Erythrocyte Aggregation
Background
Section titled “Background”Erythrocyte aggregation describes the reversible process where red blood cells (erythrocytes) adhere to one another, typically forming stacks known as rouleaux. This phenomenon is a key determinant of blood rheology, influencing the flow properties and viscosity of blood.[1]While a physiological process, altered levels of erythrocyte aggregation can have significant implications for circulatory health. The erythrocyte sedimentation rate (ESR), a common clinical test, directly reflects the propensity of red blood cells to aggregate and settle.[2]
Biological Basis
Section titled “Biological Basis”The aggregation of erythrocytes is primarily mediated by interactions between the surfaces of red blood cells and plasma proteins, such as fibrinogen. Factors affecting the concentration of these proteins, as well as the intrinsic properties of the red blood cells themselves (e.g., cell size, shape, and surface charge), and the overall hematocrit (Hct) level, play crucial roles. Blood viscosity, which is substantially influenced by erythrocyte aggregation, depends largely on hemoglobin (Hgb) and Hct levels, and is a determinant of blood pressure.[1] Genetic research has shown that variants in genes such as Complement receptor 1are associated with erythrocyte sedimentation rate, suggesting a genetic component to the regulation of erythrocyte aggregation.[2]
Clinical Relevance
Section titled “Clinical Relevance”Variations in erythrocyte aggregation and related red blood cell traits are linked to several clinical conditions. Elevated levels of Hgb and Hct, which contribute to increased blood viscosity and can be influenced by erythrocyte aggregation, are associated with a higher risk of hypertension and various vascular diseases.[1] High Hct levels can also impair organ perfusion due to increased blood viscosity. [1] Genome-wide association studies have identified multiple genetic loci that influence erythrocyte phenotypes, underscoring the genetic basis for these traits and their clinical implications [1], [3]. [4]
Social Importance
Section titled “Social Importance”The study of erythrocyte aggregation and its genetic underpinnings holds social importance due to its association with widespread health issues like hypertension and vascular diseases, which are leading causes of illness and mortality worldwide.[1] Furthermore, research indicates that genetic variants offering resistance to malaria are associated with red blood cell traits in African-Americans. [3] This highlights how erythrocyte characteristics, including their aggregation properties, can be influenced by evolutionary pressures and have significant health impacts across diverse human populations.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”Studies of erythrocyte aggregation may be underpowered to detect genetic associations involving less common variants or those with subtle effect sizes, potentially leading to missed discoveries.[5] Replication efforts are often constrained by limited statistical power in independent cohorts, meaning that some promising associations may not meet stringent replication criteria and thus require further validation. [6]This limitation impacts the ability to definitively confirm novel genetic loci and fully delineate the genetic architecture underlying erythrocyte aggregation.
Challenges in replicating findings across different cohorts are evident, as some genetic loci associated with red blood cell traits in discovery cohorts have not consistently replicated in other populations. [3] Such inconsistencies can arise from differences in study design or population characteristics, underscoring the need for robust validation studies. Furthermore, when analyzing multiple correlated erythrocyte traits, caution is necessary in interpreting results, particularly regarding the attribution of causality or independence of effects, as some observed associations might be indirectly mediated or pleiotropic. [6]
Phenotypic Heterogeneity and Environmental Confounders
Section titled “Phenotypic Heterogeneity and Environmental Confounders”A significant limitation in studies of erythrocyte aggregation stems from the inherent heterogeneity in phenotypic assessment across different research cohorts.[5] Despite attempts to harmonize erythrocyte phenotypes, variations in measurement protocols can obscure genuine genotype-phenotype associations and hinder the consistent comparison of results across studies. [5]This methodological variability can introduce noise, diminish statistical power, and impede the robust identification of genetic determinants for erythrocyte aggregation.
