Maximal Oxygen Uptake

Maximal oxygen uptake, often referred to as VO2 max, is a fundamental physiological measure representing the maximum rate at which the body can consume oxygen during intense, incremental exercise. It serves as a key indicator of an individual’s aerobic capacity and cardiorespiratory fitness. This complex physiological trait integrates the efficiency of several bodily systems to deliver and utilize oxygen for energy production.

Biological Basis

The ability to achieve a high maximal oxygen uptake relies on the coordinated function of the respiratory, cardiovascular, and muscular systems. The lungs must efficiently take in oxygen, the heart must pump oxygenated blood effectively throughout the body, and the muscles must extract and utilize this oxygen efficiently in their mitochondria to generate adenosine triphosphate (ATP) for sustained activity. Genetic factors are known to influence various components of exercise performance and cardiorespiratory fitness. Studies have shown that exercise treadmill test (ETT) measures, which are related to oxygen uptake, exhibit heritability, with estimates varying for different phenotypes such as post-exercise recovery heart rate (41%) and exercise systolic blood pressure (28%).^[1]Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with ETT traits.^[1]While specific genes directly impacting maximal oxygen uptake are numerous and complex, these genetic variations contribute to the individual differences observed in aerobic capacity.

Clinical Relevance

Clinically, maximal oxygen uptake is a powerful predictor of overall health and disease risk. It is widely recognized as a strong indicator of cardiovascular health and is inversely associated with all-cause mortality. Healthcare professionals utilize VO2 max assessments to:

• Evaluate the functional capacity of individuals, particularly those with chronic conditions such as heart failure, chronic obstructive pulmonary disease (COPD), and metabolic syndrome.
• Monitor the effectiveness of rehabilitation programs and exercise interventions.
• Guide the prescription of appropriate exercise intensities and volumes for patients and healthy individuals.
• Identify individuals at higher risk for cardiovascular events.

Social Importance

The social importance of maximal oxygen uptake extends beyond individual clinical assessments. It plays a significant role in public health initiatives aimed at promoting physical activity and combating sedentary lifestyles. Understanding and improving VO2 max can lead to:

• Enhanced athletic performance and training optimization in sports science.
• Improved quality of life and functional independence, especially in aging populations.
• Reduced burden of chronic diseases on healthcare systems.
• Insights into population-level health trends and disparities related to physical fitness. The genetic underpinnings of maximal oxygen uptake further contribute to personalized health strategies, potentially allowing for tailored exercise recommendations based on an individual’s genetic predisposition.

Methodological and Statistical Constraints

Research into complex physiological traits like maximal oxygen uptake faces inherent methodological and statistical challenges. Studies with relatively small sample sizes increase the likelihood of false negative findings, or Type II errors, potentially missing genetic associations of smaller magnitude . Alterations in these regulatory elements can modify the expression levels of genes involved in cardiovascular function, muscle energy metabolism, or mitochondrial efficiency, thereby impacting the body’s ability to deliver and utilize oxygen during intense physical activity, which directly relates to maximal oxygen uptake.^[2] Other variants affect genes with roles in cellular structure and fundamental transport processes. For instance, *rs10497529 * and *rs142556838 * in _CCDC141_ are located within a gene that codes for a coiled-coil domain-containing protein, often involved in protein-protein interactions and cellular scaffolding.^[2]Such proteins are vital for maintaining the integrity and function of muscle fibers, and variations could influence muscle contraction efficiency or resistance to fatigue, factors critical for sustained exercise performance. Similarly,*rs78291913 * in _NUP93_, a gene encoding a component of the nuclear pore complex, may impact the transport of molecules between the cell nucleus and cytoplasm.^[2]Efficient nuclear transport is essential for cellular adaptation and repair, processes that are highly active in tissues undergoing the physiological stress of exercise, and thus indirectly affecting maximal oxygen uptake.

Variants in genes with more direct physiological impacts on organ systems also contribute to individual differences in maximal oxygen uptake. The_SCN10A_ gene, with variants like *rs6801957 * and *rs9809798 *, encodes a voltage-gated sodium channel important for electrical signaling in excitable cells, including those in the heart.^[2] Variations here can affect cardiac rhythm and contractility, directly influencing the heart’s ability to pump oxygenated blood to working muscles. Additionally, *rs11190709 * and *rs1006545 * in _PAX2_, a transcription factor essential for kidney development, could indirectly impact maximal oxygen uptake.^[2]Healthy kidney function is crucial for maintaining fluid and electrolyte balance and red blood cell production, both of which are vital for optimal oxygen transport and overall exercise capacity.

