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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Am J Med. 2021 Jul 31;134(12):1476–1482. doi: 10.1016/j.amjmed.2021.07.006

Air, Land and Sea: gene-environment interaction in chronic disease

Russell A Wilke 1, Eric A Larson 1
PMCID: PMC8922305  NIHMSID: NIHMS1731221  PMID: 34343516

Abstract

Each of us reflects a unique convergence of DNA and the environment. Over the past two decades, huge biobanks linked to electronic medical records have positioned the clinical and scientific communities to understand the complex genetic architecture underlying many common diseases. Although these efforts are producing increasingly accurate gene-based risk prediction algorithms for use in routine clinical care, the algorithms often fail to include environmental factors. This review explores the concept of heritability (genetic versus non-genetic determinants of disease), with emphasis on the role of environmental factors as risk determinants for common complex diseases influenced by air and water quality. Efforts to define patient exposure to specific toxicants in practice-based datasets will deepen our understanding of diseases with low heritability, and improved land management practices will reduce the burden of disease.

Keywords: Air quality, water quality, phenotype, toxicant, toxicogenetics

Introduction

Fundamentally, the health (and unhealth) of our patients reflects their day-to-day interactions with the air, land and sea. For diseases with a large environmental component, the quantification of environmental exposure becomes a critical determinant of success in any effort to predict risk and reduce the frequency of adverse clinical events. Air quality clearly impacts the rate of progression for inflammatory lung diseases1,2, and water quality is a strong determinant of kidney disease when combined with climate in certain geographic regions3. Efforts are therefore being made to integrate geocodes as a proxy for environment within predictive models of chronic obstructive pulmonary disease (COPD)4 and chronic kidney disease (CKD)5.

This is a pivotal time in the advancement of health care delivery. Through the wide-scale and simultaneous deployment of the fields of genomics and bioinformatics, the clinical community is now faced with an unprecedented opportunity to predict the onset of disease and alter the rate of progression for many complex common disorders. Electronic medical records (EMRs) support discovery (gene-environment interaction within EMR-linked biobanks), validation (replication and risk prediction using dense longitudinal data), and implementation (automated decision support in the context of routine clinical care). As a discovery resource, practice-based biobanks are rich with phenotypic information, but typically contain sparse data related to environmental exposures. Because EMRs are designed to deliver clinical care, rather than to facilitate research, inconsistencies in coding, format, and data structure make it challenging to fully characterize environmental risk determinants in the context of genotype-phenotype association studies. Novel biobanks are emerging with the phenotypic density to quantify gene-environment interaction6.

Gene-Environment Interaction

All human traits are determined by a mix of genetic and non-genetic factors. In general, the total contribution of gene variants (versus the contribution of environmental factors) can be estimated for most common diseases by calculating how tightly the disease is distributed in large multi-generational pedigrees. Much like “r2” (a simple mathematical term used to describe the strength of correlation between any two variables), geneticists use a term called “H2” (heritability) to describe the strength of correlation between genotype and phenotype within a pedigree. Thus, H2 reflects the proportion of all variation in a disease that can be attributed to genetic factors, and the remainder of the trait must - by definition - be due to interactions with the environment.

One of the most heritable of human traits is height7. With an H2 exceeding 0.80, more than 80% of all variability in human height is due to genetic factors (less than 20% is due to environmental factors). For most human traits, however, H2 is smaller and the environmental contribution is a much stronger determinant of outcome. Consider the role of body weight and lipid abnormalities in the development of heart disease. These traits are readily available in most observational cohorts, and their heritability can easily be determined using data in genome-wide association studies (GWAS). Estimates of heritability for lipid levels have approached 50%8. Conversely, the heritability of coronary artery disease is less than 50%, and only a small fraction of the overall variability in this trait has been mapped to known gene variants9. These observations underscore the impact of environment (e.g., dietary intake, physical activity, etc.) on event rate.

