Blood Immunoglobulin Amount
Introduction
Immunoglobulins, commonly known as antibodies, are essential proteins produced by the immune system that circulate throughout the blood and lymphatic system. Their primary function is to recognize and neutralize foreign substances, such as bacteria, viruses, and toxins, forming a critical component of the body's adaptive immune response. The quantity of these immunoglobulins in the blood, referred to as blood immunoglobulin amount, serves as a key indicator of immune system health and function. Fluctuations or abnormalities in these levels can have significant implications for an individual's overall health, including susceptibility to infections, allergic reactions, and autoimmune conditions.
Biological Basis
The levels of immunoglobulins and other related immune proteins in the blood are influenced by a complex interplay of genetic predispositions and environmental factors. Genome-wide association studies (GWAS) have been instrumental in identifying specific genetic variations, particularly single nucleotide polymorphisms (SNPs), that are associated with variations in these protein levels. For instance, SNPs within the FCER1A gene, such as rs2427837, have been linked to significant differences in total serum IgE levels. The rare "G" allele of rs2427837 is associated with a notable decrease in total serum IgE, correlating with altered FCER1A expression on basophils. [1] Further genetic influences on total IgE levels have been observed with SNPs in genes like STAT6 (rs12368672) and RAD50 (rs2706347). [1] These genetic associations, often termed protein quantitative trait loci (pQTLs), demonstrate how inherited genetic variations can impact the synthesis, processing, or function of proteins. In some cases, non-synonymous SNPs can even alter antibody binding affinity, which may affect the accurate measurement of protein levels. [2] Beyond immunoglobulins, genetic factors like those determining the ABO blood group can influence the levels of other immune-related proteins, such as serum TNF-alpha and soluble E-selectin. [2]
Clinical Relevance
The assessment of blood immunoglobulin amounts is a fundamental diagnostic procedure in clinical medicine, crucial for diagnosing and managing a wide array of health conditions. Deviations from normal ranges, whether excessively high or low, can signal underlying immune system dysfunctions, including primary immunodeficiencies, autoimmune diseases, allergies, and chronic inflammatory states. For example, elevated IgE levels are a hallmark of allergic diseases and parasitic infections. Understanding the genetic factors that predispose individuals to specific immunoglobulin levels can aid in predicting disease risk, guiding personalized treatment approaches, and identifying patients who may respond uniquely to particular therapies. Genetic insights into other immune biomarkers, such as MCP1 or CRP concentrations, also offer valuable information regarding inflammatory processes and the risk of cardiovascular disease. [3]
Social Importance
Investigating the genetic determinants of blood immunoglobulin amounts carries substantial social importance. By unraveling the genetic underpinnings of immune responses, researchers can pave the way for the development of more precise preventive strategies and targeted therapeutic interventions. This knowledge contributes significantly to public health by enabling the identification of populations or individuals at heightened risk for specific immune-related disorders. Furthermore, it supports the advancement of personalized medicine, where an individual's unique genetic profile informs tailored healthcare decisions, ultimately leading to more effective disease management, improved health outcomes, and enhanced quality of life.