Environmental factors, comorbidities, and medications represent substantial confounders that can influence erythrocyte aggregation.[7] While advanced algorithms can help mitigate the impact of these factors by excluding affected trait values, their presence complicates the precise phenotyping of individuals and the isolation of direct genetic effects. [7]Moreover, the pathophysiological relevance of many identified genotype-phenotype associations for erythrocyte aggregation often remains unclear, highlighting a persistent gap in understanding how genetic variants translate into clinical outcomes and biological mechanisms.[5] Differences in population characteristics, such as BMI, can also introduce bias if not adequately accounted for. [8]
Generalizability and Ancestry-Specific Limitations
Section titled “Generalizability and Ancestry-Specific Limitations”The genetic architecture underlying erythrocyte aggregation can differ considerably across diverse populations due to variations in allele frequencies and patterns of linkage disequilibrium (LD).[8] Relying on single sentinel SNPs or imputed proxies derived primarily from European-ancestry populations can lead to spurious associations or overlook important loci when generalizing findings to other ancestries, particularly those like African-ancestry populations with more complex and diverse LD patterns. [8] This limitation restricts the broad applicability of research findings and underscores the critical need for inclusive genetic studies involving globally diverse cohorts.
A significant challenge in interpreting genetic findings for erythrocyte aggregation is the scarcity of publicly available functional genomic data, such as expression quantitative trait loci (eQTL), which have largely been collected from individuals of European ancestry.[9] This lack of diversity in functional datasets impedes the ability to accurately interpret the effects of ancestry-specific or low-expression variants identified in non-European populations. [9]Furthermore, critical tissues for erythrocyte development, such as bone marrow, are often absent from comprehensive tissue characterization efforts, thereby limiting direct insights into how genetic variation influences gene expression in the most relevant biological contexts.[9]A complete understanding of the genetic basis of erythrocyte aggregation necessitates a thorough catalog of global genetic and phenotypic variation.
Variants
Section titled “Variants”SFMBT2 (Scaffold protein Sfmbt2) plays a role in chromatin regulation, influencing gene expression, which can broadly impact cell development and function, including the characteristics of red blood cells. A variant like rs11255044 could alter this regulatory activity, potentially affecting erythrocyte morphology or membrane stability, factors known to influence aggregation. The broad genetic influence on hematological phenotypes, such as mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV), highlights how subtle genetic changes can impact blood cell properties.[4] Similarly, LINC01493 is a long non-coding RNA, and RNU6-99P is a small nuclear RNA pseudogene; both types of non-coding RNAs are involved in regulating gene expression and cellular processes essential for blood cell health. Genetic variations such as rs67538811 within or near these non-coding RNAs could affect their regulatory functions, potentially leading to subtle changes in erythrocyte properties that increase their tendency to aggregate, consistent with findings of multiple loci influencing red blood cell traits. [9]
C12orf42(Chromosome 12 open reading frame 42) encodes a protein whose precise function is still under investigation, but it is broadly implicated in cellular processes that can indirectly affect cell structure and integrity. A single nucleotide polymorphism likers56670740 could modify the protein’s activity or expression, thereby influencing the subtle characteristics of red blood cells that contribute to their aggregation behavior. Genetic variations influencing red blood cell traits, including those affecting cell volume regulation, are recognized contributors to inter-individual variability in blood phenotypes.[10] NELL1(Neural epidermal growth factor-like 1 protein) is involved in cell proliferation and differentiation, whileANO5 (Anoctamin 5) functions as a calcium-activated chloride channel, critical for membrane excitability and volume regulation in various cell types, including potential roles in red blood cell function. Variations such as rs12420881 in these genes could impact cellular homeostasis or membrane properties, which are key determinants of erythrocyte aggregation, a phenomenon influenced by numerous genetic factors across the genome.[11]
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Causes
Section titled “Causes”Genetic Influences on Aggregation Responsiveness
Section titled “Genetic Influences on Aggregation Responsiveness”Inter-individual differences in blood cell aggregation responses are significantly influenced by genetic factors, with heritability previously established in large studies such as the Framingham Heart Study and the Genetic Study of Atherosclerosis Risk.[8] Genome-wide association studies (GWAS) have identified common genetic variants associated with aggregation responses to various agonists, including ADP, collagen, and epinephrine. [8] For instance, a meta-analysis identified several loci associated with platelet aggregation, providing insights into the mechanisms underlying this variability. [8]Specific single nucleotide polymorphisms (SNPs) in genes likeANKRD26 have been associated with platelet aggregation, highlighting the role of inherited variants in modulating this trait. [12]
Further genetic analyses have pinpointed specific loci affecting aggregation. A significant variant, rs10886430 , located in the GRK5gene, has been causally linked to cardiovascular disease and affects thrombin-induced platelet aggregation, with the minor G allele associated with increased platelet reactivity.[13] Other associations have been found with SNPs in genes such as COL1A1, TTLL11, and OTOR, which may play roles in blood cell biology or related pathways, though their precise mechanisms in aggregation require further investigation. [14] These findings underscore the polygenic nature of aggregation, where multiple genes and their interactions contribute to an individual’s overall aggregation profile.