Environmental risk determinants extend far beyond the composition of our diet. Our bodies are constantly exposed to environmental toxicants through inhalation, ingestion, and transdermal absorption. For diseases with a large environmental component, such as chronic obstructive pulmonary disease and chronic kidney disease, markers of specific environmental exposures are needed for accurate risk prediction and meaningful event reduction. One approach to quantifying environmental exposure has been sampling of pollutants at fixed locations to generate estimates across larger regions10. Using approaches like these, residential address or other geocoding strategies can be used as surrogates for specific environmental toxicants in practice-based studies of gene-environment interaction.

Chronic Obstructive Pulmonary Disease (COPD)

In a healthy young adult, tidal volume is approximately 500 ml per inspiration (or 7 ml/kg). At 12–14 breaths per minute, our lungs process 10,000 liters of air each day, nearly 4 million liters each year. Correspondingly, our large and small airways remove tremendous amounts of inhaled toxicants through muco-ciliary mechanisms and the molecular detoxification processes carried out by the pulmonary epithelium and our immune system. Depending upon the toxicant, and each patient’s individual genetic architecture, defense mechanisms (airway reactivity and/or parenchymal changes causing fibrosis) can sometimes become maladaptive and lead to disease11. Chronic inflammatory lung diseases vary along a clinical spectrum ranging from asthma to COPD, and heritability estimates have actually been quite high for asthma12. Estimates of heritability for COPD however are much lower: H2 ranges from 25% based upon radiographic changes (hyperinflation on CT scan) to 37% for physiologic changes (fixed reduction in FEV1 on spirometry)13. Most of the variance in COPD can therefore be attributed to the environment.

With a low heritability, monogenic causes of obstructive lung disease are relatively uncommon. Diseases such cystic fibrosis or alpha-1 antitrypsin deficiency are typically diagnosed early in life as a part of a complex process influencing multiple organ systems. For these rare recessive lung diseases, homozygosity occurs in far less than 0.1% of the general population. For example, homozygosity for alpha-1 antitrypsin deficiency affects about 1 in 5000 individuals. The most severe form is caused by a loss of function allele in the SERPINA-1 gene. This polymorphism leads to polymerization of the nascent alpha-1 antitrypsin molecules within the liver, causing liver disease and making alpha-1 antitrypsin unavailable to modulate the normal function of neutrophil elastase within the lungs. The result is obstructive lung disease at a very young age. Interestingly, in the COPDGene cohort, a subset analysis confirmed that heterozygosity for SERPINA-1 variants also increases the risk for COPD in adults14, raising the question as to whether patients diagnosed with COPD could be screened for alpha-1 antitrypsin deficiency.

While polygenic lung disease is more common than monogenic disease, huge GWAS have revealed that the influence of genetic variants is modest, even when multiple genes are considered in combination15,16. Further, while nearly 200 candidate genes have been linked to COPD over the past decade, very few of these associated loci have been replicated consistently17. Given the phenotypic heterogeneity of COPD, and its limited heritability, predictive models will likely need to apply a flexible framework that can consider both gene-gene interaction and gene-environment interaction to be effective. Investigators from SpiroMeta and the CHARGE consortium have begun addressing this challenge by using a pathway analysis to identify gene interactions linked to FEV1 and FVC in large GWAS datasets. Their analysis highlighted an association between airflow obstruction (decreased FEV1/FVC ratio) and molecular processes linked to airway remodeling, including several matrix metalloproteinase (MMP) genes15. Subsequent functional validation, in vitro, confirmed a pathophysiological role for MMP- 10 in a mouse model of smoke- induced emphysema15. Similar progress has been made for gene-environment interaction. Case-control studies highlighting a promoter variant in MMP-9 that is 3-fold more common in COPD18 have also documented that an interaction between MMP-9 and number of cigarettes smoked alters COPD severity. Follow-up reporter gene assays confirmed an enhanced response to cigarette smoke condensate in cells transfected with this variant in vitro18.

