Exercise Induced Anaphylaxis
Introduction
Exercise-induced anaphylaxis (EIA) is a rare but potentially severe allergic reaction triggered by physical activity. It is characterized by symptoms that can range from skin manifestations like hives and angioedema to more severe systemic reactions including gastrointestinal distress, bronchospasm, and potentially cardiovascular collapse. Unlike some other forms of anaphylaxis, EIA often requires a specific co-factor, such as the ingestion of certain foods or medications, shortly before exercise to trigger the reaction.
Biological Basis
The underlying biological mechanisms of EIA involve an immune response, where specific immune cells, such as mast cells and basophils, release potent inflammatory mediators. While the precise triggers and pathways are still being investigated, the combination of physical stress from exercise and specific co-factors is thought to lead to systemic activation of these immune cells. Genetic factors are increasingly recognized to play a role in an individual's susceptibility to various physiological responses to exercise and in the development of immune-mediated conditions . [1], [2], [3], [4], [5], [6] Genome-wide association studies (GWAS) are a common approach to identify single nucleotide polymorphisms (SNPs) and other genetic variants that may influence complex traits, including individual differences in exercise responses and susceptibility to hypersensitivity reactions . [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]
Clinical Relevance
From a clinical perspective, the timely recognition and effective management of EIA are critical to prevent life-threatening episodes. Diagnosis typically involves a detailed medical history correlating symptoms with exercise and any potential co-factors, sometimes followed by supervised exercise challenges. Treatment strategies emphasize avoiding identified triggers, and patients are often advised to carry self-injectable epinephrine for immediate use. Research into the genetic underpinnings of individual variability, including responses to drugs and immune reactions, is a key area in pharmacogenomics and personalized medicine, aiming to improve risk prediction and treatment optimization . [1], [2], [3], [4], [6], [9]
Social Importance
The social impact of EIA can be substantial, as it can significantly restrict an individual's participation in physical activities, which are important for overall health and psychological well-being. This can lead to anxiety, decreased quality of life, and social limitations. A deeper understanding of the genetic factors contributing to EIA could pave the way for improved diagnostic tools, targeted prevention strategies, and novel therapies. Such advancements could empower affected individuals to engage more safely in physical activity, thereby enhancing their health and social integration. Studies exploring the genetic basis of diverse physiological responses to exercise, such as heart rate recovery or blood pressure changes, underscore the broader significance of genetics in comprehending human health and physical activity . [5], [10]
Limitations
Understanding the genetic underpinnings of complex conditions like exercise-induced anaphylaxis is subject to several limitations inherent in current research methodologies and data availability. These constraints can impact the interpretation and generalizability of findings, highlighting areas for future investigation.
Methodological and Statistical Limitations
Genetic studies, particularly for rare conditions like exercise-induced anaphylaxis, are often limited by insufficient sample sizes, which consequently reduces their statistical power to detect genetic associations. While some studies may have adequate power to identify common variants with substantial effect sizes (e.g., relative risks greater than 2.5), they are likely to miss rarer variants or those with more modest effects, potentially leading to an incomplete understanding of the genetic underpinnings of complex traits. [4] This limitation means that even moderately significant findings might not translate into clinically useful predictors, as small genetic effects may remain undetected and thus not contribute meaningfully to improving clinical utility. [12] Furthermore, the absence of independent replication cohorts for validation can hinder the confirmation of initial findings, making it challenging to differentiate true genetic signals from spurious associations. [13]
The design of genetic association studies can introduce various biases that impact the interpretation of results for conditions such as exercise-induced anaphylaxis. Researchers often control for population stratification by ensuring participants share similar genetic ancestry, frequently verified through principal component analysis; however, subtle intra-ethnic population structures or admixtures can still lead to inflated test statistics if not rigorously accounted for. [14] Additionally, the choice of genotyping platforms and the reference populations used for imputation (e.g., specific 1000 Genomes populations) can influence the spectrum of genetic variants captured and the accuracy of genotype calls, potentially affecting the discovery of relevant associations for the trait. [14]
Generalizability and Phenotypic Heterogeneity
A common limitation in genetic research, relevant to understanding exercise-induced anaphylaxis, is the predominant inclusion of individuals of European ancestry in study cohorts. [4] This demographic bias limits the generalizability of identified genetic risk factors to other ethnic groups, as the genetic architecture of complex traits can vary significantly across diverse ancestral backgrounds. Relying primarily on findings from a single ancestry group can lead to an incomplete picture of global genetic susceptibility and may exacerbate health disparities by hindering the development of universally applicable diagnostic or preventive strategies. Even within seemingly homogeneous populations, careful exclusion or correction for specific ancestral subgroups, such as Ashkenazi Jewish ancestry, highlights the importance of precise population stratification to avoid confounding results. [3]
Accurately defining and consistently measuring complex phenotypes, including exercise-induced anaphylaxis, presents a significant challenge that can affect genetic association studies. Variability in diagnostic criteria, the assessment of clinical characteristics (such as severity or triggers), or the adjudication process for cases can introduce considerable heterogeneity within study populations. [4] Such imprecision in phenotyping can dilute genuine genetic signals, making it more difficult to identify specific causal variants linked to the condition. The reliance on diverse clinical assessments or self-reported information across different research centers further contributes to this variability, potentially impacting the reliability and comparability of genetic findings.
