complex regulatory region for this enzyme.^[3] While rs119468010 and rs56378716 are also located within or near the MPO gene, their specific functional impact on MPO expression or activity and their direct association with circulating MPO levels require further exploration.

Another critical gene influencing MPO levels is CFH (Complement Factor H), located on chromosome 1q31.1, which plays a vital role in regulating the complement system, a part of the innate immune response. The variant rs800292 in CFH is strongly associated with serum MPO levels in individuals of European ancestry.^[3] This variant also influences complement activation, with carriers of the A allele having significantly lower levels of C3a-desArg, a downstream product of complement activation.^[3] Although rs800292 impacts serum MPO, it does not show a significant association with plasma MPO levels or the risk of coronary artery disease, suggesting distinct regulatory pathways for MPO in different biological compartments. The variantrs113439691 is another CFH polymorphism that may contribute to variations in complement system activity and, consequently, indirectly influence inflammatory processes reflected by MPO levels.

Beyond MPO and CFH, other genes and their variants contribute to the intricate regulation of circulating MPO. The gene ABCB10(ATP Binding Cassette Subfamily B Member 10) is involved in mitochondrial transport, and its variantrs767301 (also associated with HMGN2P19) could indirectly affect cellular metabolism and oxidative stress, potentially influencing MPO activity or release. A locus encompassing ABCB10 and other genes, specifically the variant rs12049351 , has been linked to both serum and plasma MPO levels.^[3] Similarly, the TSPOAP1 (Translocator Protein Associated Protein 1) gene, and its associated variants rs34097845 , rs11079341 , and rs2333227 , as well as the long non-coding RNA TSPOAP1-AS1 and the gene RNF43 (Ring Finger Protein 43) with variant rs144713417 , are located in the 17q22 region near MPO. RNF43is a ubiquitin ligase involved in Wnt signaling, a pathway crucial for cell development and disease, and variants in this region may have pleiotropic effects that collectively modulate MPO levels.^[3] The PPM1E (Protein Phosphatase, Mg2+/Mn2+ Dependent 1E) gene, whose variants rs375339379 and rs146148297 are noted, encodes a phosphatase that regulates cellular signaling pathways, and its proximity to the MPO locus on chromosome 17q22 suggests potential regulatory interplay affecting MPO expression.

Further genetic influences on MPO levels include variants in genes such as RRBP1 (Ribosome Binding Protein 1), with rs3790315 and rs6034875 , which is involved in protein synthesis and endoplasmic reticulum function. Alterations in these processes could impact the synthesis and packaging of MPO within neutrophils. NUCB2 (Nucleobindin 2), represented by rs757081 , encodes a calcium-binding protein that acts as a precursor to nesfatin-1, a neuropeptide with roles in appetite regulation and metabolism, potentially linking metabolic health to inflammatory markers like MPO. The CCDC26 (Coiled-Coil Domain Containing 26) gene, with variants rs1865223 and rs10103048 , is often associated with cancer susceptibility and may influence cell growth and differentiation pathways that indirectly affect immune cell function and MPO release. Lastly,BCAS3(Breast Carcinoma Amplified Sequence 3), with variantrs187961334 , is implicated in cell proliferation and angiogenesis, and its variants might influence systemic inflammation or vascular health, thereby modulating circulating MPO levels.

Key Variants

RS ID	Gene	Related Traits
rs34097845 rs11079341 rs2333227	MPO - TSPOAP1	granulocyte percentage of myeloid white cells monocyte percentage of leukocytes myeloperoxidase blood protein amount myeloperoxidase (MPO)-DNA complex
rs119468010 rs35897051 rs56378716	MPO	neutrophil count leukocyte quantity level of tumor necrosis factor receptor superfamily member 10C in blood myeloperoxidase level of carcinoembryonic antigen-related cell adhesion molecule 8 in blood
rs800292 rs113439691	CFH	myeloperoxidase age-related macular degeneration, wet macular degeneration neutrophil collagenase level chronic central serous retinopathy age-related macular degeneration
rs144713417	TSPOAP1-AS1, RNF43	myeloperoxidase
rs767301	ABCB10 - HMGN2P19	myeloperoxidase
rs3790315 rs6034875	RRBP1	eosinophil count platelet count myeloperoxidase platelet crit total blood protein
rs757081	NUCB2	pulse pressure systolic blood pressure BMI-adjusted waist-hip ratio myeloperoxidase CASP3/PPIB protein level ratio in blood
rs1865223 rs10103048	CCDC26	neutrophil count level of V-set and transmembrane domain-containing protein 1 in blood serum myeloperoxidase lymphocyte percentage of leukocytes kit ligand amount
rs187961334	BCAS3	myeloperoxidase
rs375339379 rs146148297	PPM1E	myeloperoxidase