Methodological and Statistical Constraints
Research into blood immunoglobulin levels often faces challenges related to study design and statistical power. Many studies, particularly early genome-wide association studies (GWAS), were susceptible to false negative findings due to moderate cohort sizes, limiting their power to detect associations with modest effect sizes These genetic differences are known to contribute to susceptibility to autoimmune diseases, where dysregulated immune responses often involve abnormal immunoglobulin profiles. [1]
Other key genetic variants include rs231770 and rs926169 in the CTLA4 gene, and rs3755553 in the TPO gene. CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) acts as a crucial negative regulator of T-cell activation, helping to maintain immune tolerance and prevent uncontrolled immune responses. Polymorphisms in CTLA4, such as those listed, can affect the expression or function of this inhibitory receptor, potentially leading to overactive T-cells that drive B-cell proliferation and excessive immunoglobulin synthesis, or contribute to autoimmune conditions characterized by autoantibody production. [4] Similarly, TPO (Thyroid Peroxidase) is an enzyme vital for the synthesis of thyroid hormones. The variant rs3755553 in TPO is frequently linked to autoimmune thyroid diseases, such as Hashimoto's thyroiditis, where the body produces antibodies against TPO itself. The presence of these autoantibodies is a hallmark of the disease and reflects a broader systemic immune dysregulation that can influence overall immunoglobulin levels and immune homeostasis. [5]
Further variants influence diverse cellular and immune processes. The rs16832016 variant located between VANGL2 and SLAMF6 may impact the function of SLAMF6 (Signaling Lymphocytic Activation Molecule Family Member 6), which is involved in immune cell signaling and adhesion, playing a role in the activation and differentiation of B and T lymphocytes, processes essential for effective immunoglobulin production. [6] The region containing P2RY10BP - GPR174 with variant rs5912761 may involve GPR174, a G protein-coupled receptor known to modulate immune responses and inflammation, potentially affecting B-cell maturation and antibody secretion. The ATXN2 gene variant rs77465633 is associated with Ataxin 2, a protein involved in RNA metabolism and stress responses, whose broader cellular roles can indirectly influence immune cell function and protein synthesis, including immunoglobulins. [4] The rs12411216 variant in the MUC1 - THBS3-AS1 region involves MUC1, a mucin glycoprotein that acts as a protective barrier and is implicated in immune recognition, suggesting that variations could impact mucosal immunity and systemic antibody responses. Lastly, rs9393917 and rs114708114 in the OR2E1P - GPX6 region point to GPX6 (Glutathione Peroxidase 6), an enzyme crucial for antioxidant defense. While OR2E1P is an olfactory receptor pseudogene, oxidative stress managed by GPX6 can significantly affect immune cell health and function, thereby indirectly influencing immunoglobulin synthesis and levels. [1] The rs492897 variant in SKIC2 (Ski-interacting protein 2) could also play a role in gene regulation and cellular processes that broadly impact immune system function and antibody production.
Conceptual and Operational Definitions of Blood Protein Levels
Blood protein amount, encompassing blood immunoglobulin amount, is fundamentally understood as a quantitative trait, representing the concentration of specific proteins within the bloodstream. [2] This conceptualization allows for a continuous spectrum of values across a population, often approximated by a normal distribution for analytical purposes, where individual levels can be assigned Z scores corresponding to their percentiles. [2] The precise measurement of these protein levels serves as an operational definition, providing a tangible, quantifiable metric for research and clinical assessment.
Operational definitions for blood protein levels also encompass the handling of values that fall outside the typical measurement range of laboratory assays. [2] For instance, individuals exhibiting protein levels below the assay's lower detection limit are typically assigned a numerical value, such as zero, to facilitate statistical analysis. [2] Conversely, levels exceeding the upper assay detection limits are also noted and handled appropriately, acknowledging the assay's boundaries in capturing the full range of biological variation. [2] These approaches ensure consistency in data reporting and analysis, particularly in large-scale studies.
Measurement Approaches and Diagnostic Criteria for Protein Quantification
Measurement approaches for blood protein amounts rely on assays with defined detection limits, which establish the quantifiable range for a given protein. [2] These limits determine the precision and accuracy of reported values, with instances of individuals having protein levels below or above these detectable thresholds. [2] For example, some proteins may show a small percentage of individuals with levels below detectable limits, while others might present with levels exceeding the assay's maximum measurable concentration. [2] The specific cut-off values and thresholds for defining normal or abnormal ranges are established through statistical analysis of population data, often using percentiles from a normal distribution.
In research settings, the robustness of findings related to protein amounts is often validated through specialized statistical methods. [2] Non-parametric analyses, such as quantile regression, are employed to ensure that observed associations are not unduly influenced by the inclusion of individuals whose protein levels fall outside the standard assay detection limits. [2] This rigorous analytical approach helps to confirm the reliability of findings, even when a portion of the data represents extreme values that push the boundaries of conventional measurement capabilities. [2]
Terminology and Classification of Blood Protein Traits
The terminology surrounding blood protein levels, including immunoglobulin amount, often refers to them as "protein quantitative traits" (pQTLs) when considering their genetic determinants. [2] This nomenclature highlights their continuous, measurable nature and their potential as biomarkers for various physiological or pathological states. Related concepts include "assay detection limits," which define the lowest and highest concentrations an assay can reliably measure, and "percentiles," used to position an individual's protein level within a reference population. [2]
Classification systems for blood protein amounts typically involve a dimensional approach, relying on the continuous quantitative values rather than strict categorical divisions. [2] However, for clinical interpretation or research purposes, these continuous distributions are often partitioned into categories based on thresholds or cut-off values, such as "below detectable limits" or "above detectable limits," which can signify extreme deviations from the norm. [2] The general framework for classifying protein levels involves comparing individual measurements to established population distributions.