Finally, several pseudogene variants, such as *rs58730006 * associated with _RPL23AP48_ and _HMGB3P18_, and *rs527325496 * linked to _DND1P1_ and _MAPK8IP1P2_, may also have subtle regulatory effects. While pseudogenes are typically non-functional copies of genes, they can sometimes influence the expression of their functional counterparts or act as competing endogenous RNAs, thereby modulating gene regulation.^[2]Such regulatory impacts could affect pathways related to protein synthesis, stress response, or metabolic regulation, which are fundamental for muscle adaptation and energy production during exercise. These indirect genetic influences can collectively shape an individual’s physiological response to physical exertion and their maximal oxygen uptake potential.^[2]

Historical Context and Clinical Significance of Respiratory Function

The scientific understanding of respiratory function, a fundamental component influencing overall oxygen uptake, has evolved significantly, particularly with the development of standardized techniques. Early in the 20th century, the importance of pulmonary function testing emerged, with methodologies like spirometry becoming crucial for assessing lung health.^[3]These measurements, such as forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), were recognized not merely as indicators of lung capacity but also as powerful predictors of long-term health outcomes. Landmark studies have consistently demonstrated that diminished ventilatory function is a significant marker of premature death from all causes, underscoring its profound clinical significance.^[4] This realization established respiratory function as a critical physiological parameter, warranting comprehensive epidemiological investigation.

Global Prevalence and Demographic Influences on Lung Health

Epidemiological studies have illuminated the global burden of impaired lung function, particularly chronic obstructive pulmonary disease (COPD), which represents a major worldwide health challenge with significant mortality and morbidity projections.^[5] Global initiatives have been established to standardize the diagnosis, management, and prevention of COPD, highlighting its widespread impact across diverse populations.^[6] Demographic factors such as age, sex, and ancestry significantly influence lung function prevalence and decline, with studies examining these patterns in various cohorts, including lifelong non-smokers to understand baseline physiological variations.^[7] Socioeconomic factors also play a role, influencing exposure to environmental risks and access to healthcare, thereby contributing to observed disparities in respiratory health outcomes.

Evolving Epidemiological Trends and Genetic Discoveries in Pulmonary Function

Recent decades have seen a deepening understanding of the complex interplay of genetic and environmental factors in shaping lung function, with significant shifts in epidemiological approaches. While secular trends and cohort effects continue to influence population-level respiratory health, large-scale genome-wide association studies (GWAS) have revolutionized the identification of genetic variants contributing to pulmonary function variability.^[8] These studies have pinpointed multiple genetic loci associated with measures like FEV1 and FVC, including specific genes such as CHRNA5/3 and HTR4 linked to airflow obstruction, revealing novel pathways that influence lung health.^[9]The ongoing exploration of these genetic insights, combined with continuous monitoring of environmental and lifestyle factors, is crucial for future projections and targeted interventions aimed at improving global respiratory health.

Biological Background of Maximal Oxygen Uptake

Maximal oxygen uptake, often referred to as VO2 max, represents the highest rate at which the body can consume and utilize oxygen during intense exercise. This physiological capacity is a crucial indicator of cardiorespiratory fitness and is influenced by a complex interplay of respiratory, cardiovascular, and muscular systems. Efficient oxygen transport from the atmosphere to the working muscles is paramount, involving robust pulmonary function for gas exchange, an effective circulatory system for oxygen delivery, and mitochondrial capacity within cells for oxidative phosphorylation. The biological underpinnings of this trait extend from the molecular machinery within individual cells to the integrated functions of entire organ systems, shaped by both genetic predispositions and environmental factors.

Pulmonary Mechanics and Gas Exchange Efficiency

The lungs serve as the primary interface for oxygen uptake, with their mechanical properties and the efficiency of gas exchange being critical determinants of overall oxygen availability. Pulmonary function measures, such as forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), quantify the mechanical aspects of breathing, reflecting the volume and speed of air movement in and out of the lungs.^[3]These measures are essential for assessing lung health and detecting conditions that impair ventilation, which subsequently limits the amount of oxygen that can be transferred to the bloodstream. The intricate structure of the alveoli, where gas exchange occurs, relies on a vast surface area and a thin barrier between air and blood, facilitating rapid diffusion of oxygen into the pulmonary capillaries. Any disruption to this delicate balance, whether structural or functional, directly impacts the body’s ability to extract oxygen from inhaled air, thereby compromising maximal oxygen uptake capacity.

