Epigenome-wide association studies of allergic disease and the environment.

The epigenome is at the intersection of the environment, genotype, and cellular response. DNA methylation of cytosine nucleotides, the most studied epigenetic modification, has been systematically evaluated in human studies by using untargeted epigenome-wide association studies (EWASs) and shown to be both sensitive to environmental exposures and associated with allergic diseases. In this narrative review, we summarize findings from key EWASs previously conducted on this topic; interpret results from recent studies; and discuss the strengths, challenges, and opportunities regarding epigenetics research on the environment-allergy relationship. The majority of these EWASs have systematically investigated select environmental exposures during the prenatal and early childhood periods and allergy-associated epigenetic changes in leukocyte-isolated DNA and more recently in nasal cells. Overall, many studies have found consistent DNA methylation associations across cohorts for certain exposures, such as smoking (eg, aryl hydrocarbon receptor repressor gene [AHRR] gene), and allergic diseases (eg, EPX gene). We recommend the integration of both environmental exposures and allergy or asthma within long-term prospective designs to strengthen causality as well as biomarker development. Future studies should collect paired target tissues to examine compartment-specific epigenetic responses, incorporate genetic influences in DNA methylation (methylation quantitative trait locus), replicate findings across diverse populations, and carefully interpret epigenetic signatures from bulk, target tissue or isolated cells.

Air Pollution and Atopic Dermatitis, from Molecular Mechanisms to Population-Level Evidence: A Review.

Atopic dermatitis (AD) has increased in prevalence to become the most common inflammatory skin condition globally, and geographic variation and migration studies suggest an important role for environmental triggers. Air pollution, especially due to industrialization and wildfires, may contribute to the development and exacerbation of AD. We provide a comprehensive, multidisciplinary review of existing molecular and epidemiologic studies on the associations of air pollutants and AD symptoms, prevalence, incidence, severity, and clinic visits. Cell and animal studies demonstrated that air pollutants contribute to AD symptoms and disease by activating the aryl hydrocarbon receptor pathway, promoting oxidative stress, initiating a proinflammatory response, and disrupting the skin barrier function. Epidemiologic studies overall report that air pollution is associated with AD among both children and adults, though the results are not consistent among cross-sectional studies. Studies on healthcare use for AD found positive correlations between medical visits for AD and air pollutants. As the air quality worsens in many areas globally, it is important to recognize how this can increase the risk for AD, to be aware of the increased demand for AD-related medical care, and to understand how to counsel patients regarding their skin health. Further research is needed to develop treatments that prevent or mitigate air pollution-related AD symptoms.

Association of Wildfire Air Pollution With Clinic Visits for Psoriasis.

This cross-sectional study examines whether clinic visits and online search interest for psoriasis were associated with wildfire air pollution after a delayed lag period.

Increased epigenetic age acceleration in the hidradenitis suppurativa skin.

Epigenetic (or DNA methylation) age is calculated based on methylation of certain cytosine-guanine (CpG) repeats, and it can accurately estimate one's chronologic age. Importantly, epigenetic age acceleration (EAA) is highly predictive of age-associated morbidity and all-cause mortality. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with significant systemic disease burden. Here, we performed a pilot study to calculate EAA from formalin-fixed paraffin-embedded skin samples using Illumina Infinium MethylationEpic BeadChip arrays. Our results demonstrated no significant difference in intrinsic EAA among HS compared to controls (- 1.00 years, p-value = 0.52), significant increases in both extrinsic EAA (13.72 years, p-value < 0.001) and PhenoAge acceleration (7.72 years, p-value = 0.003), and a significant decrease in GrimAge acceleration (- 5.14 years, p-value < 0.001). Our findings suggest that the acceleration of epigenetic age in the HS skin may be associated with extrinsic immune-related changes and can potentially serve as a biomarker of the present and/or future disease burden in HS patients.

Association of Exposure to Wildfire Air Pollution With Exacerbations of Atopic Dermatitis and Itch Among Older Adults.

This cross-sectional study evaluates the association of exposure to wildfire air pollution with exacerbations of atopic dermatitis and itch among adults aged 65 years or older.