Causes of Blood Immunoglobulin Amount
The amount of immunoglobulins, or antibodies, circulating in the blood is a complex trait influenced by a combination of genetic predispositions, environmental exposures, and the intricate interplay between them. These factors shape the immune system's capacity to produce and regulate various antibody classes, impacting an individual's susceptibility to infections, allergies, and autoimmune conditions. Understanding these causal pathways is crucial for comprehending the variability in immune responses across populations.
Genetic Basis of Immunoglobulin Levels
Genetic factors play a substantial role in determining an individual's blood immunoglobulin amount, with strong familial determinants influencing total immunoglobulin E (IgE) variability. [1] This genetic susceptibility is often polygenic, involving multiple gene polymorphisms that regulate immunological responses rather than a single gene. Specific loci identified include FCER1A, where the rare allele of rs2427837 is associated with a significant decrease in total serum IgE levels, and STAT6 (rs12368672) and RAD50 (rs2706347), both linked to increased IgE levels. [1] Other genes, such as FCER1B, IL-13, IL4, and CTLA4, have also been implicated in influencing IgE levels. [1] Beyond IgE, the HLA region, including HLA-SE and HLA-DR3, is known to be associated with specific antibody titers, such as anti-cyclic citrullinated peptide (anti-CCP) antibodies, which are relevant in autoimmune diseases. [7] Furthermore, copy number variations (CNVs) in genes like CCL4L1 and the CCL3L1 chemokine gene cluster can affect protein levels and influence susceptibility to conditions like HIV-1, highlighting the diverse genetic mechanisms at play. [2]
Environmental and Lifestyle Influences
Environmental factors significantly modulate blood immunoglobulin amounts, particularly IgE, which is highly responsive to external stimuli. Historically, high IgE levels have been associated with exposure to parasites and helminths, conferring resistance in regions where such exposures are common. [1] In contrast, in Western lifestyle countries with reduced contact to these pathogens, elevated IgE levels are predominantly linked to allergic disorders, suggesting a shift in immune response patterns influenced by environmental context. [1] The cellular environment also plays a critical role, as the measurement of protein levels, including immunoglobulins, can differ significantly between unstimulated and stimulated cells, indicating that environmental cues and immune activation states profoundly impact the production and secretion of these immune proteins. [2] These observations underscore how an individual's living conditions and exposures can shape their immunological profile.
Complex Regulatory Mechanisms and Interactions
The regulation of blood immunoglobulin amount involves complex interactions between an individual's genetic makeup and their environment. Genetic predispositions, such as those influencing IgE, interact with diverse environmental contexts; for instance, the same genetic variants might manifest differently depending on exposure to allergens versus parasites. [1] The precise mechanisms by which specific genetic variants affect immunoglobulin levels often involve alterations in gene expression, such as the association between the rs2427837 SNP in FCER1A and increased FCER1A expression on IgE-stripped basophils, which in turn influences total IgE levels. [1] Moreover, foundational genetic traits, such as the ABO blood group, have been shown to influence levels of immune-related proteins like tumor necrosis factor-alpha (TNF-alpha) and soluble E-selectin, suggesting a broader impact on inflammatory pathways that could indirectly affect immunoglobulin production and regulation . [5], [8] This intricate interplay between genetic background and environmental stimuli ultimately defines the dynamic range and specific composition of an individual's immunoglobulin repertoire.