Myeloperoxidase: Definition, Biological Function, and Nomenclature

Myeloperoxidase, commonly referred to as MPO, is a key lysosomal enzyme primarily stored within the azurophilic granules of circulating neutrophils, monocytes, and tissue macrophages. Its release is triggered upon leukocyte activation, initiating a crucial role in the body’s innate immune response by generating various reactive oxidants and free radicals. These potent compounds are essential for killing invading parasites and pathogens, forming a vital component of host defense mechanisms.^[3]Beyond its protective functions, MPO-derived oxidants are also implicated in numerous pathological processes, particularly in the context of cardiovascular disease. These oxidants contribute to the formation of atherogenic low-density lipoprotein (LDL) particles, the development of dysfunctional high-density lipoprotein (HDL) particles, catalytic consumption of nitric oxide, and vascular endothelial injury. Consequently, MPO plays a significant role in the progression of atherosclerotic plaque and its clinical sequelae.^[3]

Myeloperoxidase as a Clinical Biomarker and Considerations

Circulating MPO levels serve as an important biomarker with prognostic value for cardiovascular risks. High circulating levels of MPO, whether measured in serum, plasma, or leukocytes, have been shown to predict major adverse cardiac events in healthy individuals and in patients diagnosed with coronary artery disease (CAD) or heart failure.^[4]MPO levels also positively correlate with traditional and inflammatory CAD risk factors, including age, sex, blood pressure, body mass index, cigarette smoking, glucose, white blood cell count, and C-reactive protein levels.^[5] Operational definitions for MPO are critical in research and clinical settings, typically involving the quantification of MPO in serum or plasma samples. Various assays are employed for these measurements across different cohorts, with the CardioMPO assay noted as an FDA and EU-cleared in vitro diagnostic test suitable for patient care.^[3] However, harmonizing MPO assays across diverse cohorts can be challenging due to factors such as sample storage effects or acute minor infections at the time of blood collection, necessitating standardized statistical approaches like linear regression using natural log-transformed values for analysis.^[3]

Genetic Regulation and Classification of Myeloperoxidase-Related Conditions

MPO levels can be influenced by genetic factors, with studies identifying specific single-nucleotide polymorphisms (SNPs) associated with circulating MPO. Genome-wide association studies (GWAS) have pinpointed loci on chromosomes 1q31.3, 6p21.32, and 20p13 that significantly influence serum MPO levels, including variants near genes likeCFH, NOTCH4, and SIRPB2.^[3] Distinct genetic factors may regulate serum and plasma MPO levels, suggesting complex regulatory mechanisms.^[3]Beyond quantitative variations, myeloperoxidase deficiency represents a classified condition characterized by absent or reduced MPO activity. This deficiency can be hereditary, resulting from specific biochemical and molecular abnormalities.^[6]Hereditary myeloperoxidase deficiency can manifest as total or subtotal, with ongoing research exploring its clinical consequences, including potential risks or benefits.^[7] Furthermore, functional polymorphic variants within the MPOgene itself and other associated genetic variations have been linked to susceptibility to conditions like coronary artery disease and even acute promyelocytic leukemia.^[9]

Myeloperoxidase: A Key Enzyme in Immunity and Inflammation

Myeloperoxidase (MPO) is a crucial lysosomal enzyme found primarily within the azurophilic granules of circulating neutrophils, monocytes, and tissue macrophages.^[3] These immune cells release MPO upon activation, initiating an enzymatic cascade that generates various reactive oxidants and free radicals.^[3] While these powerful oxidants are essential for the body’s innate immune response, playing vital roles in neutralizing invading parasites and pathogens.^[3] their uncontrolled activity can have detrimental effects on host tissues.

The dual nature of MPO makes it a significant player in both protective immunity and chronic inflammatory processes. Its involvement extends beyond direct pathogen killing to broader systemic effects, where its reactive products can disrupt normal cellular functions and contribute to tissue damage. Understanding the precise mechanisms of MPOrelease and activity is therefore critical for comprehending its impact on overall health and disease progression.