This theme is emerging for many diseases with chronic underlying inflammatory components: environmental toxicants (inhaled, ingested, or absorbed) repeatedly trigger inflammation leading to fibrosis in the parenchyma of one or more organs, and in large populations, fibrosis appears to be worse in select patients with specific genetic risk alleles. As the genetic risk variants come into view, expanded efforts will be needed to characterize the relevant environmental triggers.

air quality

COPD has unequivocally been associated with exposure to cigarette smoke. Nearly 25% of the mortality associated with COPD in low income countries has also been attributed to smoke exposure from other sources such as coal, kerosene, and biomass fuels (e.g., wood, charcoal)19. In moderate to higher income countries, industrial emissions, vehicle emissions, and wildfires have a measurable impact on disease burden20,21. In general, smoke from any source contains many components that induce cough, increase mucus production, and activate bronchial reactivity11. These include ozone, sulfur dioxide, nitrogen dioxide, volatile organic compounds, and particulate matter. Particles less than 10μm in diameter (dust, pollen, and mold) can get deep into the lungs, and particles as small as 2.5μm (combustion products, organic matter, and heavy metals) can cross the pulmonary epithelium and enter the systemic circulation.

Particles <2.5μm in diameter (PM2.5) pose the greatest risk to human health, and geographic variability in PM2.5 level is a powerful predictor of COPD frequency and severity. Based on measurements taken by NASA, as much as 80% of the world’s population resides in locations where PM2.5 levels exceed the Air Quality Guideline set by the World Health Organization21. In the U.S., the National Oceanic and Atmospheric Administration (NOAA) regularly monitors the amount of smoke dispersed in the atmosphere. Wildfires, for example, can cause abrupt changes in spatial and temporal patterns in air quality [Figure 1]. Currently, there is tremendous interest in quantifying the impact of wildfires on human health. Using machine learning, investigators in California recently demonstrated that fine atmospheric particulate matter is a strong predictor of COPD exacerbations during wildfire events22. The PM2.5 linked to exacerbations during a single event exceeded the National Ambient Air Quality Standard (NAAQS) of 35 μg/m3 for nearly 5,000 zip-code days (sometimes reaching PM2.5 levels 6-fold higher than this standard).

Figure 1. Vertically integrated smoke in milligrams per square meter.

Figure 1.

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[reprinted from NOAA. Vertically integrated plot showing the smoke forecast on 8/20/2020.] https://www.nesdis.noaa.gov/content/noaa-satellites-monitoring-massive-wildfires-and-two-cyclones

Clearly, changes in atmospheric particulate matter lead to changes in COPD frequency and severity. In the U.S., a 10μg/m3 increase in PM2.5 is associated with a 3.1% increase in COPD hospitalization rate (95% CI, 1.6%−4.6%), and a 2.5% increase in COPD mortality (95% CI, 1.5%−3.5%)23. The effect size is even greater when all-cause mortality is considered. Within the Medicare population, a 10μg/m3 increase in PM2.5 is associated with a 7.3% increase in all-cause mortality (95% CI, 7.1%−7.5%)1. Temporal and spatial changes in PM2.5 therefore need to be monitored regularly and integrated into decision support for COPD in routine clinical care.

Chronic Kidney Disease (CKD)

Kidney disease can also be caused, or indirectly accelerated, by exposure to environmental toxicants. Causal mechanisms for chronic kidney disease are diverse, reflecting a wide variety of pathophysiology impacting the glomeruli, the interstitium, and the tubules24. Glomerular injury is common in patients with hypertension and diabetes mellitus. Importantly, however, there are geographic differences in the distribution of kidney disease that cannot solely be explained by classical hemodynamic and metabolic risk factors25. For example, young agricultural workers living in some equatorial communities develop a rapid decline in glomerular filtration rate that is independent of all known risk factors. Because this form of chronic kidney disease appears to be insufficiently explained by dehydration and/or repeated episodes of acute kidney injury, it has been referred to as “CKD of Undetermined Etiology” (CKDu)26. Many of these patients develop tubular atrophy and interstitial fibrosis, suggesting that toxin exposure may contribute to their loss of functional nephrons over time27. Environmental factors explored as potentially causal in this phenomenon have included agricultural chemicals, industrial waste products, and viruses28.