Unexplained Heritability and Complex Interactions
A substantial challenge in understanding the genetics of complex conditions like exercise-induced anaphylaxis is the phenomenon of "missing heritability," where common genetic variants identified by genome-wide association studies (GWAS) explain only a fraction of the estimated heritability. [15] This suggests that the genetic landscape of such traits is more intricate than current methods fully capture, implying a larger role for rare genetic variants, epistatic interactions between genes, or epigenetic modifications that are typically not well-powered or adequately assessed in standard GWAS designs. [4] Consequently, while identified common variants offer initial insights, they may not fully account for an individual's susceptibility or provide comprehensive predictive power for the trait.
The manifestation of complex traits, including exercise-induced anaphylaxis, is rarely determined by genetics alone but often results from intricate interplay with various environmental factors. Although studies typically endeavor to identify and control for known clinical risk factors, comprehensively capturing and modeling the full spectrum of environmental or lifestyle confounders, and their interactions with genetic predispositions, remains exceptionally difficult. [14] Unaccounted gene-environment interactions can either mask true genetic associations or lead to spurious findings, thereby limiting the accuracy and utility of genetic risk prediction models. A complete understanding requires integrating diverse data sources to elucidate how genetic susceptibility to exercise-induced anaphylaxis is modulated by external influences and individual exposures.
Variants
HLA-DPB2 is a gene located within the Major Histocompatibility Complex (MHC) region on chromosome 6, a critical area of the human genome known for its fundamental role in immune system function. While HLA-DPB2 is often classified as a pseudogene, meaning it may not produce a functional protein, variants within it can still be highly relevant due to its close proximity to other active HLA genes. The MHC region, encompassing both Class I and Class II HLA genes, is essential for presenting fragments of proteins, known as antigens, to T-cells, thereby initiating immune responses. [6] This complex process is vital for the immune system to distinguish between the body's own cells and foreign invaders, and variations in these genes can significantly impact an individual's susceptibility to various immune-mediated conditions. [8]
The single nucleotide polymorphism (SNP) rs9277630 is situated within the HLA-DPB2 gene. Although rs9277630 may not directly alter a protein-coding sequence, its presence can influence gene activity through several mechanisms, such as affecting regulatory elements that control the expression of nearby functional HLA genes. Alternatively, rs9277630 might be in strong linkage disequilibrium with other functional variants within the highly polymorphic MHC region, effectively "tagging" these causal variations. Such subtle genetic modifications can alter the efficiency or specificity of antigen presentation, leading to modified T-cell responses. The intricate nature of the MHC region, characterized by its numerous variable sites and complex patterns of linkage disequilibrium, often makes it challenging to pinpoint the exact causal variants directly responsible for a disease. [6] Nevertheless, genome-wide association studies consistently highlight the MHC region as a critical hotspot for genetic associations with a wide array of immune-related diseases and drug hypersensitivities. [2]