Immunoglobulin Structure, Function, and Regulation
Immunoglobulins, particularly IgE, are critical components of the adaptive immune system, playing diverse roles in host defense and disease pathogenesis. High levels of IgE are historically associated with resistance to parasites and helminths, reflecting their evolutionary role in combating external threats. [1] In contemporary Western societies, however, elevated IgE levels are more commonly linked to allergic disorders, highlighting a shift in their primary clinical relevance. [1] Beyond allergies, recent research indicates that IgE antibodies also contribute to anti-tumoral defense and mediate autoimmune diseases, suggesting a broader and more complex involvement in immune regulation than traditionally understood. [1]
The production of serum IgE is significantly influenced by genetic factors, with both pedigree and twin studies demonstrating a strong inherited component to its variability. [1] This genetic susceptibility is thought to arise from polymorphisms across multiple genes that regulate immune responses. Key loci previously established to influence IgE levels include FCER1B, IL-13, and STAT6, which are involved in various aspects of immune cell signaling and cytokine production. [1] More recently, FCER1A has been identified as a novel susceptibility locus, with its expression, particularly of the FCER1 alpha chain in basophils, directly correlating with total serum IgE levels. [1]
The ABO Blood Group System and Systemic Interactions
The ABO blood group system, determined by genetic variations at the ABO gene locus, exerts a profound influence on various physiological processes beyond its well-known role in blood transfusions. The three major ABO blood groups (A, B, O) are defined by specific single nucleotide polymorphisms (SNPs) within the ABO gene. [2] For instance, the O blood group polymorphism, rs8176719, involves a G deletion that results in a premature termination codon, leading to the absence of A and B antigens. [2] The B blood group differs from the A group at seven nucleotides, including four non-synonymous SNPs, which alter the glycosyltransferase enzyme responsible for antigen synthesis. [2]
Genetic variations within the ABO region are strongly associated with circulating levels of several key biomolecules, including soluble E-selectin and tumor necrosis factor-alpha (TNF-alpha). [5] Specifically, the O blood group is often linked to higher TNF-alpha levels. [5] These associations are critical because TNF-alpha is a potent inflammatory cytokine known to induce the expression of E-selectin, an adhesion molecule involved in leukocyte recruitment to sites of inflammation. [5] Such systemic influences of the ABO blood group extend to an increased risk of severe Plasmodium falciparum malaria in individuals with blood group O, while also being linked to a reduced risk of thrombotic diseases but an increased risk of gastric ulcers. [5]
Cellular and Molecular Pathways of Immune Mediators
The intricate interplay of cellular and molecular pathways governs the abundance and activity of immune mediators, directly impacting overall health. TNF-alpha, a pleiotropic cytokine, exemplifies this complexity, existing in various forms including transmembrane, freely circulating, or bound to soluble receptors. [2] The specific form or fraction of TNF-alpha being measured can vary between assays, potentially leading to discrepancies in reported levels and associations, which complicates the understanding of its physiological effects. [5] This variability also suggests that associations observed, such as that between ABO blood group and TNF-alpha, could sometimes be influenced by assay cross-reactivity with ABO antigens. [5]
The induction of E-selectin expression by TNF-alpha is a well-established molecular pathway, underscoring their functional connection in inflammatory responses. [5] Circulating levels of E-selectin are positively correlated with TNF-alpha levels, even after accounting for conventional risk factors, suggesting a direct or tightly regulated relationship. [5] Furthermore, the ABO blood group has been identified as a major locus associated with serum levels of soluble E-selectin and soluble intercellular adhesion molecule-1 (ICAM-1), both of which are crucial for leukocyte-endothelial interactions during inflammation. [5] These findings highlight how genetic variations can modulate the expression and circulating levels of key immune molecules, thereby influencing inflammatory and physiological processes.
Genetic Determinants of Protein Levels and Disease Susceptibility
Genetic mechanisms play a fundamental role in determining the levels of circulating proteins and influencing susceptibility to a wide array of diseases. Genome-wide association studies (GWAS) have identified protein quantitative trait loci (pQTLs), which are genetic variants that influence protein levels. [2] For example, specific SNPs within or near the ABO gene, such as rs505922 and rs8176746, are strongly associated with serum TNF-alpha levels, demonstrating a trans-acting genetic effect. [2] These SNPs are in linkage disequilibrium with the alleles that determine the A, B, and O blood groups, directly linking ABO genetic variation to inflammatory mediator levels. [2]