Oxidative Stress and Cardiovascular Health

Beyond its beneficial roles in host defense, MPO-derived oxidants are strongly implicated in the development and progression of various pathophysiological conditions, particularly cardiovascular diseases. These reactive species contribute to the formation of atherogenic low-density lipoprotein particles and the dysfunction of high-density lipoprotein.^[3]both of which are central to atherosclerosis. Furthermore,MPO can catalytically consume nitric oxide, impairing its vital role in vascular relaxation, and directly injure vascular endothelial cells, leading to the development of atherosclerotic plaques and their clinical complications.^[3] Elevated circulating levels of MPO, measured in serum or plasma, serve as a significant biomarker, predicting major adverse cardiac events in otherwise healthy individuals as well as in patients already diagnosed with coronary artery disease or heart failure.^[4] Research indicates a positive correlation between MPOlevels and established cardiovascular risk factors such as age, sex, blood pressure, body mass index, cigarette smoking, glucose levels, white blood cell count, and C-reactive protein.^[5]highlighting its systemic impact on inflammation and oxidative stress that contributes to chronic inflammatory diseases like age-related macular degeneration.^[3]

Genetic Influences on Myeloperoxidase Levels

The levels of circulating MPO are significantly shaped by an individual’s genetic makeup, extending beyond the MPO gene itself to encompass a network of interacting genes. Rare coding sequence variants within the MPO gene, such as rs28730837 and rs35897051 , have been directly associated with altered serum MPO levels.^[3] These genetic variations can influence the enzyme’s production or function, with some polymorphisms, like the MPO-463 G/A variant, being linked to coronary artery disease.^[16] Moreover, hereditary MPO deficiency, characterized by specific biochemical and molecular alterations, demonstrates the critical role of these genetic factors in determining the presence and activity of the enzyme.^[6] Beyond the MPO gene, other genomic regions contribute to the regulation of MPO levels. A prominent locus on chromosome 1q31.1, harboring the complement factor H (CFH) gene, shows a strong association with serum MPO levels, exemplified by variants such as rs800292 and rs505102 .^[3] CFH is a key regulator of the complement system, an innate immune pathway, and also binds malondialdehyde, a product of lipid peroxidation.^[3] This suggests a mechanistic link between complement system activity, oxidative stress, and MPO regulation, where genetic variants that decrease complement activation, perhaps through increased CFH activity, might lead to lower MPO levels in serum.^[3]

Complex Genetic Regulation and Systemic Consequences

Further genetic insights reveal additional regulatory mechanisms influencing MPO levels and their systemic consequences. A locus on chromosome 6p21.32 contains several genes vital to the immune system, including complement component 2 (C2) and HLA, with a lead SNP (rs3134931 ) within NOTCH4.^[3] Variants decreasing C2 activity could also contribute to reduced MPO levels.^[3] further emphasizing the interplay between complement regulation and MPO. Additionally, a variant (rs6042507 ) in the signal-regulatory protein beta 2 (SIRPB2) gene, predominantly expressed in myeloid cells, has been linked to serum MPO levels.^[3] SIRPB2 plays a role in innate immunity and complement receptor-mediated phagocytosis, and its involvement in T-cell activation provides another biological connection to systemic inflammation.^[3] Ethnic-specific genetic factors also play a role, as seen with a promoter variant (rs2814778 ) of the Duffy antigen receptor for chemokines (DARC) gene on chromosome 1q23.3, which is associated with serum MPO levels in individuals of African descent.^[3]This variant’s G allele leads to the loss of the Duffy antigen on red blood cells, impacting neutrophil counts and, consequently,MPO levels, given its abundance in neutrophils.^[3] These findings underscore that MPO levels are not solely determined by the MPO gene but are a result of complex genetic interactions involving various immune and inflammatory pathways, with distinct genetic factors regulating serum versus plasma MPO.^[3] suggesting diverse clinical implications for various acute and chronic inflammatory disorders.