Dermatology Societies Should Explore Fossil Fuel Divestment.

This Viewpoint describes the importance of dermatology societies and health care organizations divesting from fosile fuel investments to help mitigate the effects of climate change.

Ultraviolet A radiation exposure and melanoma: a review.

The incidence of cutaneous melanoma has been increasing worldwide, and melanoma disproportionately contributes to skin cancer mortality. The pathogenesis of melanoma involves genetic and environmental factors, and while the effects of ultraviolet B radiation on melanoma development are well researched, fewer studies have investigated the role of ultraviolet A (UVA) radiation. We comprehensively reviewed cell, animal and epidemiology studies on the association between UVA exposure and melanomagenesis. UVA radiation has been found to have negative effects on melanocytes due to the induction of oxidative stress, dysregulation of gene transcription and creation of mutagenic photoproducts in DNA. Animal studies demonstrate adverse effects of UVA on melanocytes, including the development of melanoma. Epidemiology studies, of varying quality, that examined participants' exposure to tanning devices which use UVA radiation primarily found that UVA exposure increased the risk for melanoma. Some studies reported larger associations with increased frequency of device use, suggestive of a dose-response relationship. Overall, we found that many studies supported a positive association between UVA exposure and melanoma on both molecular and population levels. Understanding the role of UVA in the development of melanoma will inform the implementation of preventive health interventions, such as those related to sunscreen development and use and increasing restrictions on indoor tanning.

Disparities in access for melanoma screening by region, specialty, and insurance: A cross-sectional audit study.

Background: Early detection of melanoma is critical for positive outcomes. However, access for the diagnosis of melanoma remains problematic for segments of the general population. Objective: To compare the rates of dermatology and family medicine practitioner acceptances for a public insurance (Medicaid) versus private insurance (Anthem Blue Cross) and clinic wait times for an appointment for a changing pigmented skin lesion concerning melanoma in rural and urban regions in California. Methods: Cross-sectional audit study between June 2017 and March 2019; scripted phone calls were made to dermatology and family medicine practices (FMPs). Results: Family medicine and dermatology practices in both regions had significantly decreased acceptance of Medicaid. Dermatology practices had 11.3% to 13.0% Medicaid acceptance rates that were less than FMP rates of 28% to 36%. In both regions, FMP wait times were 2.4- to 3.2-fold longer for public versus private insurance; there were little differences in wait times for the 2 insurance types in dermatology practices, in both regions. Limitations: Assessment of only 2 regions in the state of California. Conclusion: Delays at FMPs and insurance types limit access to melanoma screening in California for underserved segments of the general population, which has implications for melanoma outcomes and health policy.

Epigenome-wide association study and epigenetic age acceleration associated with cigarette smoking among Costa Rican adults.

Smoking-associated DNA methylation (DNAm) signatures are reproducible among studies of mostly European descent, with mixed evidence if smoking accelerates epigenetic aging and its relationship to longevity. We evaluated smoking-associated DNAm signatures in the Costa Rican Study on Longevity and Healthy Aging (CRELES), including participants from the high longevity region of Nicoya. We measured genome-wide DNAm in leukocytes, tested Epigenetic Age Acceleration (EAA) from five clocks and estimates of telomere length (DNAmTL), and examined effect modification by the high longevity region. 489 participants had a mean (SD) age of 79.4 (10.8) years, and 18% were from Nicoya. Overall, 7.6% reported currently smoking, 35% were former smokers, and 57.4% never smoked. 46 CpGs and five regions (e.g. AHRR, SCARNA6/SNORD39, SNORA20, and F2RL3) were differentially methylated for current smokers. Former smokers had increased Horvath's EAA (1.69-years; 95% CI 0.72, 2.67), Hannum's EAA (0.77-years; 95% CI 0.01, 1.52), GrimAge (2.34-years; 95% CI1.66, 3.02), extrinsic EAA (1.27-years; 95% CI 0.34, 2.21), intrinsic EAA (1.03-years; 95% CI 0.12, 1.94) and shorter DNAmTL (- 0.04-kb; 95% CI - 0.08, - 0.01) relative to non-smokers. There was no evidence of effect modification among residents of Nicoya. Our findings recapitulate previously reported and novel smoking-associated DNAm changes in a Latino cohort.