Molecular Pathways and Receptor Signaling
Section titled “Molecular Pathways and Receptor Signaling”The mechanisms of blood cell aggregation involve complex molecular pathways, often initiated by specific agonists that trigger receptor activation and downstream signaling cascades. Agonists like ADP, collagen, epinephrine, and thrombin are known to induce aggregation responses, and genetic variations can modulate these responses.[8] For example, the GRK5 gene variant rs10886430 influences thrombin-induced aggregation by mediating its inhibitory effects via thePAR4 receptor, which is crucial for sustained platelet activation, intracellular calcium responses, and fibrin deposition. [13] This suggests that specific genetic predispositions can alter the sensitivity and effectiveness of these critical signaling pathways, impacting overall aggregation capacity and potentially influencing the efficacy of anti-aggregatory therapies.
The identified genetic associations also provide insights into the molecular components involved in aggregation. For instance, the ANKRD26 gene, associated with aggregation, codes for a protein whose function may impact platelet biology, though its exact role in aggregation requires further elucidation. [12] Similarly, genes like COL1A1, which encodes part of type I collagen, may affect aggregation through structural interactions or signaling pathways, as collagen is a known inducer of aggregation. [14] Understanding these molecular underpinnings is vital for elucidating how genetic variations translate into functional differences in aggregation.
Modulating Factors: Environment, Lifestyle, and Comorbidities
Section titled “Modulating Factors: Environment, Lifestyle, and Comorbidities”Beyond direct genetic predispositions, various environmental, lifestyle, and physiological factors can significantly modulate aggregation, often interacting with an individual’s genetic makeup. Lifestyle elements such as diet, physical activity, and exposure to certain substances can influence aggregation, although specific details regarding their direct impact on the mechanisms of aggregation are still being explored.[8]For instance, studies have noted differences in body mass index (BMI) among cohorts, which could represent an environmental influence on overall cardiovascular health and, indirectly, on aggregation.[8]
Furthermore, comorbidities and medication effects play a crucial role in modifying aggregation. The presence of thrombotic outcomes like myocardial infarction highlights the pathophysiologic relevance of aggregation, indicating that underlying health conditions can affect its regulation. [12]Anti-platelet medications are specifically designed to target aggregation mechanisms for the treatment and prevention of cardiovascular disease, underscoring the impact of pharmacological interventions.[8] Age-related changes also contribute to variability, as evidenced by studies that adjust for age and sex in their analyses of aggregation phenotypes, suggesting that these demographic factors influence aggregation responses. [4]
Biological Background
Section titled “Biological Background”Erythrocyte Structure, Function, and Rheology
Section titled “Erythrocyte Structure, Function, and Rheology”Erythrocytes, also known as red blood cells, are fundamental components of the blood, constituting approximately 40% to 50% of its total volume. [1] Their primary function is to transport oxygen from the lungs to tissues and carbon dioxide from tissues back to the lungs for exhalation. [1]Routine clinical assessments often involve measuring erythrocyte quantity, size, and composition, as variations in these characteristics, even within normal physiological ranges, are associated with various non-hematologic diseases and overall mortality.[1]
The physical properties of erythrocytes significantly influence blood rheology, which is the study of blood flow. Blood viscosity, a crucial determinant of blood pressure, is largely dependent on the levels of hemoglobin (Hgb) and hematocrit (Hct).[1] There is an inverse relationship between blood viscosity and vascular blood flow, implying that elevated Hct levels, for instance, can impede organ perfusion. [1]Erythrocyte aggregation, where red blood cells clump together, directly contributes to increased blood viscosity and can thus impact microcirculation and overall cardiovascular health.
