Whole-Genome Sequencing of Individuals from a Founder Population Identifies Candidate Genes for Asthma

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS

The Effects of Temperature and Use of Air Conditioning on Hospitalizations

Several investigators have documented the effect of temperature on mortality, although fewer have studied its impact on morbidity. In addition, little is known about the effectiveness of mitigation strategies such as use of air conditioners (AC). We investigated the association between temperatures and hospital admissions in California from 1999 to 2005. We also determined whether AC ownership and usage, assessed at the zip code level, mitigates this association. Because of the unique spatial pattern of income and climate in the state, confounding of AC effects by other local factors is less likely. We only included individuals who had a temperature monitor within 25 kilometers of their residential zip codes. Using a time-stratified case-crossover approach, we observed a significantly increased risk for hospitalization for multiple diseases including cardiovascular, ischemic heart disease, ischemic stroke, respiratory disease, pneumonia, dehydration, heat stroke, diabetes and acute renal failure with same-day apparent temperature. We also found that ownership and usage of air conditioning significantly reduced the effects of temperature on these health outcomes, after controlling for the potential confounding effects of family income and other socioeconomic factors. Our results demonstrate important effects of temperature on public health and the potential for mitigation. Several investigators have documented the acute effect of temperature on mortality in the U.S. and Europe, and in developing nations(1-3). There are far fewer studies, however, on the effects of temperature on morbidity outcomes, such as hospitalizations (4-6). According to the recent IPCC report (7), temperatures are expected to increase in the future with more frequent and severe heat waves. Therefore, it is important to obtain a better understanding of these heat-associated health risks and susceptible populations for future surveillance and targeted interventions. In addition, relatively little is known about the effectiveness of proposed mitigation strategies, such as cooling shelters, and personal use of air conditioners (AC). Studies on the effects of actual AC use on temperature-related health outcomes, however, are limited, since data are typically available for AC prevalence, rather than AC use, and only for broad geographic regions. Thus, effects of AC may be confounded by other regional characteristics (8) such as demographic and economic factors. As a result, there is need for more localized estimates of the effects of temperature on morbidity and on the effectiveness of AC use in mitigating these effects. For several reasons, California serves as an ideal study area for examining the effects of AC use on temperature-related adverse health. First, it includes a large and diverse population, residing within a wide array of climatic regions. Second, individual-level data at small levels of spatial scale over a majority of the state are available from surveys conducted by the California Public Utilities Commission (9). Finally, income is less likely to confound the estimates of the effects of AC. In general, incomes are higher in the coastal regions, but lower in the inland areas, such as the Central Valley. However, AC use is greater in the Central Valley where the summers are much hotter, and many homes in the coastal areas of California lack AC (9). In this study, we used temperature data during the warm season in California to estimate the impact on several disease-specific categories of hospitalizations. To limit exposure misclassification, we limited our study to buffer areas with individuals living in zip codes within 25 kilometers (km) of a temperature monitor. Next, we quantified the likely reduction in health impacts based on both ownership and use of ACs using individual-level data for each buffer. Finally, we examined the potential confounding effect that local measures of family income may have on our effect estimates

A Statewide Evaluation of the California Medical Supervision Program Using Cholinesterase Electronic Laboratory Reporting Data

The California Medical Supervision program is designed to protect workers who regularly mix, load, or apply the highly toxic Category I and II organophosphates and carbamates from overexposure by monitoring cholinesterase (ChE) inhibition in plasma and red blood cells. Since January 2011, testing laboratories are required to report test results electronically to the California Department of Pesticide Regulation who shares it with the Office of Environmental Health Hazard Assessment for evaluation. The purpose of this study is to assess the utility of this reporting in evaluating the effectiveness of the Program for illness surveillance and prevention. From 2011 to 2013, we received more than 90 000 test results. Despite data gaps and data quality issues, we were able to perform spatial and temporal analyses and developed a screening tool to identify individuals potentially at risk of overexposure. The data analysis provided some evidence that the Program is effective in protecting agricultural workers handling the most toxic ChE-inhibiting pesticides even though it also identified some areas of potential concerns with individuals that appeared lacking corrective actions in the workplace in response to excessive ChE depressions and parts of the state with disproportionately at-risk individuals. However, changes to the electronic reporting are needed to more accurately identify tests related to the Program and therefore improve the utility of the data received. Moreover, data analysis also revealed that electronic reporting has its limitation in evaluating the Program

Association between gaseous air pollutants and inflammatory, hemostatic and lipid markers in a cohort of midlife women