The impact of genetic variation extends to the regulation of protein processing and secretion. For instance, the number of kringle IV repeats in apolipoprotein(a) (LPA) affects its secretion rate from the liver into the bloodstream. [2] Similarly, copy number variations (CNVs) in genes like CCL4L1 may influence the levels of related proteins. [2] These genetic determinants of protein levels can have significant pathophysiological consequences, influencing disease status ranging from metabolic disorders to various inflammatory conditions. Understanding these genetic underpinnings is crucial for dissecting the causal pathways between protein levels and correlated traits, offering insights into disease mechanisms and potential therapeutic targets. [2]
Immune Cell Activation and Immunoglobulin Receptor Pathways
The regulation of blood immunoglobulin amounts is intricately linked to immune cell activation and the signaling cascades initiated by immunoglobulin receptors. A genome-wide scan identified FCER1A, which encodes the alpha chain of the high-affinity IgE receptor, as a novel susceptibility locus influencing total serum IgE levels. [1] The expression of this FCER1A chain can be measured on immune cells, indicating its direct involvement in the cellular machinery that processes and presents IgE. [1] Furthermore, studies suggest that genetic variations impacting gene expression levels in lymphocytes, while not always directly correlating with protein abundance, represent crucial steps in modulating the overall production and availability of immune proteins, including immunoglobulins. [2]
Inflammatory Mediators and Their Regulatory Roles
Inflammatory pathways play a significant role in modulating blood protein levels, including those related to the immune system. For instance, the ABO blood group has been identified as a major locus associated with serum levels of soluble E-selectin and ICAM-1, both critical adhesion molecules in inflammatory responses. [5] The mechanism linking the ABO blood group to inflammatory markers like TNF-alpha is under investigation, with possibilities including cross-reactivity with ABO antigens or effects on the different forms of the TNF-alpha molecule. [2] These inflammatory markers, such as TNF-alpha and interleukin 6 (IL6), are known to be significantly elevated upon immune stimulation, highlighting their dynamic regulation within the body's defense mechanisms. [2]
Genetic and Post-Transcriptional Modulation of Protein Abundance
Genetic variations, particularly protein quantitative trait loci (pQTLs), significantly contribute to the observed variability in blood protein levels. Genome-wide association studies have identified various single nucleotide polymorphisms (SNPs) that are associated with the abundance of specific proteins, including those involved in immune and inflammatory processes. [2] Beyond gene expression, post-transcriptional and post-translational mechanisms also influence the final circulating protein amount. For example, the precise measurement of certain proteins like TNF-alpha can be complicated by its existence in multiple forms—transmembrane, freely circulating, or bound to soluble receptors—suggesting that protein modification and processing pathways are critical determinants of effective protein levels. [2] The poor correlation between different assays for the same protein suggests these assays might be measuring distinct fractions or modifications of the molecule, further emphasizing the complexity of protein regulation. [2]
Inter-Pathway Crosstalk and Disease Context
The interplay between different biological pathways creates a complex regulatory network that ultimately influences blood immunoglobulin amounts and related immune responses. The association of the ABO blood group with inflammatory markers like TNF-alpha, soluble E-selectin, and ICAM-1 demonstrates how seemingly disparate genetic factors can converge to influence immune and vascular health. [2] Such associations are not merely academic; changes in serum and plasma protein concentrations are often indicative of disease status, ranging from metabolic disorders to immune dysregulation. [2] Understanding these integrated pathways, including the role of genetic variants in influencing inflammatory cytokines and immune receptors, is crucial for deciphering the mechanisms behind various disease risks, such as the link between blood group O and altered risks of thrombotic diseases or gastric ulcers. [2]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs6927022 rs9272371 rs9272624 |
HLA-DQA1 | Epstein Barr virus nuclear antigen 1 IgG measurement ulcerative colitis inflammatory bowel disease Epstein-Barr virus seropositivity streptococcus seropositivity |
| rs16832016 | VANGL2 - SLAMF6 | blood immunoglobulin amount |
| rs9393917 rs114708114 |
OR2E1P - GPX6 | blood immunoglobulin amount psoriasis |
| rs231770 rs926169 |
CTLA4 | Myasthenia gravis blood immunoglobulin amount Graves disease type 1 diabetes mellitus |
| rs3755553 | TPO | blood immunoglobulin amount |
| rs1794280 | HLA-DQB1 - MTCO3P1 | blood immunoglobulin amount hyperthyroidism rheumatoid arthritis, hypothyroidism |
| rs5912761 | P2RY10BP - GPR174 | blood immunoglobulin amount |
| rs77465633 | ATXN2 | rheumatoid arthritis blood immunoglobulin amount platelet count systemic lupus erythematosus |
| rs12411216 | MUC1 - THBS3-AS1 | blood immunoglobulin amount occipital lobe volume heel bone mineral density calcium measurement forced expiratory volume |
| rs492899 | SKIC2 | Candidemia blood immunoglobulin amount leukocyte immunoglobulin-like receptor subfamily B member 4 measurement |
Frequently Asked Questions About Blood Immunoglobulin Amount
These questions address the most important and specific aspects of blood immunoglobulin amount based on current genetic research.