Molecular and Genetic Determinants of Erythrocyte Traits
Section titled “Molecular and Genetic Determinants of Erythrocyte Traits”Erythrocyte production and their qualitative characteristics are shaped by a complex interplay of environmental factors and genetic influences. The heritability of erythrocyte traits is notably high, ranging from 40% to 90%, underscoring the significant role of genetic mechanisms. [1] Both common and rare genetic variants contribute to the observed inter-individual variability in these traits. [1]Furthermore, disorders involving hemoglobin production and various hemoglobinopathies are recognized as some of the most common genetic diseases worldwide, often a result of natural selection.[1]
Specific genes and their variants have been identified as key players in modulating erythrocyte characteristics. For example, variants within the Complement receptor 1 (CR1) gene have been associated with erythrocyte sedimentation rate (ESR). [2] ESR is a widely used clinical measure that reflects the rate at which red blood cells settle in a tube, a process influenced by their tendency to aggregate. Studies on gene expression patterns during hematopoiesis reveal that a set of genes pertinent to red blood cell biology exhibit differential regulation, with their expression increasing progressively along the erythroid lineage, particularly in the later stages of erythroblast development. [15] These findings highlight the intricate molecular pathways and regulatory networks that govern the development and functional integrity of erythrocytes.
Pathophysiological Implications of Erythrocyte Aggregation
Section titled “Pathophysiological Implications of Erythrocyte Aggregation”Disruptions in erythrocyte homeostasis and rheological properties can lead to significant pathophysiological outcomes. The phenomenon of red cell adhesion, closely related to aggregation, is implicated in the pathogenesis of various human diseases. [16]Systemic consequences of altered erythrocyte traits are evident, with research indicating associations between hemoglobin and hematocrit levels and an elevated risk for hypertension and other vascular diseases.[1]
Genetic adaptations shaped by evolutionary pressures, such as resistance to malaria, profoundly influence the human genome, particularly with regard to genes affecting erythrocyte traits. [3] While the precise mechanisms are diverse, such genetic variants can alter red blood cell structure or function, potentially impacting aggregation properties and conferring protection against parasitic infections. [17]These interconnected biological processes illustrate the broad impact of erythrocyte aggregation and related traits on both susceptibility to disease and the course of human evolution.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Genetic and Regulatory Control of Erythrocyte Traits
Section titled “Genetic and Regulatory Control of Erythrocyte Traits”Genetic variants significantly influence erythrocyte phenotypes, with multiple genomic loci identified through genome-wide association studies (GWAS) [1], [11], [15], [18], [19], [20], [21]. [12] These variants impact various red blood cell characteristics, suggesting a complex genetic architecture underlying erythrocyte properties relevant to aggregation. Gene expression analyses during hematopoiesis reveal that candidate genes associated with erythrocyte traits are often upregulated in late erythroblasts, underscoring their critical roles in erythroid lineage differentiation and maturation. [15]
Regulatory mechanisms, including coding and non-coding variants, play a crucial role in modulating erythrocyte function and aggregation potential. Active enhancer regions, characterized by specific histone modifications such as H3K4me1/H3K27ac, show significant enrichment for red-cell-associated variants, highlighting the importance of epigenetic regulation in controlling gene expression relevant to erythrocyte biology. [22]This intricate interplay between genetic predisposition and regulatory elements dictates the cellular properties that can influence erythrocyte aggregation and broader hematological parameters.
Cellular Adhesion and Receptor Signaling
Section titled “Cellular Adhesion and Receptor Signaling”Erythrocyte aggregation is fundamentally influenced by mechanisms governing cell-cell adhesion and receptor-mediated interactions. Variants in theCR1 (Complement Receptor 1) gene have been directly associated with erythrocyte sedimentation rate (ESR), which is a measure of red cell aggregation in plasma. [2] This suggests that components of the complement system or their receptors on the red cell surface can modulate the propensity for erythrocytes to clump together, impacting blood rheology.
Beyond specific receptors, general red cell adhesion mechanisms are implicated in various human diseases [16] indicating broader cellular interactions that contribute to aggregation. These adhesive properties, potentially involving membrane proteins and their interactions with plasma components, dictate the rheological behavior of blood and contribute to its viscosity. Blood viscosity, in turn, is a key determinant of vascular flow and blood pressure. [1]
Metabolic Homeostasis and Erythrocyte Function
Section titled “Metabolic Homeostasis and Erythrocyte Function”The metabolic state of erythrocytes is critical for maintaining their structural integrity and functional characteristics, which in turn influence aggregation. Energy metabolism, particularly the activity of enzymes like G6PD(glucose 6-phosphate dehydrogenase), is essential for red blood cell survival and protection against oxidative stress.[23] Dysregulation in these metabolic pathways can compromise membrane stability and deformability, altering the cellular properties that govern erythrocyte-erythrocyte interactions.