Myeloperoxidase Production and Release

Myeloperoxidase (MPO) is a critical lysosomal enzyme primarily synthesized and stored within the azurophilic granules of circulating neutrophils, monocytes, and tissue macrophages.^[3] Its cellular production and subsequent release are tightly regulated processes, forming an initial point of control in the inflammatory response. Upon leukocyte activation, which involves complex cellular signaling cascades often initiated by pattern recognition receptor activation, MPO is rapidly secreted into the extracellular space.^[3] This regulated release mechanism ensures that MPO’s potent oxidative capabilities are deployed precisely when needed to combat invading pathogens, underscoring its role as a key effector molecule in innate immunity.^[1]

Oxidative Catalysis and Metabolic Dysregulation

The primary mechanistic function of myeloperoxidase (MPO) lies in its potent oxidative catalysis, generating a spectrum of reactive oxidants and free radicals, including hypochlorous acid, from hydrogen peroxide and chloride.^[3] While these highly reactive species are essential for the host’s defense against pathogens, their uncontrolled activity leads to significant metabolic dysregulation and tissue damage. MPO-derived oxidants are implicated in modifying crucial lipid components, such as the oxidation of low-density lipoprotein (LDL) particles to become atherogenic, and the modification of high-density lipoprotein (HDL), particularly its apolipoprotein A-I (ApoA-I) component, rendering HDL dysfunctional and pro-inflammatory.^[2] Furthermore, MPO contributes to vascular endothelial injury and catalytic consumption of nitric oxide, disrupting its critical role in vasodilation and vascular homeostasis.^[3]

Genetic Modulators and Cellular Communication

The circulating levels of myeloperoxidase (MPO) are subject to intricate genetic and regulatory mechanisms, influencing its expression and activity. Rare coding sequence variants within the MPO gene itself, such as rs28730837 and rs35897051 , have been directly linked to altered serum MPO levels, highlighting the direct impact of genetic polymorphisms on enzyme production.^[3] Beyond the MPO gene, variants in other genes modulate MPO levels through diverse cellular communication pathways and regulatory networks. For instance, the Val62Ile substitution encoded by rs800292 in the complement factor H (CFH) gene significantly associates with serum MPO levels, suggesting a regulatory link between complement system integrity and MPO homeostasis.^[3] Further illustrating this genetic influence on cellular signaling, a non-synonymous substitution in the SIRPB2 (signal-regulatory protein beta 2) gene, rs6042507 , also shows association with serum MPO levels.^[3] As SIRPB2is a transmembrane glycoprotein predominantly expressed on myeloid cells, it plays a role in regulating innate immunity, complement receptor-mediated phagocytosis, and T-cell activation, indicating a pathway whereSIRPB2-mediated cellular communication could impact MPO release or production.^[3] Similarly, a promoter variant of the DARC (Duffy antigen receptor for chemokines) gene, rs2814778 , affects serum MPOlevels, particularly by influencing neutrophil counts, which are the primary cellular source ofMPO.^[3] This demonstrates how genetic variations can regulate MPO indirectly by altering the cellular milieu and the expression of related immune components.

Interconnected Pathways and Disease Emergence

The biological significance of myeloperoxidase (MPO) extends to its intricate integration within broader physiological systems, where pathway crosstalk and network interactions profoundly influence its role in both health and disease. Genetic variants that decrease complement activation, such as those impactingCFH or C2 activity, offer a mechanistic link to reduced MPO levels in serum, suggesting a hierarchical regulation where the complement system can modulate inflammatory processes involving MPO.^[3] The SIRPB2 gene, through its role in innate immunity and complement receptor-mediated phagocytosis, also exemplifies how signaling pathways from myeloid cells can converge to influence MPO levels, potentially linking antigen-specific T-cell activation to MPO regulation.^[3]Dysregulation within these interconnected pathways is a critical disease-relevant mechanism, particularly in the context of cardiovascular disease. TheMPO-catalyzed oxidative damage to lipoproteins and the vascular wall represents an emergent property of chronic inflammation, leading to the development and progression of atherosclerosis and its clinical sequelae.^[2] Elevated circulating MPO levels serve as a strong predictor for major adverse cardiac events in various patient populations, highlighting MPOas a key biomarker of systemic inflammatory burden and a potential contributor to disease pathogenesis.^[4] While genetic variants affecting MPOlevels have not been causally linked to some inflammatory diseases like age-related macular degeneration (AMD), their strong association with cardiovascular risk factors underscores the complex interplay between genetic predisposition, inflammatory pathways, and the systemic impact ofMPO activity.^[3]

