IMPORTANCE: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory ...lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. OBJECTIVE: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). EXPOSURES: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. MAIN OUTCOMES AND MEASURES: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)–related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. RESULTS: Among all participants (mean SD age, 53.2 15.8 years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio PR, 1.68 95% CI, 1.55-1.82), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 95% CI, 1.72-2.82), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 95% CI, 1.01-1.13), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 95% CI, 1.22-1.45). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years 95% CI, 10.0-13.1; adjusted hazard ratio HR, 1.50 95% CI, 1.42-1.59), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years 95% CI, 0.7-1.6; adjusted HR, 1.95 95% CI, 1.54-2.48), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years 95% CI, 2.1-3.4; adjusted HR, 1.55 95% CI, 1.36-1.77), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years 95% CI, 4.9-7.5; adjusted HR, 1.90 95% CI, 1.69-2.14), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years 95% CI, 3.7-5.8; adjusted HR, 1.30 95% CI, 1.18-1.42). CONCLUSIONS AND RELEVANCE: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.
The prenatal environment influences lifetime health; epigenetic mechanisms likely predominate. In 2016, the first international consortium paper on cigarette smoking during pregnancy and offspring ...DNA methylation identified extensive, reproducible exposure signals. This finding raised expectations for epigenome-wide association studies (EWAS) of other exposures.
We review the current state-of-the-science for DNA methylation associations across prenatal exposures in humans and provide future recommendations.
We reviewed 134 prenatal environmental EWAS of DNA methylation in newborns, focusing on 51 epidemiological studies with meta-analysis or replication testing. Exposures spanned cigarette smoking, alcohol consumption, air pollution, dietary factors, psychosocial stress, metals, other chemicals, and other exogenous factors. Of the reproducible DNA methylation signatures, we examined implementation as exposure biomarkers.
Only 19 (14%) of these prenatal EWAS were conducted in cohorts of 1,000 or more individuals, reflecting the still early stage of the field. To date, the largest perinatal EWAS sample size was 6,685 participants. For comparison, the most recent genome-wide association study for birth weight included more than 300,000 individuals. Replication, at some level, was successful with exposures to cigarette smoking, folate, dietary glycemic index, particulate matter with aerodynamic diameter
and
, nitrogen dioxide, mercury, cadmium, arsenic, electronic waste, PFAS, and DDT. Reproducible effects of a more limited set of prenatal exposures (smoking, folate) enabled robust methylation biomarker creation.
Current evidence demonstrates the scientific premise for reproducible DNA methylation exposure signatures. Better powered EWAS could identify signatures across many exposures and enable comprehensive biomarker development. Whether methylation biomarkers of exposures themselves cause health effects remains unclear. We expect that larger EWAS with enhanced coverage of epigenome and exposome, along with improved single-cell technologies and evolving methods for integrative multi-omics analyses and causal inference, will expand mechanistic understanding of causal links between environmental exposures, the epigenome, and health outcomes throughout the life course. https://doi.org/10.1289/EHP12956.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background: Various factors can modify the health effects of outdoor air pollution. Prior findings about modifiers are inconsistent, and most of these studies were conducted in developed countries. ...Objectives: We conducted a time-series analysis to examine the modifying effect of season, sex, age, and education on the association between outdoor air pollutants particulate matter < 10 μm in aerodynamic diameter (PM₁₀), sulfur dioxide, nitrogen dioxide, and ozone and daily mortality in Shanghai, China, using 4 years of daily data (2001-2004). Methods: Using a natural spline model to analyze the data, we examined effects of air pollution for the warm season (April-September) and cool season (October-March) separately. For total mortality, we examined the association stratified by sex and age. Stratified analysis by educational attainment was conducted for total, cardiovascular, and respiratory mortality. Results: Outdoor air pollution was associated with mortality from all causes and from cardio-respiratory diseases in Shanghai. An increase of 10 μg/m³ in a 2-day average concentration of PM₁₀, SO₂, NO₂, and O₃ corresponds to increases in all-cause mortality of 0.25% 95% confidence interval (CI), 0.14-0.37), 0.95% (95% CI, 0.62-1.28), 0.97% (95% CI, 0.66-1.27), and 0.31% (95% CI, 0.04-0.58), respectively. The effects of air pollutants were more evident in the cool season than in the warm season, and females and the elderly were more vulnerable to outdoor air pollution. Effects of air pollution were generally greater in residents with low educational attainment (illiterate or primary school) compared with those with high educational attainment (middle school or above). Conclusions: Season, sex, age, and education may modify the health effects of outdoor air pollution in Shanghai. These findings provide new information about the effects of modifiers on the relationship between daily mortality and air pollution in developing countries and may have implications for local environmental and social policies.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Limited prior data suggest an association between traffic-related air pollution and incident asthma in adults. No published studies assess the effect of long-term exposures to particulate matter less ...than 2.5 μm in diameter (PM2.5) on adult incident asthma.
