Traffic exposure is a major contributor to ambient air pollution for people living close to busy roads. The relationship between traffic exposure and lung function remains inconclusive in adults.
A cross‐sectional study was conducted to investigate the association between traffic exposure and lung function in the Atherosclerosis Risk in Communities (ARIC) study, a community based cohort of 15 792 middle aged men and women. Traffic density and distance to major roads were used as measures of traffic exposure.
After controlling for potential confounders including demographic factors, personal and neighbourhood level socioeconomic characteristics, cigarette smoking and background air pollution, higher traffic density was significantly associated with lower forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in women. Relative to the lowest quartile of traffic density, the adjusted differences across increasing quartiles were 5.1, −15.4 and −21.5 ml for FEV1 (p value of linear trend across the quartiles = 0.041) and 1.2, −23.4 and −34.8 ml for FVC (p trend = 0.010). Using distance from major roads as a simpler index of traffic related air pollution exposure, the FEV1 was −15.7 ml (95% CI −34.4 to 2.9) lower and the FVC was −24.2 ml (95% CI −46.2 to −2.3) lower for women living within 150 m compared with subjects living further away. There was no significant effect of traffic density or distance to major roads on lung function in men. The FEV1/FVC ratio was not significantly associated with traffic exposure in either men or women.
This is the largest published study of traffic exposure and pulmonary function in adults to date. These results add to growing evidence that chronic exposure to traffic related air pollution may adversely affect respiratory health.
The Illumina Infinium HumanMethylation450 BeadChip has emerged as one of the most popular platforms for genome wide profiling of DNA methylation. While the technology is wide-spread, systematic technical biases are believed to be present in the data. For example, this array incorporates two different chemical assays, i.e., Type I and Type II probes, which exhibit different technical characteristics and potentially complicate the computational and statistical analysis. Several normalization methods have been introduced recently to adjust for possible biases. However, there is considerable debate within the field on which normalization procedure should be used and indeed whether normalization is even necessary. Yet despite the importance of the question, there has been little comprehensive comparison of normalization methods. We sought to systematically compare several popular normalization approaches using the Norwegian Mother and Child Cohort Study (MoBa) methylation data set and the technical replicates analyzed with it as a case study. We assessed both the reproducibility between technical replicates following normalization and the effect of normalization on association analysis. Results indicate that the raw data are already highly reproducible, some normalization approaches can slightly improve reproducibility, but other normalization approaches may introduce more variability into the data. Results also suggest that differences in association analysis after applying different normalizations are not large when the signal is strong, but when the signal is more modest, different normalizations can yield very different numbers of findings that meet a weaker statistical significance threshold. Overall, our work provides useful, objective assessment of the effectiveness of key normalization methods.
association testing; cotinine exposure; genome wide methylation profiling; normalization; reproducibility
food allergy; food allergen sensitization; skin prick test; genetic association; candidate gene; single nucleotide polymorphism; Hispanic
Oral contraceptive pills (OCPs) are often used soon before, and sometimes during, pregnancy. A few studies have suggested that OCP use before pregnancy may increase risks for childhood respiratory outcomes, but data are inconclusive. No studies have analyzed the two types of OCPs, estrogen-progestin combined pills and progestin-only pills, separately. In the Norwegian Mother and Child Cohort Study (MoBa), we prospectively examined associations of OCP use before pregnancy, by type, with lower respiratory tract infections in 60,225 children followed to 6 months old, lower respiratory tract infections and wheezing in 42,520 children followed to 18 months old, and asthma in 24,472 children followed to 36 months old. We used logistic regression to estimate odds ratios and their 95% confidence intervals crudely and with adjustment for a wide range of potential confounders. Combined pills were used much more commonly than progestin-only pills. Taking combined pills before pregnancy was not associated with lower respiratory tract infections, wheezing, or asthma. Progestin-only pill use in the year before pregnancy had a slight positive association with wheezing at 6–8 months old [adjusted odds ratio (95% confidence interval)=1.19 (1.05–1.34)]. Our finding that combined pill use before pregnancy was not related to respiratory outcomes should provide reassurance to the vast majority of mothers using OCPs before becoming pregnant. The small association with progestin-only pill use and early respiratory outcomes may reflect uncontrolled confounding or other bias but does suggest that these two types of pills should be examined separately in future analyses of respiratory and other childhood outcomes.
Two recent case-control studies in Italy reported that long-term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists about long-term traffic-related air pollution and incident venous thromboembolism (VTE).
To examine the association between long-term traffic exposure and incident VTE in a population-based prospective cohort study.
We studied 13,143 middle-aged men and women in the Atherosclerosis Risk in Communities Study without history of DVT or pulmonary embolus (PE) at baseline examination (1987-1989). Geographical Information System (GIS)-mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE using proportional hazards regression models.