Molecular and Cellular Regulation of Lung Integrity

At a molecular level, the maintenance of lung structure and function involves numerous proteins, enzymes, and regulatory networks within pulmonary cells. Key biomolecules play roles in tissue repair, immune response, and the structural integrity of the airways and alveoli. For instance, the SERPINE2gene, which encodes for a serine protease inhibitor, has been associated with chronic obstructive pulmonary disease (COPD), indicating its involvement in proteolytic balance and tissue remodeling within the lung.^[10] Similarly, Secreted modular calcium-binding protein 2 (SMC2) haplotypes have been linked to variations in pulmonary function, suggesting a role for calcium-binding proteins in cellular signaling and structural organization within the respiratory system.^[11] These molecular components influence cellular functions such as epithelial cell maintenance, extracellular matrix turnover, and inflammatory responses, all of which are crucial for preserving the delicate architecture necessary for optimal gas exchange and, consequently, efficient oxygen uptake.

Genetic Architecture of Respiratory Capacity

Genetic mechanisms significantly influence an individual’s respiratory capacity and susceptibility to lung diseases, thereby impacting maximal oxygen uptake. Genome-wide association studies (GWAS) have identified multiple genetic loci associated with pulmonary function measures like FEV1 and FVC, highlighting the polygenic nature of these traits.^[8] These studies reveal specific gene functions and regulatory elements that modulate lung development, structure, and physiological performance. For example, genetic variations on chromosome 6q27 have shown linkage and association with pulmonary function measures, suggesting that genes in this region contribute to the regulation of lung capacity.^[12]Such genetic predispositions can dictate the baseline lung function and influence how individuals respond to environmental challenges, ultimately contributing to the wide variability observed in maximal oxygen uptake across the population.

Pathophysiological Processes Affecting Oxygen Uptake

Pathophysiological processes, including both acute and chronic conditions, can profoundly disrupt lung function and impede maximal oxygen uptake. Chronic obstructive pulmonary disease (COPD), characterized by persistent airflow limitation, serves as a prime example where homeostatic disruptions lead to progressive deterioration of respiratory capacity.^[6] Conditions like alpha1-antitrypsin deficiency, a genetic disorder, predispose individuals to early-onset emphysema, where the destruction of alveolar walls significantly reduces the surface area available for gas exchange.^[10]These disease mechanisms impair the structural integrity and elastic recoil of the lungs, increasing airway resistance and reducing the efficiency of oxygen transfer to the blood. Such impairments result in systemic consequences, including reduced oxygen availability for cellular metabolism, particularly during periods of high demand, thereby directly limiting an individual’s maximal oxygen uptake.

Integrated Metabolic Pathways for Energy Substrate Provision

Glucose serves as the primary energy substrate in humans, with its availability tightly regulated through a balance of absorption from the gut, hepatic production, and utilization by various tissues, including both insulin-sensitive and insulin-insensitive cells.^[13]This intricate metabolic equilibrium is crucial for sustaining cellular functions and providing the necessary fuel for physiological demands. Beyond glucose, lipid concentrations also play a vital role in energy metabolism, serving as a significant fuel reserve and contributing to overall energy homeostasis.^[14]The interplay between these major metabolic pathways ensures a continuous supply of ATP, which is fundamental for processes requiring high energy flux.

Humoral and Neural Signaling in Metabolic Control

The homeostatic control of glucose levels is orchestrated by complex interactions between humoral and neural mechanisms.^[13]Humoral signaling involves hormones like insulin and glucagon, which act via receptor activation on target cells to trigger intracellular signaling cascades that modulate glucose uptake, production, and storage. Concurrently, neural pathways, through direct innervation and neurotransmitter release, provide rapid feedback and feedforward regulation to fine-tune metabolic responses. These integrated signaling networks ensure dynamic adjustments in metabolic flux, allowing the body to adapt to varying energy demands and nutrient availability.