To estimate the association between ambient air pollution exposures (PM2.5 and nitrogen dioxide, NO2) and development of asthma and incident respiratory symptoms.
The Sister Study is a U.S. cohort study of risk factors for breast cancer and other health outcomes (n = 50,884) in sisters of women with breast cancer (enrollment, 2003-2009). Annual average (2006) ambient PM2.5 and NO2 concentrations were estimated at participants' addresses, using a national land-use/kriging model incorporating roadway information. Outcomes at follow-up (2008-2012) included incident self-reported wheeze, chronic cough, and doctor-diagnosed asthma in women without baseline symptoms.
Adjusted analyses included 254 incident cases of asthma, 1,023 of wheeze, and 1,559 of chronic cough. For an interquartile range (IQR) difference (3.6 μg/m(3)) in estimated PM2.5 exposure, the adjusted odds ratio (aOR) was 1.20 (95% confidence interval CI = 0.99-1.46, P = 0.063) for incident asthma and 1.14 (95% CI = 1.04-1.26, P = 0.008) for incident wheeze. For NO2, there was evidence for an association with incident wheeze (aOR = 1.08, 95% CI = 1.00-1.17, P = 0.048 per IQR of 5.8 ppb). Neither pollutant was significantly associated with incident cough (PM2.5: aOR = 0.95, 95% CI = 0.88-1.03, P = 0.194; NO2: aOR = 1.00, 95% CI = 0.93-1.07, P = 0.939).
Results suggest that PM2.5 exposure increases the risk of developing asthma and that PM2.5 and NO2 increase the risk of developing wheeze, the cardinal symptom of asthma, in adult women.
The notion that oxidative stress plays a role in virtually every human disease and environmental exposure has become ingrained in everyday knowledge. However, mounting evidence regarding the lack of ...specificity of biomarkers traditionally used as indicators of oxidative stress in human disease and exposures now necessitates re-evaluation. To prioritize these re-evaluations, published literature was comprehensively analyzed in a meta-analysis to quantitatively classify the levels of systemic oxidative damage across human disease and in response to environmental exposures.
In this meta-analysis, the F
2
-isoprostane, 8-iso-PGF
2α
, was specifically chosen as the representative marker of oxidative damage. To combine published values across measurement methods and specimens, the standardized mean differences (Hedges’ g) in 8-iso-PGF
2α
levels between affected and control populations were calculated.
The meta-analysis resulted in a classification of oxidative damage levels as measured by 8-iso-PGF
2α
across 50 human health outcomes and exposures from 242 distinct publications. Relatively small increases in 8-iso-PGF
2α
levels (g<0.8) were found in the following conditions: hypertension (g=0.4), metabolic syndrome (g=0.5), asthma (g=0.4), and tobacco smoking (g=0.7). In contrast, large increases in 8-iso-PGF
2α
levels were observed in pathologies of the kidney, e.g.
,
chronic renal insufficiency (g=1.9), obstructive sleep apnoea (g=1.1), and pre-eclampsia (g=1.1), as well as respiratory tract disorders, e.g.
,
cystic fibrosis (g=2.3).
In conclusion, we have established a quantitative classification for the level of 8-iso-PGF
2α
generation in different human pathologies and exposures based on a comprehensive meta-analysis of published data. This analysis provides knowledge on the true involvement of oxidative damage across human health outcomes as well as utilizes past research to prioritize those conditions requiring further scrutiny on the mechanisms of biomarker generation.
fx1
•
Oxidative damage is highly variable in human conditions as measured by F
2
-isoprostanes.
•
Respiratory tract and urogenital diseases have the highest F
2
-isoprostanes.