405 subjects developed VTE through 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95%CI 0.88-1.57), 0.99 (95%CI 0.74-1.34) and 1.14 (95%CI 0.86-1.51) (p for trend across quartiles = 0.64). For residents living within 150 meters of major roads compared to subjects living further away, the adjusted hazard ratio was 1.16 (95%CI 0.95-1.42, p=0.14).
This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE.
traffic exposure; VTE; air pollution; cohort
COPD; Genetics; Association analysis; Consortium
Over two hundred asthma candidate genes have been examined in human association studies or identified with knockout mouse approaches. However, many have not been systematically replicated in human populations, especially those containing a large number of tagging single nucleotide polymorphisms (SNPs).
We comprehensively evaluated the association of previously implicated asthma candidate genes with childhood asthma in a Mexico City population.
We identified, from the literature, candidate genes with at least one positive report of association with asthma phenotypes in humans or implicated in asthma pathogenesis by knockout mouse experiments. We performed a genome-wide association study in 492 asthmatic children aged 5 to 17 years and both parents using the Illumina HumanHap 550v3 BeadChip. Separate candidate gene analyses were performed for 2,933 autosomal SNPs in the 237 selected genes using the log-linear method with a log-additive risk model.
Sixty-one of the 237 genes had at least one SNP with p < 0.05 for association with asthma. The nine most significant results were observed for rs2241715 in TGFB1 (p=3.3×10−5), rs13431828 and rs1041973 in IL1RL1 (p=2×10−4 and 3.5×10−4), five SNPs in DPP10 (p=1.6×10−4 to 4.5×10−4), and rs17599222 in CYFIP2 (p=4.1×10−4). False discovery rates were <0.1 for all 9 SNPs. Multimarker analysis identified TGFB1, IL1RL1, IL18R1, and DPP10 as the genes most significantly associated with asthma.
This comprehensive analysis of literature-based candidate genes suggests that SNPs in several candidate genes including TGFB1, IL1RL1, IL18R1 and DPP10 may contribute to childhood asthma susceptibility in a Mexican population.
Allergy; asthma; genetic predisposition to disease; genome-wide association study (GWAS); single nucleotide polymorphism (SNP)
Farmer's lung, or hypersensitivity pneumonitis, is an important contributor to respiratory morbidity among farmers.
Using the 1993–7 enrolment data from the Agricultural Health Study, we conducted a cross‐sectional study of occupational risk factors for farmer's lung among ∼50 000 farmers and farm spouses in Iowa and North Carolina using hierarchical logistic regression controlling for age, state, and smoking status. Participants provided information on agricultural exposures, demographic characteristics, and medical history via self‐administered questionnaires. Approximately 2% of farmers (n = 481) and 0.2% of spouses (n = 51) reported doctor‐diagnosed farmer's lung during their lifetime. We assessed farmers and spouses separately due to different information on occupational exposure history. Only pesticide exposures represented lifetime exposure history, all other farm exposures represented current activities at enrolment.
Among farmers, handling silage (OR = 1.41, 95% CI 1.10 to 1.82), high pesticide exposure events (OR = 1.75, 95% CI 1.39 to 2.21), and ever use of organochlorine (OR = 1.34, 95% CI 1.04 to 1.74) and carbamate pesticides (OR = 1.32, 95% CI 1.03 to 1.68) were associated with farmer's lung in mutually‐adjusted models. The insecticides DDT, lindane, and aldicarb were positively associated with farmer's lung among farmers. Current animal exposures, while not statistically significant, were positively associated with farmer's lung, particularly for poultry houses (OR = 1.55, 95% CI 0.93 to 2.58) and dairy cattle (OR = 1.28, 95% CI 0.86 to 1.89). The occupational data were more limited for spouses; however, we saw similar associations for dairy cattle (OR = 1.50, 95% CI 0.72 to 3.14) and organochlorine pesticides (OR = 1.29, 95% CI 0.64 to 2.59).
While historic farm exposures may contribute to the observed associations with pesticides, these results suggest that organochlorine and carbamate pesticides should be further evaluated as potential risk factors for farmer's lung.
The immediate postnatal period is the period of the fastest growth in the entire life span and a critical period for lung development. Therefore, it is interesting to examine the association between growth during this period and childhood respiratory disorders.
We examined the association of peak weight and height velocity to age 36 months with maternal report of current asthma at 36 months (n = 50,311), recurrent lower respiratory tract infections (LRTIs) by 36 months (n = 47,905) and current asthma at 7 years (n = 24,827) in the Norwegian Mother and Child Cohort Study. Peak weight and height velocity was calculated using the Reed1 model through multilevel mixed-effects linear regression. Multivariable log-binomial regression was used to calculate adjusted relative risks (adj.RR) and 95% confidence intervals (CI). We also conducted a sibling pair analysis using conditional logistic regression.