Genetic Regulatory Mechanisms of Fuel Homeostasis

Genetic variations play a significant role in shaping an individual’s metabolic profile and, consequently, their capacity for energy provision. For instance, specific genomic regions, such as those encompassing G6PC2 and ABCB11, have been identified as being associated with fasting glucose levels, influencing the baseline availability of this critical energy substrate.^[13] Similarly, other genetic loci have been found to influence lipid concentrations, thereby impacting the body’s ability to store and mobilize fat for energy.^[14] These genetic predispositions highlight how gene regulation can subtly or profoundly alter metabolic flux, affecting the efficiency and capacity of energy systems.

Systemic Integration and Potential Dysregulation

Dysregulation within these intricate metabolic pathways can lead to significant physiological consequences, potentially impacting overall energy capacity. Imbalances in glucose homeostasis, whether due to impaired insulin signaling or altered hepatic glucose production, can compromise the efficient supply of energy to tissues.^[13] Likewise, aberrant lipid metabolism, influenced by various genetic loci, can contribute to systemic metabolic dysfunction.^[14] Understanding these pathway dysregulations and identifying compensatory mechanisms or therapeutic targets is crucial for maintaining robust metabolic health, which underpins the body’s ability to perform energy-demanding functions.

Clinical Relevance

The assessment of cardiorespiratory function provides critical insights into an individual’s physiological capacity and overall health. While direct maximal oxygen uptake testing is a comprehensive measure, the clinical relevance of its constituent physiological systems, such as pulmonary and cardiac function, is extensively documented. Evaluations of lung mechanics and cardiac performance serve as foundational indicators for diagnostic, prognostic, and therapeutic decision-making in patient care.

Prognostic and Diagnostic Significance of Cardiopulmonary Function

Measurements of lung function, including forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), are robust indicators of respiratory health with significant prognostic value. These measures are not merely diagnostic tools for conditions like chronic obstructive pulmonary disease (COPD) but also serve as long-term predictors of mortality from all causes, even among lifelong non-smokers.^[15]Declines in pulmonary function have been consistently associated with an increased risk of premature death, underscoring their utility in identifying individuals at higher risk for adverse health outcomes and monitoring disease progression.^[4] This diagnostic and prognostic utility is crucial for early risk assessment and can inform personalized prevention strategies.

Beyond pulmonary assessments, the evaluation of cardiac structure and function provides complementary insights into overall physiological resilience. Echocardiographic traits, such as left ventricular (LV) mass, LV diastolic internal dimension, LV wall thickness, aortic root size, left atrial size, and indicators of LV systolic dysfunction (e.g., ejection fraction <50%), are important markers of cardiovascular health.^[16]Genetic variants associated with these cardiac parameters highlight their heritable nature and their role in determining cardiovascular risk.^[16] Diastolic heart function, a key aspect of cardiac performance, is also influenced by both genetic and environmental determinants, further emphasizing the multifactorial basis of cardiorespiratory health and its implications for patient outcomes.^[17]

Clinical Applications in Personalized Cardiopulmonary Care

Detailed assessment of pulmonary function facilitates personalized medicine approaches, enabling clinicians to tailor treatment selection and monitoring strategies for patients at risk or with established respiratory conditions. For instance, understanding the genetic determinants of lung function, identified through genome-wide association studies (GWAS) for FEV1 and FVC, can potentially refine risk stratification beyond conventional spirometry.^[15]This genetic insight, combined with spirometric measures, aids in identifying high-risk individuals for conditions like COPD and in guiding interventions, including the diagnosis, management, and prevention strategies advocated by global initiatives.^[18]Continuous monitoring of lung function changes over time is essential for assessing treatment response and adjusting therapeutic regimens to optimize patient care and prevent disease progression.

Similarly, understanding the genetic and structural aspects of cardiac function is pivotal for integrated cardiopulmonary care. Identifying individuals with genetic predispositions to altered cardiac structure or function, such as variants influencing LV mass or diastolic function, enables earlier risk assessment and potentially more targeted prevention strategies.^[16]This personalized approach can inform the selection of appropriate pharmacological or lifestyle interventions, as well as guide ongoing monitoring to detect early signs of cardiac dysfunction. The comprehensive integration of pulmonary and cardiac assessments offers a holistic view of a patient’s physiological capacity, supporting more effective and individualized management plans.