Cardiovascular Risk Stratification and Prognosis

Myeloperoxidase is a strong predictor of adverse cardiovascular outcomes across various patient populations. Elevated circulating myeloperoxidase levels are associated with an increased risk of major adverse cardiac events in healthy individuals, as well as in patients diagnosed with coronary artery disease (CAD) or chronic heart failure.^{[4], [17]}For instance, plasma myeloperoxidase levels have been shown to predict incident cardiovascular risks even in stable patients who are already undergoing medical management for CAD.^[18]This prognostic utility positions myeloperoxidase as a valuable biomarker for identifying high-risk individuals and for monitoring disease progression, complementing traditional risk factors.^{[5], [14]}The clinical utility of myeloperoxidase extends to risk assessment, where its can aid in stratifying patients based on their likelihood of future cardiovascular events. Its positive correlation with established CAD risk factors such as age, sex, blood pressure, body mass index, cigarette smoking, glucose levels, white blood cell count, and C-reactive protein further underscores its role as an indicator of systemic inflammation and cardiovascular risk.^[5] The availability of FDA and EU-cleared assays, such as CardioMPO, supports its potential integration into routine clinical practice for diagnostic purposes and guiding patient care.^[3]

Pathophysiological Mechanisms and Therapeutic Insights

Myeloperoxidase plays a critical role in the pathophysiology of atherosclerosis and related cardiovascular complications through its pro-oxidant activities. Released by activated leukocytes, myeloperoxidase generates reactive oxidants that contribute to the formation of atherogenic low-density lipoprotein (LDL) particles and the development of dysfunctional high-density lipoprotein (HDL) particles.^{[11], [19], [20], [21]}These modifications impair lipoprotein function and promote inflammation within the vasculature, initiating and accelerating atherosclerotic plaque formation.^[2]Beyond lipoprotein modification,MPO-derived oxidants also consume nitric oxide and induce vascular endothelial injury, further contributing to vascular dysfunction and the clinical sequelae of atherosclerosis.^{[1], [2]}Understanding these mechanisms highlights myeloperoxidase as not just a biomarker, but also a potential therapeutic target for interventions aimed at mitigating oxidative stress and inflammation in cardiovascular diseases.^[22]Its involvement in these fundamental processes makes it a valuable marker for assessing the inflammatory burden and oxidative stress contributing to disease progression.

Genetic Determinants and Personalized Medicine

Circulating myeloperoxidase levels are influenced by genetic factors, offering insights into personalized medicine approaches and risk stratification. Genome-wide association studies (GWAS) have identified specific genetic loci associated with myeloperoxidase levels, including a strong association with a region on chromosome 1q31.1 containing theComplement Factor H (CFH) gene and a region on chromosome 17q22 near the MPO gene itself.^[3] Furthermore, gene-centric analyses have revealed rare coding sequence variants within the MPO gene, such as rs28730837 and rs35897051 , that are significantly associated with serum myeloperoxidase levels.^[3]These genetic insights suggest that individual genetic predispositions can influence myeloperoxidase levels, potentially contributing to varying risks of inflammatory and cardiovascular disorders. While someMPOpolymorphisms have been linked to cardiovascular events and severity in coronary artery disease.^{[8], [9], [16], [23]} direct associations between MPOlevel-influencing single-nucleotide polymorphisms and overall CAD risk require further study.^[3] The existence of hereditary MPO deficiency also underscores the genetic control over MPO activity and its potential clinical consequences.^{[6], [7], [24]}

Frequently Asked Questions About Myeloperoxidase

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

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1. Why do some people get heart disease easily, even if they seem healthy?

It’s often due to a combination of factors, including genetics. Your body’s myeloperoxidase (MPO) levels, for example, can be influenced by genetic variations. Higher MPO levels, even in seemingly healthy individuals, are linked to an increased risk of heart disease and related events, regardless of how healthy you feel.

2. My parents had heart problems. Does that mean I will too?

Not necessarily, but your risk might be higher. Genetic predispositions, including variations in the MPO gene, can be inherited and influence your MPO levels, which are a strong predictor of heart disease. However, lifestyle choices like diet and exercise play a crucial role and can significantly impact your personal risk.

3. Can my diet and exercise really beat my family’s heart history?

Yes, your lifestyle choices are incredibly powerful. While you might inherit genetic factors that increase your risk, like certain MPO gene variations, healthy habits can significantly mitigate these risks. Maintaining a healthy weight, exercising regularly, and not smoking are crucial for managing your heart health, even with a family history.