Proper metabolic flux control ensures the continuous supply of ATP and reducing equivalents necessary for membrane pumps and antioxidant defenses within the erythrocyte. Any imbalance in biosynthesis or catabolism can lead to cellular fragility or changes in surface charge, making erythrocytes more prone to aggregation. These metabolic underpinnings are fundamental to the overall physiological behavior of red blood cells within the circulatory system.
Systems-Level Regulation and Disease Implications
Section titled “Systems-Level Regulation and Disease Implications”Erythrocyte aggregation is an emergent property influenced by the systems-level integration of various biological pathways and network interactions. Blood viscosity, which is largely determined by hemoglobin and hematocrit levels, is directly linked to erythrocyte aggregation and has an inverse relationship with vascular blood flow.[1] This rheological property is hierarchically regulated by the collective behavior of individual red cells, plasma proteins, and vessel characteristics.
Dysregulation of erythrocyte aggregation and related traits has significant disease relevance, serving as both a marker and a contributor to pathological conditions. For instance, elevated blood viscosity and red cell traits are associated with increased risk for hypertension and cardiovascular diseases[24], [25]. [26] Compensatory mechanisms might attempt to mitigate these effects, but sustained pathway dysregulation can lead to chronic conditions, making the underlying mechanisms potential therapeutic targets. Furthermore, resistance to malaria has been linked to specific red blood cell traits, illustrating how alterations in erythrocyte properties can confer protection against certain diseases. [3]
Clinical Relevance
Section titled “Clinical Relevance”Influence on Blood Rheology and Vascular Health
Section titled “Influence on Blood Rheology and Vascular Health”Erythrocyte aggregation significantly impacts blood rheology, a critical determinant of cardiovascular health. Blood viscosity, which is substantially influenced by the aggregation of red blood cells, depends largely on hemoglobin (Hgb) and hematocrit (Hct) levels. [1] Elevated Hct increases blood viscosity, which in turn acts as a determinant of blood pressure. [1] This increased viscosity establishes an inverse relationship with vascular blood flow, potentially hampering organ perfusion and contributing to the risk of various vascular diseases. [1]Furthermore, studies have identified altered blood viscosity as a factor in patients with conditions such as borderline essential hypertension.[24]
Genetic Determinants and Related Phenotypes in Risk Assessment
Section titled “Genetic Determinants and Related Phenotypes in Risk Assessment”Genetic factors play a role in modulating traits related to erythrocyte aggregation, offering potential insights for risk stratification and personalized medicine approaches. For instance, variants within the complement receptor 1 gene have been found to be associated with erythrocyte sedimentation rate.[2] Erythrocyte sedimentation rate is a recognized clinical measure that reflects the propensity of red blood cells to aggregate. Additionally, red cell adhesion is a related phenomenon implicated in various human diseases. [16] Identifying genetic predispositions to altered red blood cell rheology and aggregation, such as through these associations, can support the assessment of an individual’s risk for related complications and inform potential prevention strategies.
Frequently Asked Questions About Erythrocyte Aggregation
Section titled “Frequently Asked Questions About Erythrocyte Aggregation”These questions address the most important and specific aspects of erythrocyte aggregation based on current genetic research.
1. My family has high blood pressure; am I at risk?
Section titled “1. My family has high blood pressure; am I at risk?”Yes, a family history of high blood pressure can indicate a higher genetic predisposition. Genes that influence how your red blood cells aggregate and affect blood viscosity, like Complement receptor 1, can be passed down. This can contribute to a higher risk of conditions like hypertension and vascular diseases, as variations in these traits are often genetically influenced.
2. Does my ancestry affect my blood health?
Section titled “2. Does my ancestry affect my blood health?”Yes, your ancestry can influence your blood health. Genetic factors affecting red blood cell traits and aggregation can vary significantly across different populations. For example, some genetic variants common in African-American populations, often linked to malaria resistance, are associated with specific red blood cell characteristics. This means your genetic background can play a role in your predisposition to certain blood-related conditions.
3. What does my ESR test tell me about my blood?
Section titled “3. What does my ESR test tell me about my blood?”Your ESR test measures how quickly your red blood cells settle, which directly shows how much they are aggregating or “sticking together.” A higher ESR can indicate increased aggregation, which might suggest inflammation or other health issues affecting your blood’s properties. This aggregation affects your blood’s flow and viscosity, which are important for overall circulatory health.