BackgroundExposures to ambient gaseous pollutants have been linked to cardiovascular diseases (CVDs), but the biological mechanisms remain uncertain.ObjectivesThis study examined the changes in CVD marker levels resulting from elevated exposure to ambient gaseous pollutants in midlife women.MethodsAnnual repeated measurements of several inflammatory, hemostatic and lipid makers were obtained from 2306 midlife women enrolled in the longitudinal Study of Women's Health Across the Nation (SWAN) between 1999 and 2004. Ambient carbon monoxide (CO), nitrogen dioxide (NO2), and sulfur dioxide (SO2) data were assigned to each woman based on proximity of the monitoring station to her residential address. Short- and long-term exposures were calculated, and their associations with markers were examined using linear mixed-effects regression models, adjusted for demographic, health and other factors.ResultsShort-term CO exposure was associated with increased fibrinogen, i.e., every interquartile increase of average prior one-week exposure to CO was associated with 1.3% (95% CI: 0.6%, 2.0%) increase in fibrinogen. Long-term exposures to NO2 and SO2 were associated with reduced high-density lipoproteins and apolipoprotein A1, e.g., 4.0% (1.7%, 6.3%) and 4.7% (2.8%, 6.6%) decrease per interquartile increment in prior one-year average NO2 concentration, respectively. Fine particle (PM2.5) exposure confounded associations between CO/NO2 and inflammatory/hemostatic markers, while associations with lipoproteins were generally robust to PM2.5 adjustment.ConclusionsExposures to these gas pollutants at current ambient levels may increase thrombotic potential and disrupt cholesterol metabolism, contributing to greater risk of CVDs in midlife women. Caution should be exercised in evaluating the confounding by PM2.5 exposure

The health burden of fall, winter and spring extreme heat events in Southern California and contribution of Santa Ana Winds

Background : Extreme heat is associated with increased morbidity but most studies examine this relationship in warm seasons. In Southern California, Santa Ana winds (SAWs) are associated with high temperatures during the fall, winter and spring, especially in the coastal region. Objective s: Our aim was to examine the relationship between hospitalizations and extreme heat events in the fall, winter and spring, and explore the potential interaction with SAWs. Methods: Hospitalizations from 1999–2012 were obtained from the Office of Statewide Health Planning and Development Patient Discharge Data. A time-stratified case crossover design was employed to investigate the association between off-season heat and hospitalizations for various diagnoses. We examined the additive interaction of SAWs and extreme heat events on hospitalizations. Results : Over 1.5 million hospitalizations occurred in the Southern California coastal region during non-summer seasons. The 99th percentile-based thresholds that we used to define extreme heat events varied from a maximum temperature of 22.8 °C to 35.1 °C. In the fall and spring, risk of hospitalization increased for dehydration (OR: 1.23, 95% CI: 1.04, 1.45 and OR: 1.47 95% CI: 1.25, 1.71, respectively) and acute renal failure (OR: 1.35, 95% CI: 1.15, 1.58 and OR: 1.39, 95% CI: 1.19, 1.63, respectively) during 1-day extreme heat events. We also found an association between 1-day extreme heat events and hospitalization for ischemic stroke, with the highest risk observed in December. The results indicate that SAWs correspond to extreme heat events, particularly in the winter. Finally, we found no additive interaction with SAWs. Discussion : Results suggest that relatively high temperatures in non-summer months are associated with health burdens for several hospitalization outcomes. Heat action plans should consider decreasing the health burden of extreme heat events year-round

Estimating the associations of apparent temperature and inflammatory, hemostatic, and lipid markers in a cohort of midlife women

Associations between temperature and cardiovascular (CVD) mortality have been reported, but the underlying biological mechanisms remain uncertain. We explored the association between apparent temperature and serum biomarkers for CVD. Using linear mixed effects models, we examined the relationships between residence-proximate apparent temperature (same day and 1, 7, and 30 days prior) and several inflammatory, hemostatic, and lipid biomarkers for midlife women from 1999 through 2004. Our study population consisted of 2,306 women with mean age of 51 years (± 3 years) enrolled in Study of Women's Health Across the Nation (SWAN) in Chicago, Illinois; Detroit, Michigan; Los Angeles and Oakland, California; Newark, New Jersey; and Pittsburgh, Pennsylvania. Mean daily apparent temperature was calculated using temperature and relative humidity data provided by the National Climatic Data Center and the US Environmental Protection Agency, while daily data for fine particles, ozone, carbon monoxide, and nitrogen dioxide from the US Environmental Protection Agency Air Quality Data Mart were considered as confounders. All analyses were stratified by warm and cold seasons. More significant (p < 0.10) negative associations were found during the warm season for various lag times, including hs-CRP, fibrinogen, tissue plasminogen activator antigen (tPA-ag), tissue plasminogen activator antigen (PAI-1), Factor VIIc, high-density lipoprotein (HDL), and total cholesterol. During the cold season, significant negative associations for fibrinogen and HDL, but significant positive associations for tPA-ag, PAI-1, and triglycerides were observed for various lag times. With the exception of ozone, pollutants did not confound these associations. Apparent temperature was associated with several serum biomarkers of CVD risk in midlife women, shedding light on potential mechanisms