4. Does constant stress or being sick often affect my heart risk?

Yes, it can. Stress and frequent illness activate your immune cells, leading to the release of myeloperoxidase (MPO). While MPO is vital for fighting infections, chronic activation can mean persistently high MPO levels. These elevated levels are linked to inflammation and damage that contribute to heart disease.

5. Is there a special blood test for my heart attack risk?

Yes, there is. Measuring circulating myeloperoxidase (MPO) levels in your blood (serum or plasma) is a significant biomarker. Elevated MPO levels can predict your risk of major adverse cardiac events, even if you don’t have existing heart disease. The CardioMPO assay is an FDA and EU cleared test available for this purpose.

6. Why do I get sick often, but also worry about my heart?

This might relate to how your immune system works. Myeloperoxidase (MPO) is a key enzyme in fighting infections, but the same powerful oxidants it produces can also damage your blood vessels and contribute to heart disease. So, an active immune response, while protective against pathogens, can have a downside for cardiovascular health.

7. Does getting older automatically raise my heart disease risk?

Yes, age is a known risk factor for heart disease. Studies show a positive correlation between age and myeloperoxidase (MPO) levels, which are linked to heart disease risk. While you can’t stop aging, understanding this connection helps you focus on other modifiable risk factors to keep your heart healthy.

8. My doctor checks my blood pressure and weight. How does that link to my heart?

These are important indicators because high blood pressure and body mass index (BMI) are traditional risk factors for heart disease. Research shows a positive correlation between these factors and elevated myeloperoxidase (MPO) levels. High MPO, in turn, is a strong predictor of increased risk for heart problems.

9. Can my immune system actually cause heart problems?

In a way, yes. While your immune system is crucial for defense, some of its powerful tools, like myeloperoxidase (MPO), can have detrimental effects. The oxidants MPO produces, meant to kill pathogens, can also damage healthy tissues, contribute to dysfunctional cholesterol, and promote the development of atherosclerotic plaque, leading to heart disease.

10. If I quit smoking, does my heart risk go down quickly?

Quitting smoking is one of the best things you can do for your heart! Smoking is strongly correlated with higher myeloperoxidase (MPO) levels, which significantly increase your risk of heart disease. While it takes time for all the damage to reverse, quitting immediately starts reducing inflammation and MPO-related harm, lowering your risk over time.

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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.

References

[1] Arnhold, J. and Flemmig, J. “Human myeloperoxidase in innate and acquired immunity.”Arch. Biochem. Biophys., vol. 500, 2010, pp. 92–106.

[2] Nicholls, S.J. and Hazen, S.L. “Myeloperoxidase and cardiovascular disease.”Arterioscler. Thromb. Vasc. Biol., vol. 25, 2005, pp. 1102–1111.

[3] Reiner AP, Hartiala J, Zeller T, Bis JC, Dupuis J, Fornage M, Baumert J, Kleber ME, Wild PS, Baldus S, Bielinski SJ, Fontes JD, Illig T, Keating BJ, Lange LA, Ojeda F, Müller-Nurasyid M, Munzel TF, Psaty BM, Rice K, Rotter JI, Schnabel RB, Tang WH, Thorand B, Erdmann J, CARDIoGRAM Consortium, Jacobs Jr DR, Wilson JG, Koenig W, Tracy RP, Blankenberg S, März W, Gross MD, Benjamin EJ, Hazen SL, Allayee H. Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. Hum Mol Genet. 2013 Jul 15;22(14):2929-41.

[4] Brennan, M.L., et al. “Prognostic Value of Myeloperoxidase in Patients with Chest Pain.”New England Journal of Medicine, vol. 349, 2003, pp. 1595–1604.

[5] Schnabel, R.B., et al. “The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations.”Circ. Cardiovasc. Genet., vol. 2, 2009, pp. 229–237.

[6] Romano, M., Dri, P., Dadalt, L., Patriarca, P. and Baralle, F.E. “Biochemical and molecular characterization of hereditary myeloperoxidase deficiency.”Blood, vol. 90, 1997, pp. 4126–4134.

[7] Kutter, D., Devaquet, P., Vanderstocken, G., Paulus, J.M., Marchal, V. and Gothot, A. “Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit ?”Acta Haematol., vol. 104, 2000, pp. 10–15.

[8] Wainstein, R.V., et al. “Association between Myeloperoxidase Polymorphisms and Its Plasma Levels with Severity of Coronary Artery Disease.”Clinical Biochemistry, vol. 43, 2010, pp. 57–62.

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