•
Cancer and cardiovascular diseases have surprisingly low F
2
-isoprostanes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
For most of the world, human genome structure at a population level is shaped by interplay between ancient geographic isolation and more recent demographic shifts, factors that are captured by the ...concepts of biogeographic ancestry and admixture, respectively. The ancestry of non-admixed individuals can often be traced to a specific population in a precise region, but current approaches for studying admixed individuals generally yield coarse information in which genome ancestry proportions are identified according to continent of origin. Here we introduce a new analytic strategy for this problem that allows fine-grained characterization of admixed individuals with respect to both geographic and genomic coordinates. Ancestry segments from different continents, identified with a probabilistic model, are used to construct and study "virtual genomes" of admixed individuals. We apply this approach to a cohort of 492 parent-offspring trios from Mexico City. The relative contributions from the three continental-level ancestral populations-Africa, Europe, and America-vary substantially between individuals, and the distribution of haplotype block length suggests an admixing time of 10-15 generations. The European and Indigenous American virtual genomes of each Mexican individual can be traced to precise regions within each continent, and they reveal a gradient of Amerindian ancestry between indigenous people of southwestern Mexico and Mayans of the Yucatan Peninsula. This contrasts sharply with the African roots of African Americans, which have been characterized by a uniform mixing of multiple West African populations. We also use the virtual European and Indigenous American genomes to search for the signatures of selection in the ancestral populations, and we identify previously known targets of selection in other populations, as well as new candidate loci. The ability to infer precise ancestral components of admixed genomes will facilitate studies of disease-related phenotypes and will allow new insight into the adaptive and demographic history of indigenous people.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Environmental exposures to phthalates, particularly high-molecular-weight (HMW) phthalates, are suspected to contribute to allergy.
We assessed whether phthalate metabolites are associated with ...allergic symptoms and sensitization in a large nationally representative sample.
We used data on urinary phthalate metabolites and allergic symptoms (hay fever, rhinitis, allergy, wheeze, asthma) and sensitization from participants ≥ 6 years of age in the National Health and Nutrition Examination Survey (NHANES) 2005-2006. Allergen sensitization was defined as a positive response to at least one of 19 specific IgE antigens (≥ 0.35 kU/L). Odds ratios (ORs) per one log10 unit change in phthalate concentration were estimated using logistic regression adjusting for age, race, body mass index, gender, creatinine, and cotinine. Separate analyses were conducted for children (6-17 years of age) and adults.
The HMW phthalate metabolite monobenzyl phthalate (MBzP) was the only metabolite positively associated with current allergic symptoms in adults (wheeze, asthma, hay fever, and rhinitis). Mono-(3-carboxypropyl) phthalate and the sum of diethylhexyl phthalate metabolites (both representing HMW phthalate exposures) were positively associated with allergic sensitization in adults. Conversely, in children, HMW phthalate metabolites were inversely associated with asthma and hay fever. Of the low-molecular-weight phthalate metabolites, monoethyl phthalate was inversely associated with allergic sensitization in adults (OR = 0.79; 95% CI: 0.70, 0.90).
In this cross-sectional analysis of a nationally representative sample, HMW phthalate metabolites, particularly MBzP, were positively associated with allergic symptoms and sensitization in adults, but there was no strong evidence for associations between phthalates and allergy in children 6-17 years of age.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Exposure to air pollution has been consistently associated with cardiovascular morbidity and mortality, but mechanisms remain uncertain. Associations with blood pressure (BP) may help to explain the ...cardiovascular effects of air pollution.
We examined the cross-sectional relationship between long-term (annual average) residential air pollution exposure and BP in the National Institute of Environmental Health Sciences' Sister Study, a large U.S. cohort study investigating risk factors for breast cancer and other outcomes.
This analysis included 43,629 women 35-76 years of age, enrolled 2003-2009, who had a sister with breast cancer. Geographic information systems contributed to satellite-based nitrogen dioxide (NO2) and fine particulate matter (≤ 2.5 μm; PM2.5) predictions at participant residences at study entry. Generalized additive models were used to examine the relationship between pollutants and measured BP at study entry, adjusting for cardiovascular disease risk factors and including thin plate splines for potential spatial confounding.
A 10-μg/m(3) increase in PM2.5 was associated with 1.4-mmHg higher systolic BP (95% CI: 0.6, 2.3; p < 0.001), 1.0-mmHg higher pulse pressure (95% CI: 0.4, 1.7; p = 0.001), 0.8-mmHg higher mean arterial pressure (95% CI: 0.2, 1.4; p = 0.01), and no significant association with diastolic BP. A 10-ppb increase in NO2 was associated with a 0.4-mmHg (95% CI: 0.2, 0.6; p < 0.001) higher pulse pressure.
Long-term PM2.5 and NO2 exposures were associated with higher blood pressure. On a population scale, such air pollution-related increases in blood pressure could, in part, account for the increases in cardiovascular disease morbidity and mortality seen in prior studies.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (>100 kbp) events, we estimate the ...rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of ∼30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of μ = 1.2 × 10(-2) CNVs per genome per transmission (μ = 6.5 × 10(-3) for CNVs >500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (>500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 × 10(-3)) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied.
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