Epigenetic aging biomarkers and occupational exposure to benzene, trichloroethylene and formaldehyde.

Epigenetic aging biomarkers are associated with increased morbidity and mortality. We evaluated if occupational exposure to three established chemical carcinogens is associated with acceleration of epigenetic aging. We studied workers in China occupationally exposed to benzene, trichloroethylene (TCE) or formaldehyde by measuring personal air exposures prior to blood collection. Unexposed controls matched by age and sex were selected from nearby factories. We measured leukocyte DNA methylation (DNAm) in peripheral white blood cells using the Infinium HumanMethylation450 BeadChip to calculate five epigenetic aging clocks and DNAmTL, a biomarker associated with leukocyte telomere length and cell replication. We tested associations between exposure intensity and epigenetic age acceleration (EAA), defined as the residuals of regressing the DNAm aging biomarker on chronological age, matching factors and potential confounders. Median differences in EAA between exposure groups were tested using a permutation test with exact p-values. Epigenetic clocks were strongly correlated with age (Spearman r > 0.8) in all three occupational studies. There was a positive exposure-response relationship between benzene and the Skin-Blood Clock EAA biomarker: median EAA was -0.91 years in controls (n = 44), 0.78 years in workers exposed to <10 ppm (n = 41; mean benzene = 1.35 ppm; p = 0.034 vs. controls), and 2.10 years in workers exposed to ≥10 ppm (n = 9; mean benzene = 27.3 ppm; p = 0.019 vs. controls; ptrend = 0.0021). In the TCE study, control workers had a median Skin-Blood Clock EAA of -0.54 years (n = 71) compared to 1.63 years among workers exposed to <10 ppm of TCE (n = 27; mean TCE = 4.22 ppm; p = 0.035). We observed no evidence of EAA associations with formaldehyde exposure (39 controls, 31 exposed). Occupational benzene and TCE exposure were associated with increased epigenetic age acceleration measured by the Skin-Blood Clock. For TCE, there was some evidence of epigenetic age acceleration for lower exposures compared to controls. Our results suggest that some chemical carcinogens may accelerate epigenetic aging.

Dietary fat intake during early pregnancy is associated with cord blood DNA methylation at IGF2 and H19 genes in newborns.

Maternal fat intake during pregnancy affects fetal growth, but mechanisms underlying this relationship are unclear. We performed an exploratory study of the associations of fat consumption during pregnancy with cord blood DNA methylation of the insulin-like growth factor 2 (IGF2) and H19 genes. We used data from 96 uncomplicated full-term pregnancies of mothers of whom majority had normal body mass index (BMI) (66%) in Project Viva, a prospective pre-birth cohort. We assessed maternal diet with validated food frequency questionnaires during the first and second trimesters and measured DNA methylation in segments of the IGF2- and H19-differentially methylated regions (DMRs) by pyrosequencing DNA extracted from umbilical cord blood samples. Mean (SD) age was 32.8 (4.1) years and prepregnancy BMI was 24.0 (4.4) kg/m2 . Mean DNA methylation was 56.3% (3.9%) for IGF2-DMR and 44.6% (1.9%) for H19-DMR. Greater first trimester intake of omega-6 polyunsaturated fat (effect per 1% of calories at the expense of carbohydrates) was associated with lower DNA methylation of IGF2-DMR (-1.2%; 95% confidence interval [CI]: -2.2%, -0.2%) and higher DNA methylation at H19-DMR (0.8%; 95% CI: 0.3%, 1.3%). On the other hand, greater first trimester intake of omega-3 polyunsaturated fat was associated with lower DNA methylation of the H19-DMR (-4.3%; 95% CI: -7.9%, -0.8%). We did not find significant associations of IGF2 and H19 methylation with IGF2 cord blood levels. Our findings suggest that early prenatal fat intake (omega-3, omega-6, and saturated fatty acids) may influence DNA methylation at the IGF2 and H19 locus, which could impact fetal development and long-term health.