1. Why do I get sick more often than my friends?
Your susceptibility to infections can be influenced by your genetic makeup, which affects your blood immunoglobulin levels. These levels, along with other immune proteins, are critical for fighting off foreign substances like bacteria and viruses. Variations in genes can lead to differences in how effectively your immune system recognizes and neutralizes these threats, making some people naturally more resistant.
2. My family has allergies; will my kids inherit them?
Yes, your children can inherit a predisposition to allergies, as genetic factors significantly influence immunoglobulin E (IgE) levels. Specific variations in genes like FCER1A, STAT6, and RAD50 have been linked to differences in total serum IgE, which is a key marker for allergic diseases. Understanding these genetic links can help predict their risk for developing allergies.
3. Does my ethnic background affect my immune health risks?
Yes, genetic factors that vary among different populations can influence your immune health risks. Research into genetic determinants of immune responses helps identify specific populations or individuals at heightened risk for certain immune-related disorders. This knowledge is crucial for developing personalized medicine approaches tailored to diverse genetic profiles.
4. Can I improve my immune system if my genes aren't great?
While genetic predispositions play a significant role in determining your baseline immunoglobulin levels and immune responses, environmental factors also contribute. Understanding your genetic profile can guide personalized strategies, but maintaining a healthy lifestyle, even with certain genetic tendencies, supports overall immune function. Genetic insights are paving the way for targeted interventions to improve health outcomes.
5. Why are my allergy test results sometimes confusing?
Blood test results for immunoglobulins can sometimes be complex due to genetic factors that affect measurement itself. For instance, non-synonymous genetic variations can alter the binding affinity of antibodies used in tests, potentially influencing the reported protein levels rather than just the actual concentration. This can make interpreting your specific results more challenging without further genetic context.
6. Does my blood type influence my overall immune response?
Yes, genetic factors determining your ABO blood group can influence levels of certain immune-related proteins, though not always directly immunoglobulins. For example, your blood type can affect the levels of proteins like serum TNF-alpha and soluble E-selectin, which play roles in inflammatory processes. These connections highlight the complex genetic interplay within the immune system.
7. Could my family's history explain my autoimmune issues?
Yes, a family history of autoimmune issues suggests a potential genetic predisposition. Genetic variations influence the production and function of immunoglobulins, and deviations from normal levels can signal underlying immune system dysfunctions, including autoimmune diseases. Identifying these genetic factors can help understand your risk and guide personalized treatment approaches.
8. Why do some people seem to have super strong immunity?
Differences in immune strength can often be attributed to individual genetic variations that influence immunoglobulin levels and overall immune system function. Some people may have genetic predispositions that lead to more robust immune responses, making them naturally more resilient to infections and certain diseases. These variations affect how their bodies produce and utilize antibodies.
9. Is checking my antibody levels useful for my general health?
Stress is an environmental factor that can certainly impact your immune system, even if you have a generally healthy genetic profile. While genetics establish a baseline for your immune response, factors like stress can influence the production and function of immune proteins. The interplay between genetic predispositions and environmental influences like stress shapes your overall immune resilience.
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] Weidinger, S. et al. "Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus." PLoS Genet, 2008.
[2] Melzer, D. et al. "A genome-wide association study identifies protein quantitative trait loci (pQTLs)." PLoS Genet, 2008.
[3] Benjamin, Emelia J., et al. "Genome-wide association with select biomarker traits in the Framingham Heart Study." BMC Medical Genetics, vol. 8, no. Suppl 1, 2007, p. S11.
[4] Kullo, Iftikhar J., et al. "A genome-wide association study of red blood cell traits using the electronic medical record." PLoS ONE, vol. 5, no. 9, 2010, e13011.
[5] Paterson, A. D. et al. "Genome-wide association identifies the ABO blood group as a major locus associated with serum levels of soluble E-selectin." Arteriosclerosis, Thrombosis, and Vascular Biology, 2009.
[6] Yang, Qiong, et al. "Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study." BMC Medical Genetics, vol. 8, 2007, p. 62.
[7] Cui, J. et al. "Genome-wide association study of determinants of anti-cyclic citrullinated peptide antibody titer in adults with rheumatoid arthritis." Molecular Medicine, 2009.
[8] Qi, L. et al. "Genetic variants in ABO blood group region, plasma soluble E-selectin levels and risk of type 2 diabetes." Human Molecular Genetics, 2010.