Associations with Comorbidities and Systemic Health

Cardiopulmonary function is intricately linked with various comorbidities and systemic health conditions, highlighting overlapping phenotypes that impact overall patient well-being. Reduced lung function, for example, is associated with a range of conditions beyond direct respiratory disease and serves as a broader marker of general health and functional capacity.^[19]The presence of conditions like obstructive sleep apnea (OSA) can further complicate cardiopulmonary health, with genetic loci such asRAI1 potentially influencing OSA susceptibility in specific populations.^[20] These interconnections emphasize the importance of a holistic clinical perspective, recognizing that impairments in one component of the cardiorespiratory system can have cascading effects on other physiological systems and overall health outcomes.

Genetic studies further illuminate these associations, identifying shared genetic variants that influence both pulmonary and cardiac traits. For instance, some genetic loci are implicated in airflow obstruction, a hallmark of many respiratory diseases, while others are linked to specific cardiac structural and functional parameters.^[9] This genetic overlap suggests common underlying biological pathways that contribute to various cardiopulmonary disorders and can inform comprehensive risk assessment for complex presentations. Understanding these complex associations is crucial for developing integrated prevention and management strategies that address the multifaceted nature of cardiorespiratory health and its impact on broader systemic conditions.

Key Variants

RS ID	Gene	Related Traits
rs111299422	MGC32805 - LINC02201	maximal oxygen uptake heart rate response to exercise
rs10497529	CCDC141	heart rate response to exercise heart rate maximal oxygen uptake heart failure left ventricular mass index
rs6801957 rs9809798	SCN10A	QT interval P wave duration PR segment PR interval QRS duration
rs11190709 rs1006545	PAX2	heart rate response to exercise maximal oxygen uptake pulse pressure heart rate systolic blood pressure
rs269071	LINC02884	maximal oxygen uptake
rs78291913	NUP93	maximal oxygen uptake
rs17116985	LINC02248	maximal oxygen uptake
rs142556838	CCDC141	maximal oxygen uptake heart failure heart rate response to recovery post exercise heart rate response to exercise diastolic blood pressure
rs58730006	RPL23AP48 - HMGB3P18	maximal oxygen uptake aortic
rs527325496	DND1P1 - MAPK8IP1P2	maximal oxygen uptake

Frequently Asked Questions About Maximal Oxygen Uptake

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

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1. Why can my sibling run circles around me, even if we both exercise?

Your individual genetic makeup plays a significant role in your aerobic capacity. While consistent exercise is crucial for everyone, variations in genes that influence your heart’s pumping efficiency, lung function, and how your muscles use oxygen can mean some people naturally have a higher potential for fitness or respond differently to training. For example, some exercise-related traits, like recovery heart rate, have a heritability of around 41%.

2. Can I really get super fit even if my family isn’t athletic at all?

Absolutely, you can significantly improve your fitness regardless of your family’s athletic history. While genetics provide a foundation, exercise interventions are very effective in boosting your maximal oxygen uptake. Your lifestyle and training interact strongly with your genes, meaning consistent physical activity can overcome some genetic predispositions and lead to substantial improvements in your cardiorespiratory fitness.

3. Is it worth doing a DNA test to know my fitness potential?

A DNA test can offer insights into your genetic predispositions related to different aspects of fitness, such as how efficiently your heart and muscles might work. These insights can potentially help tailor exercise recommendations to your unique genetic profile. However, it’s important to remember that these are predispositions, not destiny, and regular training remains the most powerful tool for improving your fitness.

4. Why do some older people stay so much fitter than me?

While fitness generally declines with age, the rate and extent of this decline are influenced by genetic factors. Some individuals have genetic variations that contribute to more efficient cardiovascular function and muscle metabolism throughout their lives. These genetic differences, combined with consistent activity, help some older adults maintain higher levels of maximal oxygen uptake compared to others.

5. Can what I eat really affect how well my body uses oxygen during exercise?

Yes, definitely. Your diet is a key environmental factor that interacts with your genes. Specific dietary factors can modulate how your genetic variants influence metabolic processes within your muscles, affecting their ability to efficiently extract and utilize oxygen for energy production during physical activity.

6. Does my ethnic background affect my potential VO2 max?

It’s possible that your ethnic background could play a role. Many large-scale genetic studies on fitness traits have historically focused on individuals of European descent. This means that our understanding of how genetic variations related to maximal oxygen uptake might differ and influence potential across diverse ancestries is still growing.