Variations like rs9277630 in the HLA-DPB2 gene, or other functional variants it may tag, can contribute to an individual's predisposition to hypersensitivity reactions, including exercise-induced anaphylaxis. This severe, potentially life-threatening allergic reaction is triggered by physical activity, sometimes in combination with specific cofactors like certain foods or medications. An altered immune recognition profile, potentially influenced by HLA variants, could lead the immune system to mistakenly identify otherwise harmless exercise-related molecules or cofactors as threats, thereby provoking an exaggerated and systemic immune response. The complementary roles of Class I and Class II HLA gene products in orchestrating T-cell responses highlight how complex interactions between different HLA alleles can collectively drive these sophisticated immune outcomes. [6] Gaining a deeper understanding of these genetic influences is crucial for unraveling the underlying biological mechanisms of such severe immune reactions and potentially identifying individuals at higher risk. [12]
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs9277630 | HLA-DPB2 | exercise induced anaphylaxis |
Physiological Responses to Exercise
Regular physical activity induces a range of physiological adaptations across various organ systems, which are crucial for maintaining homeostasis and enhancing performance. At the molecular level, exercise can activate specific signaling pathways, such as the mitogen-activated protein kinase (MAPK) pathway in skeletal muscle, influencing cellular functions and metabolic processes. [5] Key biomolecules like the AMPK enzyme play a central role in controlling exercise endurance, mitochondrial oxidative capacity, and maintaining skeletal muscle integrity. [16] These adaptations contribute to improvements in cardiovascular function, muscle efficiency, and overall metabolic health, though adverse metabolic responses to regular exercise can also occur. [10]
Exercise profoundly impacts cardiac and vascular biology. For instance, calcium trafficking during cardiac muscle excitation-contraction coupling relies on the ryanodine receptor, which can influence heart rate responses to exercise. [5] Vascular smooth muscle cells are also responsive to signaling molecules like Angiotensin II, which can increase the expression of phosphodiesterase 5A, thereby antagonizing cGMP signaling. [17] Furthermore, intense exercise, such as a mountain marathon, has been linked to inflammation and atrial remodeling, indicating broader systemic consequences. [18]
Genetic Modulators of Exercise Adaptation
Genetic mechanisms play a significant role in individual variations in physiological responses and adaptations to exercise. Polymorphisms in genes like RYR2 (ryanodine receptor 2) are consistently associated with exercise heart rate responses, reflecting the gene's fundamental role in cardiac calcium handling. [5] Similarly, variants in PRKAG2, an enzyme that modulates glucose uptake and glycolysis, have been linked to heart rate during the post-exercise recovery period and are associated with conditions like ventricular hypertrophy. [5] Other genetic factors, such as the ACE (angiotensin-converting enzyme) I/D polymorphism, can influence cardiovascular hemodynamics during exercise. [19]
Genetic studies have also identified associations between CHRM2 (acetylcholine receptor M2) gene polymorphism and heart rate recovery after maximal exercise, highlighting the genetic influence on autonomic nervous system responses to physical exertion. [20] Beyond cardiovascular traits, integrative pathway analyses have explored genome-wide associations with VO2max response to exercise training, indicating a complex genetic architecture underlying aerobic capacity. [21] Molecular networks involved in human muscle adaptation to exercise also exhibit genetic influences, demonstrating the intricate regulatory networks governing tissue-level responses. [22]
Molecular and Cellular Foundations of Immune Reactivity
The immune system's reactivity involves complex molecular and cellular pathways that can lead to inflammatory and hypersensitivity responses. For instance, the activation of NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) through G(q)-dependent pathways stimulates proinflammatory gene expression in lung epithelial cells. [23] Similarly, reduced levels of CEBP (CCAAT/enhancer-binding protein) can stimulate cell proliferation and the release of proinflammatory cytokines, contributing to inflammation. [11] These pathways are critical in mediating cellular functions during immune challenges.