Controlled human exposures to diesel exhaust: a human epigenome-wide experiment of target bronchial epithelial cells.

Diesel exhaust (DE) is a major contributor to ambient air pollution around the world. It is a known human carcinogen that targets the respiratory system and increases risk for many diseases, but there is limited research on the effects of DE exposure on the epigenome of human bronchial epithelial cells. Understanding the epigenetic impact of this environmental pollutant can elucidate biological mechanisms involved in the pathogenesis of harmful DE-related health effects. To estimate the causal effect of short-term DE exposure on the bronchial epithelial epigenome, we conducted a controlled single-blinded randomized crossover human experiment of exposure to DE and used bronchoscopy and Illumina 450K arrays for data collection and analysis, respectively. Of the 13 participants, 11 (85%) were male and 2 (15%) were female, and 12 (92%) were White and one (8%) was Hispanic; the mean age was 26 years (SD = 3.8 years). Eighty CpGs were differentially methylated, achieving the minimum possible exact P-value of P = 2.44 × 10-4 (i.e. 2/213). In regional analyses, we found two differentially methylated regions (DMRs) annotated to the chromosome 5 open reading frame 63 genes (C5orf63; 7-CpGs) and unc-45 myosin chaperone A gene (UNC45A; 5-CpGs). Both DMRs showed increased DNA methylation after DE exposure. The average causal effects for the DMRs ranged from 1.5% to 6.0% increases in DNA methylation at individual CpGs. In conclusion, we found that short-term DE alters DNA methylation of genes in target bronchial epithelial cells, demonstrating epigenetic level effects of exposure that could be implicated in pulmonary pathologies.

Association of Wildfire Air Pollution and Health Care Use for Atopic Dermatitis and Itch.

IMPORTANCE: Air pollution is a worldwide public health issue that has been exacerbated by recent wildfires, but the relationship between wildfire-associated air pollution and inflammatory skin diseases is unknown. OBJECTIVE: To assess the associations between wildfire-associated air pollution and clinic visits for atopic dermatitis (AD) or itch and prescribed medications for AD management. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional time-series study assessed the associations of air pollution resulting from the California Camp Fire in November 2018 and 8049 dermatology clinic visits (4147 patients) at an academic tertiary care hospital system in San Francisco, 175 miles from the wildfire source. Participants included pediatric and adult patients with AD or itch from before, during, and after the time of the fire (October 2018 through February 2019), compared with those with visits in the same time frame of 2015 and 2016, when no large wildfires were near San Francisco. Data analysis was conducted from November 1, 2019, to May 30, 2020. EXPOSURES: Wildfire-associated air pollution was characterized using 3 metrics: fire status, concentration of particulate matter less than 2.5 µm in diameter (PM2.5), and satellite-based smoke plume density scores. MAIN OUTCOMES AND MEASURES: Weekly clinic visit counts for AD or itch were the primary outcomes. Secondary outcomes were weekly numbers of topical and systemic medications prescribed for AD in adults. RESULTS: Visits corresponding to a total of 4147 patients (mean [SD] age, 44.6 [21.1] years; 2322 [56%] female) were analyzed. The rates of visits for AD during the Camp Fire for pediatric patients were 1.49 (95% CI, 1.07-2.07) and for adult patients were 1.15 (95% CI, 1.02-1.30) times the rate for nonfire weeks at lag 0, adjusted for temperature, relative humidity, patient age, and total patient volume at the clinics for pediatric patients. The adjusted rate ratios for itch clinic visits during the wildfire weeks were 1.82 (95% CI, 1.20-2.78) for the pediatric patients and 1.29 (95% CI, 0.96-1.75) for adult patients. A 10-µg/m3 increase in weekly mean PM2.5 concentration was associated with a 7.7% (95% CI, 1.9%-13.7%) increase in weekly pediatric itch clinic visits. The adjusted rate ratio for prescribed systemic medications in adults during the Camp Fire at lag 0 was 1.45 (95% CI, 1.03-2.05). CONCLUSIONS AND RELEVANCE: This cross-sectional study found that short-term exposure to air pollution due to the wildfire was associated with increased health care use for patients with AD and itch. These results may provide a better understanding of the association between poor air quality and skin health and guide health care professionals' counseling of patients with skin disease and public health practice.