Overall, chronic kidney disease is an extremely heterogeneous disorder and in many patients environmental factors appear to play a larger role than genetic factors. With an estimated H2 of only 0.15, the contribution of genetic factors to chronic kidney disease is small within the general population29. Monogenic forms are relatively rare. For example, the autosomal recessive form of polycystic kidney disease is extremely uncommon, occurring in less than 1 in 20,000 live births and presenting early in life. Most cases are due to rare variants in PKHD130. Conversely, autosomal dominant polycystic kidney disease occurs in 1 in 1000 individuals in the general population, and this form of the disease typically presents later in life. A single loss of function allele in either the PKD1 gene or the PKD2 gene can lead to extensive cyst development, fibrosis, and progression to end stage renal disease in mid- to late-adulthood31.

Multigenic forms of kidney disease are also relatively uncommon. GWAS have revealed that the great majority of gene variants linked to chronic kidney disease have rather small effect sizes. While more than 50 loci have been associated with glomerular filtration rate in large cohorts such as CKD-Gen [45] and the Million Veterans Program29, these variants only explain 3% of the overall variance in the trait cross-sectionally. Further, while several loci have been associated with change in filtration rate longitudinally in studies like the Chronic Renal Insufficiency Cohort (CRIC), only a few have replicated across cohorts of diverse ancestry32,33. In patients of African ancestry, however, the APOL1 gene has consistently been associated with change in glomerular filtration rate34,35. African American patients with two loss of function alleles at this locus often develop chronic kidney disease independent of known risk determinants, and these patients have a 2- to 6-fold higher frequency of end stage renal disease36,37. Because chronic interstitial nephritis occurs in many communities where APOL1 gene variants are common, these variants may alter patient vulnerability to environmental nephrotoxins26,37.

water quality

For many forms of chronic kidney disease, rate of progression is influenced by environmental factors. In the glomerular diseases characterized by a gradual loss of nephrons (e.g., hypertension and diabetes), the remaining healthy nephrons typically undergo changes that compensate for the loss38. In the presence of nephrotoxins, however, additional pathology develops in the renal parenchyma (tubulointerstitial fibrosis), and the normal compensatory changes fail, shifting the slope in glomerular filtration rate downward over time39. Potential nephrotoxins capable of causing sustained or periodic tubular injury include numerous pollutants present in the environment. Patients residing in agricultural communities are frequently exposed to fertilizers, herbicides, and pesticides, as well as a variety of heavy metals. Depending on soil conditions, climate, and runoff, these agricultural chemicals can find their way into drinking water40. Other industries with a potential impact on water quality include the petroleum industry41 and the mining industry42. In the Western U.S., for example, soil and water quality have been influenced by more than 150,000 abandoned hard rock mines41, and based on data from the Strong Heart Study (SHS), Native Americans residing in these rural communities have higher urinary heavy metal concentrations than the participants of a more urban/suburban comparison group, the Multi-Ethnic Study of Atherosclerosis (MESA) cohort43. Given that 20% of the U.S. population lives in rural areas44, and 2% claim Native heritage45, this exposure to potentially nephrotoxic metals must be monitored and included in models of risk being developed from clinical data.

The impact of heavy metals on nephrotoxicity can also be influenced by water hardness46. The amount of polyvalent metal cations like calcium, magnesium, and iron in drinking water impacts the severity of heavy metal-induced nephrotoxicity in experimental animal models. Mice exposed to heavy metals in their drinking water experience a synergistic effect between water hardness and metal concentration on the tubulo-interstitial pathology that they develop, even at maximal allowable metal concentrations set by the World Health Organization47. Furthermore, physiologic changes in calcium homeostasis are also capable of altering patient susceptibility to nephrotoxic heavy metals through a variety of direct and indirect mechanisms, including changes in vitamin D-dependent uptake of divalent cations by the gastrointestinal epithelium and active elimination at the level of the renal tubules48. Both of these processes vary with geography.

Thus, the source of water is important. In the U.S., nearly 50 million people residing in both urban and rural communities (about 15% of the U.S. population), rely on private domestic wells as their source of drinking water [Figure 2]. The USGS National Water Quality Program regularly investigates the quality of water pumped from these domestic wells. The National Water Quality Assessment (NAWQA) Project has assessed conditions for about 2,100 domestic wells across the U.S. [ https://water.usgs.gov/nawqa/pnsp/usage/maps/compound_listing.php ]. Although agricultural pesticides and solvents were detected in more than half of the sampled wells, concentrations rarely exceed human-health benchmarks (<1% of wells). While this is reassuring, the content of environmental nephrotoxins in drinking water must continually be monitored, and the data should be integrated into predictive models deployed in clinical care49.