Antigen processing and presentation are fundamental cellular functions in adaptive immunity, involving various proteins that bind and transport molecules to initiate immune responses. [11] B-lymphocytes play a role in metabolism related to immune responses, influencing the production of immunoglobulins such as IgE and IgG. [24] Disruptions in homeostatic processes, such as those caused by certain drug exposures, can trigger adverse immune reactions like acute urticaria/angioedema, involving complex signaling and regulatory networks within immune cells. [25]
Genetic Predisposition to Allergic and Inflammatory Conditions
Genetic mechanisms significantly influence an individual's susceptibility to allergic and inflammatory diseases. Genome-wide association studies have identified specific genetic variants associated with chemically induced asthma, such as a novel locus on chromosome 10q21 encompassing the CTNNA3 (alpha-T-catenin) gene. [24] Other studies have revealed associations of diisocyanate-induced occupational asthma with variants in genes involved in antigen processing and adaptive immunity, including specific CDH17, HERC2, and ODZ3 genes, which are involved in antigen presentation and immune response pathways. [11]
The HLA (human leukocyte antigen) region, a critical component of the major histocompatibility complex, harbors genetic variants strongly associated with various immune-mediated diseases, including type 1 diabetes, highlighting its broad impact on immune regulation. [1] Genetic variations in HLA class I and class II genes are also associated with diisocyanate-induced asthma, suggesting a role for inherited immune response differences in susceptibility. [26] Furthermore, genetic variants in antioxidant genes have been linked to diisocyanate-induced asthma, indicating that oxidative stress response pathways may also play a role in predisposition to certain allergic conditions. [27]
Neuro-Immune Signaling and Inflammatory Responses
Exercise can profoundly influence neuro-immune signaling pathways, which, when dysregulated, may contribute to exercise-induced anaphylaxis. Physical exertion can trigger systemic inflammation, as observed in studies following events like a mountain marathon. [18] Key signaling cascades involved include the activation of the MAPK pathway, which is responsive to acute exercise in human skeletal muscle. [5] Furthermore, the tachykinin-1 receptor plays a role in stimulating proinflammatory gene expression in lung epithelial cells through activation of NF-kappaB via a G(q)-dependent pathway [23] indicating a direct link between receptor signaling and inflammatory mediators relevant to allergic responses. Angiotensin II can also modulate vascular smooth muscle cell function by increasing phosphodiesterase 5A expression, thereby antagonizing cGMP signaling [17] which points to complex feedback loops impacting vascular tone and permeability, critical factors in anaphylaxis.
The body's innate immune responses can also be activated or sensitized by specific exposures, which might then be exacerbated by exercise. Studies on human innate immune responses to sensitizers like hexamethylene diisocyanate have identified mechanisms that could be relevant to how the immune system reacts to exercise-induced triggers . [11], [28] These responses often involve receptor activation on immune cells, leading to intracellular signaling cascades that prime the immune system for a heightened reaction. The intricate interplay of these pathways, from initial receptor binding to the downstream transcriptional regulation of inflammatory genes, dictates the severity and manifestation of an allergic or anaphylactic response during physical activity.
Metabolic Remodeling and Energy Homeostasis
Exercise initiates significant metabolic remodeling to support energy demands, and dysregulation in these pathways can contribute to adverse responses. Regular exercise impacts energy metabolism, particularly mitochondrial oxidation and phosphorylation, which are crucial for cellular ATP production . [29], [30] Defects in these mitochondrial processes are associated with conditions like insulin resistance and type 2 diabetes [29], [30] highlighting the metabolic vulnerability that exercise might expose. While exercise generally improves insulin sensitivity and increases intramyocellular lipid (IMCL) content, enhancing lipid flux and mitochondrial contact [29] an adverse metabolic response can occur in some individuals. [10]
The AMPK pathway is a central regulator of energy homeostasis, controlling exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity. [16] This enzyme system modulates glucose uptake and glycolysis, and mutations in its subunit PRKAG2 are associated with glycogen-filled vacuoles in cardiomyocytes and cardiac hypertrophy. [5] Such metabolic dysregulation can affect cellular resilience and contribute to the physiological stress that, in susceptible individuals, might lower the threshold for anaphylactic reactions. Understanding how exercise-induced metabolic shifts interact with pre-existing metabolic vulnerabilities is crucial for elucidating the mechanisms of exercise-induced anaphylaxis.
Genetic Regulation and Molecular Adaptation
The molecular adaptation to exercise is under tight genetic and epigenetic control, influencing individual susceptibility to adverse events. Integrated omics profiling, encompassing genomics, epigenomics, transcriptomics, metabolomics, and proteomics, is employed to identify genes and DNA variants that predict responses to regular exercise. [29] These approaches reveal the complex regulatory mechanisms, including gene regulation and post-translational modifications, that govern cellular functions during and after physical activity. For instance, transcription factor sequence specificity is a critical aspect of gene regulation, determining which genes are activated or repressed in response to exercise-induced signals. [31]
Protein modification, such as ubiquitination, also plays a significant regulatory role. HERC2, for example, coordinates the ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes [32] illustrating how protein modifications are essential for maintaining cellular integrity during physiological stress. These molecular networks of human muscle adaptation to exercise and age demonstrate the intricate regulatory control over cellular processes. [22] Genetic polymorphisms in various genes, like those affecting the beta1-adrenoceptor or CHRM2, can alter cardiovascular responses to exercise, including heart rate recovery [20], [33] further highlighting the genetic predisposition influencing physiological adaptations.