7. Why do some people seem to get fit so much faster than me, even with the same workout?

Individual differences in how quickly your body adapts to exercise are influenced by your unique genetic variations. Genes affecting the efficiency of your heart, lungs, and muscles can dictate how rapidly you build aerobic capacity. This means some people are naturally “high responders” to training, while others may need more consistent effort to see similar gains.

8. Is my “lung capacity” something I’m just born with and can’t change much?

While genetics certainly influence the inherent structure and potential of your respiratory system, your “lung capacity” for exercise is highly trainable. Your maximal oxygen uptake isn’t just about lung size, but how efficiently your lungs take in oxygen and how effectively your heart and blood deliver it to your working muscles, all of which can be significantly improved with consistent training.

9. If my parents have heart problems, will my VO2 max be lower?

A family history of heart problems suggests you might have a genetic predisposition that could influence your cardiovascular health and, consequently, your maximal oxygen uptake. Genetic factors are known to affect components like exercise systolic blood pressure. However, regular physical activity is a powerful intervention that can significantly improve your heart health and aerobic capacity, even with a genetic predisposition.

10. Does where I live or my daily environment affect my fitness potential?

Yes, your environment and daily habits interact with your genetic predispositions to influence your fitness. Things like your access to safe places for activity, exposure to pollution, and overall lifestyle choices (e.g., sedentary vs. active) can modulate how your genes express themselves. This gene-environment interplay significantly impacts your body’s ability to develop and maintain its capacity to use oxygen.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

[1] Khurshid, Samia, et al. “Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass.”Nature Communications, vol. 14, no. 1, 2023, p. 1599.

[2] Vasan, R. S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, vol. 8, suppl. 1, 2007, p. S2.

[3] Crapo, R. O. “Pulmonary-function testing.” N Engl J Med, vol. 331, 1994, pp. 25-30.

[4] Young, R. P., et al. “Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes.”Eur Respir J, vol. 30, 2007, pp. 616-622.

[5] Lopez, A. D., et al. “Chronic obstructive pulmonary disease: current burden and future projections.”Eur Respir J, vol. 27, 2006, pp. 397-412.

[6] Pauwels, R. A., et al. “Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary.”Am J Respir Crit Care Med, vol. 163, 2001, pp. 1256-1276.

[7] Strachan, D. P. “Ventilatory function, height, and mortality among lifelong non-smokers.”J Epidemiol Community Health, vol. 46, 1992, pp. 66-70.

[8] Hancock, D. B., et al. “Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.” Nat Genet, vol. 42, 2010, pp. 45-52.

[9] Wilk, J. B., et al. “A genome-wide association study of pulmonary function measures in the Framingham Heart Study.” PLoS Genet, vol. 5, 2009, p. e1000429.

[10] Silverman, EK, and Sandhaus, RA. “Clinical practice. Alpha1-antitrypsin deficiency.” N Engl J Med, 2009.

[11] Wilk, J. B., et al. “Framingham Heart Study genome-wide association: results for pulmonary function measures.” BMC Med Genet, vol. 8 Suppl 1, 2007, p. S8.

[12] Wilk, JB et al. “Linkage and association with pulmonary function measures on chromosome 6q27 in the Framingham Heart Study.” Human molecular genetics, 2003.

[13] Chen, WM, et al. “Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels.”J Clin Invest, 2008.

[14] Willer, CJ, et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, 2008.

[15] Soler Artigas, M., et al. “Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.” Nat Genet, 2011, PMID: 21946350.

[16] Vasan, R. S., et al. “Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.” JAMA, vol. 302, 2009, pp. 168–178.

[17] Thanaj, M., et al. “Genetic and environmental determinants of diastolic heart function.” Nat Cardiovasc Res, 2022, PMID: 35479509.

[18] Rabe, K. F., et al. “Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.”Am J Respir Crit Care Med, vol. 176, 2007, pp. 532-555.

[19] Myint, P. K., et al. “Respiratory function and self-reported functional health: EPIC-Norfolk population study.” Eur Respir J, vol. 26, 2005, pp. 494-502.

[20] Chen, H., et al. “Multi-ethnic Meta-analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea Related Quantitative Trait Locus in Men.”Am J Respir Cell Mol Biol, 2017, PMID: 29077507.