Peak weight velocity was positively associated with current asthma at 36 months [adj.RR 1.22 (95%CI: 1.18, 1.26) per standard deviation (SD) increase], recurrent LRTIs by 36 months [adj.RR 1.14 (1.10, 1.19) per SD increase] and current asthma at 7 years [adj.RR 1.13 (95%CI: 1.07, 1.19) per SD increase]. Peak height velocity was not associated with any of the respiratory disorders. The positive association of peak weight velocity and asthma at 36 months remained in the sibling pair analysis.
Higher peak weight velocity, achieved during the immediate postnatal period, increased the risk of respiratory disorders. This might be explained by an influence on neonatal lung development, shared genetic/epigenetic mechanisms and/or environmental factors.
Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low-frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls and 590 case–parent trios representing European Americans, African Americans/African Caribbeans and Latinos. Our study reveals one low-frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31 × 10−6; OR=1.25; MAF=1.21%) and two genes harbouring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12–21 asthma locus in the Latino and combined samples (P=7.81 × 10−8 and 4.09 × 10−8, respectively) and MTHFR in the African ancestry sample (P=1.72 × 10−6). Our results suggest that associations with rare and low-frequency variants are ethnic specific and not likely to explain a significant proportion of the ‘missing heritability’ of asthma.
Common variants account for only a small amount of the heritable risk for developing asthma. Using a meta-analysis approach, Igartua et al. identify one low-frequency missense mutation and two genes with functional variants that are associated with asthma, but only in specific ethnic groups.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
Whether probiotics, which can influence the microbiome, prevent infant eczema or allergic diseases remains an open question. Most studies have focused on high-risk infants.
To assess whether consumption of probiotic milk products protects against atopic eczema, rhinoconjuctivitis, and asthma in early childhood in a large population-based pregnancy cohort (The Norwegian Mother and Child Cohort Study).
We examined associations between consumption of probiotic milk products in pregnancy and infancy with questionnaire-reported atopic eczema, rhinoconjuctivitis, and asthma in 40,614 children. Relative risks (RR) were calculated using general linear models, adjusted for potential confounders.
Consumption of probiotic milk in pregnancy was associated with a slightly reduced risk [(adjusted RR (aRR)] of atopic eczema at 6 months aRR=0.94 (95% CI: 0.89, 0.99) and of rhinoconjuctivitis between 18 and 36 months, aRR=0.87 (95% CI: 0.78, 0.98) compared with no consumption during pregnancy. Maternal history of allergic disease did not notably influence the associations. When both mother (during pregnancy) and infant (after 6 months of age) had consumed probiotic milk, the adjusted relative risk of rhinoconjunctivitis was aRR=0.80 (95% CI: 0.68, 0.93) relative to no consumption by either. Probiotic milk consumption was not associated with asthma at 36 months.
In this population-based cohort, consumption of probiotic milk products was related to a reduced incidence of atopic eczema and rhinoconjuctivitis, but no association was seen for incidence of asthma by 36 months of age.
allergy; asthma; eczema; microbiome; MoBa; probiotics; rhinoconjunctivitis
Breastfeeding clearly protects against early wheezing, but recent data suggest that it may increase later risk of atopic disease and asthma.
To examine the relationship between breastfeeding and later asthma and allergy outcomes using data from the Avon Longitudinal Study of Parents and Children, a large birth cohort in the United Kingdom.
We used adjusted logistic regression models to evaluate the association between breastfeeding and atopy at age 7 years, bronchial responsiveness to methacholine at age 8 years, and wheeze at ages 3 and 7½ years. Bayesian methods were used to assess the possibility of bias due to an influence of early wheezing on duration of breastfeeding as well as selection bias.
Breastfeeding was protective for wheeze in the first 3 years of life (OR =0.80, 95% CI 0.70-0.90 for 6+ months relative to never) but not wheeze (OR=0.98, 95% CI 0.79-1.22), atopy (OR=1.12, 95% CI 0.92-1.35) or BHR (1.07, 95% CI 0.82-1.40) at ages 7-8 years. Bayesian models adjusting for the longer duration of breastfeeding among children with wheezing in early infancy gave virtually identical results.
We did not find consistent evidence for either a deleterious effect or a protective effect of breastfeeding on later risk of allergic disease in a large prospective birth cohort of children with objective outcome measures and extensive data on potential confounders and effect modifiers. Neither reverse causation nor loss to follow-up appears to have materially biased our results.
Breastfeeding does not increase the risk of asthma or atopy in children, even when their mothers are asthmatic.
This study supports the evidence that breastfeeding does not adversely affect children with regard to asthma and other allergic outcomes. Breastfeeding’s protective role against early wheezing is a benefit for respiratory health.
asthma; atopy; breastfeeding; bronchial hyperresponsiveness; allergy
Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1,000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between sub-continental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide.