Pathway Crosstalk and Disease Susceptibility
Exercise-induced anaphylaxis involves complex pathway crosstalk and network interactions that integrate various physiological systems, leading to emergent disease properties. Integrative pathway analysis of genome-wide association studies is used to interpret the comprehensive response to exercise training [21], [34] revealing how multiple pathways converge to influence physiological outcomes. Genetic variations can significantly impact these integrated responses, as seen with RYR2 gene polymorphisms, which are associated with exercise heart rate responses and implicated in exercise-induced polymorphic ventricular tachyarrhythmias. [5] These examples illustrate how specific genetic predispositions can dysregulate cardiac electrical stability during exertion.
The susceptibility to exercise-induced adverse events often arises from a combination of genetic factors and environmental triggers, leading to pathway dysregulation. For instance, specific genetic loci have been associated with conditions like diisocyanate-induced occupational asthma [11], [24] or NSAID-induced acute urticaria/angioedema [25] where chemical exposure triggers an immune response that could be exacerbated by exercise. These conditions demonstrate how a genetic background, interacting with external stimuli, can lead to hypersensitivity reactions. The collective integration of signaling, metabolic, and regulatory pathways determines an individual's overall resilience and susceptibility to the unique stressors posed by physical activity, ultimately defining the risk for exercise-induced anaphylaxis.
Frequently Asked Questions About Exercise Induced Anaphylaxis
These questions address the most important and specific aspects of exercise induced anaphylaxis based on current genetic research.
1. My sibling has EIA; does that mean I'm at risk too?
Yes, genetic factors are known to play a role in conditions like exercise-induced anaphylaxis. If a close family member has it, you might have a higher genetic susceptibility, though it's complex and not a simple inheritance pattern. Your unique genetic makeup can influence your body's specific immune responses.
2. Why can my friend eat before exercise, but I get hives?
Your body's unique genetic makeup influences how your immune system responds to exercise and co-factors. Some people are genetically predisposed to hypersensitivity reactions, while others are not. This individual genetic variation helps explain why reactions differ so much between people.
3. Could a DNA test tell me if I'm likely to get EIA?
Research into the genetic factors behind conditions like EIA aims to improve risk prediction. While current tests might not offer a definitive answer for EIA specifically, understanding genetic underpinnings is a key area for future personalized medicine and better diagnostic tools.
4. Is my EIA just bad luck, or am I genetically prone?
Genetic factors are increasingly recognized to play a role in an individual's susceptibility to immune-mediated conditions. While environmental triggers are important, your genes can make you more predisposed to developing EIA. It's often a combination of your genetic profile and specific triggers.
5. Does my family's background affect my EIA risk?
Yes, genetic ancestry and population-specific genetic variants can influence susceptibility to various conditions, including immune responses. Researchers carefully consider these factors, like intra-ethnic population structures, to understand how they might impact your risk and the prevalence of conditions like EIA.
6. Will knowing my genes help doctors treat my EIA better?
Absolutely. Research into genetic underpinnings is crucial for personalized medicine, aiming to optimize treatment strategies. Understanding your specific genetic profile could lead to more targeted and effective management of your EIA, potentially improving drug responses and immune reactions.
7. Can genetics help prevent my kids from getting EIA?
A deeper understanding of genetic factors could pave the way for improved diagnostic tools and targeted prevention strategies. This research aims to empower affected individuals and potentially reduce risk for future generations, enhancing their ability to engage safely in physical activity.
8. I always feel sick after exercise; could my genes be why?
Genetic factors influence an individual's susceptibility to various physiological responses to exercise and immune-mediated conditions. Your unique genetic makeup might contribute to your body's specific reactions, including hypersensitivity or other unusual symptoms after physical activity.
9. If I have genetic risk, can I still exercise safely?
Yes, even with a genetic predisposition, avoiding identified triggers and carrying self-injectable epinephrine are critical management strategies. Understanding your genetic risk can help tailor prevention and allow safer participation in physical activity, improving your overall health and well-being.
10. Why do some people never get EIA even with triggers?
Individual genetic variation plays a significant role in susceptibility to immune reactions. Some individuals have genetic profiles that make them less prone to the systemic activation of immune cells, even when exposed to typical exercise and co-factor triggers, while others are more sensitive.
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] Chen, P. L. et al. "Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study." Nat Commun, vol. 6, 2015, p. 7613.
[2] Dai Y et al. Performance of genetic risk factors in prediction of trichloroethylene induced hypersensitivity syndrome. Sci Rep. 2015; PMID: 26190474.