4. Can my medications make my blood ‘thicker’?
Section titled “4. Can my medications make my blood ‘thicker’?”Yes, certain medications can influence how your red blood cells aggregate, potentially affecting your blood’s “thickness” or viscosity. While advanced methods try to account for these effects in research, it’s a known factor that can alter erythrocyte properties. Always discuss any concerns about medication side effects on your blood with your doctor.
5. Could my blood cells make me feel sluggish?
Section titled “5. Could my blood cells make me feel sluggish?”It’s possible. When red blood cells aggregate excessively, it can increase blood viscosity, making your blood “thicker.” This increased viscosity, especially with high hematocrit, can impair blood flow and oxygen delivery to your organs. If your organs aren’t getting enough blood flow, it could potentially contribute to feelings of sluggishness or fatigue.
6. Does being overweight affect my blood’s ‘thickness’?
Section titled “6. Does being overweight affect my blood’s ‘thickness’?”Yes, characteristics like your BMI can influence factors that affect your blood’s “thickness.” While BMI is often considered a confounder in studies, it can be associated with levels of hemoglobin and hematocrit, which in turn impact blood viscosity and red blood cell aggregation. Maintaining a healthy weight can help manage these factors.
7. Why might my blood be ‘thicker’ than my friend’s?
Section titled “7. Why might my blood be ‘thicker’ than my friend’s?”Your blood’s “thickness” or viscosity can be influenced by a combination of genetics and lifestyle. Genetic variations, such as those in theComplement receptor 1 gene, can affect how your red blood cells aggregate and settle, contributing to differences in blood viscosity. Your unique genetic makeup, along with other factors, plays a role in these individual variations.
8. Could my ancestors’ malaria history affect my blood?
Section titled “8. Could my ancestors’ malaria history affect my blood?”Yes, surprisingly, it can. If your ancestors came from regions where malaria was common, you might carry genetic variants that once offered protection against the disease. These genetic variants are associated with specific red blood cell traits, which could influence characteristics like how your red blood cells aggregate. This highlights how evolutionary pressures can shape your blood’s properties.
9. Does my diet affect my blood’s ‘thickness’?
Section titled “9. Does my diet affect my blood’s ‘thickness’?”Yes, your diet can indirectly affect your blood’s “thickness” by influencing the levels of certain plasma proteins, like fibrinogen, in your blood. These proteins play a crucial role in how your red blood cells aggregate. Maintaining a balanced diet can help support healthy levels of these proteins and overall blood rheology.
10. Will my kids inherit my blood aggregation tendencies?
Section titled “10. Will my kids inherit my blood aggregation tendencies?”Yes, there’s a genetic component to how red blood cells aggregate, so your children could inherit some of your tendencies. Research has identified various genetic loci and specific gene variants, like those in Complement receptor 1, that influence these erythrocyte traits. This means a predisposition to certain blood characteristics can be passed down through families.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
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[3] Ding, K et al. “Genetic variants that confer resistance to malaria are associated with red blood cell traits in African-Americans: an electronic medical record-based genome-wide association study.” G3 (Bethesda), 2013. PMID: 23696099.
[4] Yang Q, et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Med Genet, 2007, 8(Suppl 1):S12.
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[8] Johnson, A. D., et al. “Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists.” Nat Genet, 2010. PMID: 20526338.
[9] Hodonsky CJ, et al. “Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics.” BMC Genomics, 2020.
[10] Hodonsky CJ, et al. “Genome-wide association study of red blood cell traits in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos.” PLoS Genet, 2017.
[11] Soranzo N, et al. “A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.”Nat Genet, 2009.
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[13] Rodriguez BAT et al. “A Platelet Function Modulator of Thrombin Activation Is Causally Linked to Cardiovascular Disease and Affects PAR4 Receptor Signaling.”American Journal of Human Genetics, 2020.
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[15] van der Harst, P., et al. “Seventy-five genetic loci influencing the human red blood cell.” Nature, vol. 492, no. 7429, 2012, pp. 369–375.
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[19] Kamatani, Y., et al. “Genome-wide association study of hematological and biochemical traits in a Japanese population.”Nature Genetics, vol. 42, 2010, pp. 210–215.
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