Figure 2. People using domestic water supplies per square kilometer.

Figure 2.

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[reprinted from USGS. United States Geological Survey, Department of the Interior] https://www.usgs.gov/media/images/people-using-domestic-supply-wells-square-kilometer

The Path Forward

The health of our patients is strongly influenced by the health of the environment. As the world focuses its attention on environmental stewardship, renewable energy, and mitigation of climate change, clinicians and healthcare scientists are presented with a timely opportunity to lead. Huge retrospective studies are now rapidly advancing 3 agendas as they quantify the impact of specific environmental toxicants on outcomes for common chronic diseases: (A) these studies deepen our understanding of the pathophysiology driving diseases with a strong environmental component; (B) they allow us to prioritize public health interventions for specific toxicants; (C) they catalyze development of increasingly accurate risk prediction models that can be deployed prospectively.

For many diseases, the path toward management not only depends on accurate risk stratification through a deeper understanding of the biology, but also on a reduction in exposure to specific environmental toxicants. Because non-genetic factors have such a strong influence on the onset and rate of progression for lung disease and kidney disease, environmental stewardship remains key to reducing the severity of these disorders [Table 1]. Sound land management practices will therefore be a critical determinant of both the health of our planet and the health of our patients.

Table 1.

Responsible Land Management

Contamination of air and water by point source pollutants (from sewage treatment plants, natural gas and oil refineries, paper mills, factories and farms), as well as non-point source pollutants (from atmospheric deposition, precipitation, and land run-off), can be greatly reduced through responsible land management. For example, soil erosion due to deforestation is associated with increased mobilization of nephrotoxic heavy metals50,51. Where erosion is extensive, the surface water concentrations of lead and cadmium often exceed international guidelines52. Agricultural soils specifically located near mineral extraction mines contain particularly high levels of lead and cadmium, as well as copper, zinc, and arsenic53; and the large volumes of water used during the mining process can mobilize these metals allowing them to get into the ground water54.

Maintaining Water Quality. In agricultural communities, changes in tillage strategy and crop rotation can be leveraged to decrease the runoff of nephrotoxic metals55. In the U.S., the Conservation Reserve Program (CRP) pays landowners to preserve land from being plowed using funds available through the 2018 Agriculture Improvement Act (Farm Bill). By allowing landowners to maintain forest, prairie and wetland areas as natural landscape, programs such as these maintain soil integrity and improve public health by reducing the runoff of non-point source pollutants. Many states already have over 1 million acres set aside within this program.

Optimizing Air Quality. Efforts to control soil erosion through the preservation of natural landscapes and the optimization of agricultural practices also synergize with efforts to improve air quality through carbon capture (reduction of atmospheric CO2). The earth’s atmosphere, for example, contains approximately 1,000 gigatons of carbon. By comparison, soils contain almost 3,000 gigatons of carbon below ground, and global plant biomass contains another 500 gigatons above ground56,57. These resources represent enormous carbon sinks (nearly 4-fold the amount of carbon in the atmosphere). As the world continues moving toward renewable energy in an effort to decrease carbon emissions58, the optimization of land management will not only markedly increase the storage of carbon, it will in many geographic locations reduce patient exposure to environmental toxicants capable of accelerating diseases influenced by air and water quality.
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Clinical Significance.

  • For many common diseases (e.g., chronic obstructive pulmonary disease and chronic kidney disease), studies of heritability reveal that the impact of non-genetic factors often exceeds the impact of genetic factors

  • In order to identify causal factors, and build accurate risk prediction models, markers of air quality and water quality need to be included in observational studies across institutions

Acknowledgments

This work was funded by National Institutes of Health (1U01HG007253) and through a generous gift from T. Denny Sanford that created Imagenetics (merging internal medicine and genetics).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of interest statement: The authors (R.A.W., E.A.L.) declare no conflicts of interest.

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