Bridge the Gap: Reducing Inequity in Hospital Readmissions for African American Patients with Heart Failure Through Quality Improvement Initiatives.

Purpose: Heart failure (HF) disproportionately impacts African Americans. We evaluated existing quality improvement (QI) initiatives and patient and provider perceptions of barriers to HF care to develop equity-centered QI recommendations. Methods: We performed a literature review, interviewed providers and patients (N=11), and conducted a root cause analysis at a safety net hospital in San Francisco, California. Results: We have identified four elements to foster a more equitable HF care model: screening for social determinants of health, technological innovation, optimization of space, and implicit bias training. Conclusion: QI initiatives for HF should integrate health equity elements in their design and implementation.

Stress testing reveals gaps in clinic readiness of image-based diagnostic artificial intelligence models.

Artificial intelligence models match or exceed dermatologists in melanoma image classification. Less is known about their robustness against real-world variations, and clinicians may incorrectly assume that a model with an acceptable area under the receiver operating characteristic curve or related performance metric is ready for clinical use. Here, we systematically assessed the performance of dermatologist-level convolutional neural networks (CNNs) on real-world non-curated images by applying computational "stress tests". Our goal was to create a proxy environment in which to comprehensively test the generalizability of off-the-shelf CNNs developed without training or evaluation protocols specific to individual clinics. We found inconsistent predictions on images captured repeatedly in the same setting or subjected to simple transformations (e.g., rotation). Such transformations resulted in false positive or negative predictions for 6.5-22% of skin lesions across test datasets. Our findings indicate that models meeting conventionally reported metrics need further validation with computational stress tests to assess clinic readiness.

Differences in the Estimation of Wildfire-Associated Air Pollution by Satellite Mapping of Smoke Plumes and Ground-Level Monitoring.

Wildfires, which are becoming more frequent and intense in many countries, pose serious threats to human health. To determine health impacts and provide public health messaging, satellite-based smoke plume data are sometimes used as a proxy for directly measured particulate matter levels. We collected data on particulate matter <2.5 µm in diameter (PM2.5) concentration from 16 ground-level monitoring stations in the San Francisco Bay Area and smoke plume density from satellite imagery for the 2017-2018 California wildfire seasons. We tested for trends and calculated bootstrapped differences in the median PM2.5 concentrations by plume density category on a 0-3 scale. The median PM2.5 concentrations for categories 0, 1, 2, and 3 were 16, 22, 25, and 63 µg/m3, respectively, and there was much variability in PM2.5 concentrations within each category. A case study of the Camp Fire illustrates that in San Francisco, PM2.5 concentrations reached their maximum many days after the peak for plume density scores. We found that air pollution characterization by satellite imagery did not precisely align with ground-level PM2.5 concentrations. Public health practitioners should recognize the need to combine multiple sources of data regarding smoke patterns when developing public guidance to limit the health effects of wildfire smoke.

Distinct mechanisms of microRNA sorting into cancer cell-derived extracellular vesicle subtypes.

Extracellular vesicles (EVs) encompass a variety of vesicles secreted into the extracellular space. EVs have been implicated in promoting tumor metastasis, but the molecular composition of tumor-derived EV sub-types and the mechanisms by which molecules are sorted into EVs remain mostly unknown. We report the separation of two small EV sub-populations from a metastatic breast cancer cell line, with biochemical features consistent with different sub-cellular origins. These EV sub-types use different mechanisms of miRNA sorting (selective and non-selective), suggesting that sorting occurs via fundamentally distinct processes, possibly dependent on EV origin. Using biochemical and genetic tools, we identified the Lupus La protein as mediating sorting of selectively packaged miRNAs. We found that two motifs embedded in miR-122 are responsible for high-affinity binding to Lupus La and sorting into vesicles formed in a cell-free reaction. Thus, tumor cells can simultaneously deploy multiple EV species using distinct sorting mechanisms that may enable diverse functions in normal and cancer biology.