[3] Goldstein, J. I. et al. "Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles." Nat Commun, vol. 5, 2014, p. 4707.
[4] Urban, T. J. et al. "Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs." Pharmacogenet Genomics, vol. 22, no. 12, 2012, pp. 870-9.
[5] Vasan RS, et al. "Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study." BMC Med Genet, 2007.
[6] Lucena MI et al. Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology. 2011; PMID: 21570397.
[7] De Moor, M. H. et al. "Genome-wide association study of exercise behavior in Dutch and American adults." Med Sci Sports Exerc, vol. 41, no. 12, 2009, pp. 2186-92.
[8] Genin E et al. Genome-wide association study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Europe. Orphanet J Rare Dis. 2011; PMID: 21801394.
[9] Heap, G. A. et al. "HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants." Nat Genet, vol. 46, no. 10, 2014, pp. 1131-5.
[10] Sarzynski MA, et al. "Adverse metabolic response to regular exercise: is it a rare or common occurrence?" PLoS ONE, 2012.
[11] Yucesoy B, et al. "Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma." Toxicol Sci, 2015.
[12] Parham LR et al. Comprehensive genome-wide evaluation of lapatinib-induced liver injury yields a single genetic signal centered on known risk allele HLA-DRB1*07:01. Pharmacogenomics J. 2015; PMID: 25987243.
[13] Marciante, K. D., et al. "Cerivastatin, genetic variants, and the risk of rhabdomyolysis." Pharmacogenet Genomics, 2011. PMID: 21386754.
[14] Aminkeng, F., et al. "A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer." Nat Genet, vol. 47, no. 9, 2015, pp. 1079–84.
[15] Eichler, E. E., et al. "Missing heritability and strategies for finding the underlying causes of complex disease." Nat Rev Genet, vol. 11, 2010, pp. 446–50.
[16] Lantier L, et al. "AMPK controls exercise endurance, mitochondrial oxidative capacity, and skeletal muscle integrity." FASEB J, 2014.
[17] Kim D, et al. "Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling." J Mol Cell Cardiol, 2005.
[18] Wilhelm M, et al. "Inflammation and atrial remodeling after a mountain marathon." Scand J Med Sci Sports, 2012.
[19] Celentano, A., et al. "Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension." Am J Cardiol, vol. 83, 1999, pp. 1196-1200.
[20] Hautala AJ, et al. "Heart rate recovery after maximal exercise is associated with acetylcholine receptor M2 (CHRM2) gene polymorphism." Am J Physiol Heart Circ Physiol, 2006.
[21] Ghosh S, et al. "Integrative pathway analysis of a genome-wide association study of (V)O(2max) response to exercise training." J Appl Physiol (1985), 2013.
[22] Phillips BE, et al. "Molecular networks of human muscle adaptation to exercise and age." PLoS Genet., 2013.
[23] Williams, R., et al. "Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-kappaB via a G(q)-dependent pathway." Am. J. Physiol. Lung Cell. Mol. Physiol., vol. 292, 2007.
[24] Kim SH, et al. "Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis." Clin Exp Allergy, 2009.
[25] Cornejo-Garcia JA, et al. "Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations." Pharmacogenomics, 2013.
[26] Yucesoy, B., et al. "Genetic variants in the major histocompatibility complex class i and class ii genes are associated with diisocyanate-induced asthma." J. Occup. Environ. Med., vol. 56, 2014, pp. 382–387.
[27] Yucesoy, B., et al. "Genetic variants in antioxidant genes are associated with diisocyanate-induced asthma." Toxicol Sci, vol. 129, 2012, pp. 166–173.
[28] Wisnewski, A.V., et al. "Human innate immune responses to hexamethylene diisocyanate (HDI) and HDI-albumin conjugates." Clin. Exp. Allergy, 2008.
[29] Sarzynski MA, et al. "Genomic and transcriptomic predictors of triglyceride response to regular exercise." Br J Sports Med, 2016.
[30] Mootha VK, et al. "PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes." Nat Genet, 2003.
[31] Weirauch, M. T., et al. "Determination and inference of eukaryotic transcription factor sequence specificity." Cell, 2014.
[32] Bekker-Jensen, S., et al. "HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes." Nat. Cell. Biol., 2010.
[33] Defoor J, et al. "The CAREGENE study: polymorphisms of the beta1-adrenoceptor gene and aerobic power in coronary artery disease." Eur Heart J, 2006.
[34] Subramanian A, et al. "Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles." Proc Natl Acad Sci U S A., 2005.