The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.
We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990–2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.
292 982 (95% UI 261 017–327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483–407 574) in 1990. The global annual rate of change in the MMR was −0·3% (−1·1 to 0·6) from 1990 to 2003, and −2·7% (−3·9 to −1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290–2866) maternal deaths were related to HIV in 2013, 0·4% (0·2–0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1–1262·8) in South Sudan to 2·4 (1·6–3·6) in Iceland.
Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
Bill & Melinda Gates Foundation.
Recent data suggest beneficial effects of fiber intake on chronic respiratory symptoms in adults that are independent of antioxidant vitamin intake, but little is known about fiber consumption in relation to lung function and chronic obstructive pulmonary disease (COPD). The authors investigated the association of fiber intake with lung function and COPD in 11,897 men and women from the Atherosclerosis Risk in Communities (ARIC) study. After controlling for potential confounders, positive associations between lung function and fiber intake from all sources as well as from cereal or fruit alone were found. Participants in the highest quintile of total fiber intake had 60.2 ml higher forced expiratory volume in 1 second (FEV1) (p for trend<0.001), 55.2 ml higher forced vital capacity (FVC) (p=0.001), 0.4% higher FEV1/FVC ratio (p=0.040), 1.8% higher percent predicted FEV1 (p<0.001), and 1.4% higher percent predicted FVC (p=0.001), compared with those in the lowest quintile. The adjusted odds ratios of COPD for the highest versus lowest quintiles of intake were 0.85 (p=0.044) for total fiber, 0.83 (p=0.021) for cereal fiber, and 0.72 (p=0.005) for fruit fiber. This study provides the first evidence that dietary fiber is independently associated with better lung function and reduced prevalence of COPD.
COPD; FEV1; FVC; fiber; pulmonary function
Traffic exposure is a major contributor to ambient air pollution for people living close to busy roads. The relationship between traffic exposure and lung function remains inconclusive in adults.
We conducted a cross-sectional study to investigate the association between traffic exposure and lung function in the Atherosclerosis Risk in Communities (ARIC) study, a community-based cohort of 15,792 middle-aged men and women. Traffic density and distance to major roads were used as measures of traffic exposure.
After controlling for potential confounders including demographic factors, personal and neighborhood level socioeconomic characteristics, cigarette smoking, and background air pollution, higher traffic density was significantly associated with lower forced expiratory volume at 1s (FEV1) and forced vital capacity (FVC) in females. Relative to the lowest quartile of traffic density, the adjusted differences across increasing quartiles were 5.1, −15.4 and −21.5ml for FEV1 (p value of linear trend across the quartiles =0.041), and 1.2, −23.4 and −34.8ml for FVC (p trend =0.010). Using distance from major roads as a simpler index of traffic related air pollution exposure, the FEV1 was −15.7ml (95%CI −34.4ml, 2.9ml) lower and the FVC was −24.2ml (95%CI −46.2ml, −2.3ml) lower for women living within 150 meters compared to subjects living further away. We did not find a significant effect of traffic density or distance to major roads on lung function among men. The FEV1/FVC ratio was not significantly associated with traffic exposure in either gender.
This is the largest published study of traffic exposure and pulmonary function in adults to date. These results add to growing evidence that chronic exposure to traffic-related air pollution may adversely affect respiratory health.
air pollution; traffic; pulmonary function; FEV1; FVC
Transforming growth factor beta-1 (TGFB1) may influence asthma by modulating allergic airway inflammation and airway remodeling. The role of single nucleotide polymorphisms (SNPs) of TGFB1 in asthma remains inconclusive. We examined TGFB1 SNPs in relation to asthma risk and degree of atopy among 546 case-parent triads, consisting of asthmatics aged 4 to 17 years and their parents in Mexico City. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped five TGFB1 SNPs, including two known functional SNPs [C-509T (rs1800469), T869C (rs1982073)] and three others (rs7258445, rs1800472, rs8179181), using TaqMan and Masscode assays. We analyzed the data using log-linear and polytomous logistic methods. Three associated SNPs, including the two known functional SNPs, were statistically significantly related to asthma risk. Individuals carrying the T allele of C-509T had an increased risk of asthma [relative risk (RR) = 1.42, 95% confidence interval (CI) = 1.08–1.87 for one copy; RR (95%CI) = 1.95 (1.36–2.78) for two copies]. For T869C, the RRs (95%CI) were 1.47 (1.09–1.98) for one and 2.00 (1.38–2.90) for two copies of the C allele. Similar results were found for rs7258445. The haplotype containing all three risk alleles conferred an increased risk of asthma (RR = 1.48, 95% CI = 1.11–1.95 for one copy; RR = 1.77, 95% CI = 1.22–2.57 for two copies). These three SNPs were also related to the degree of atopy. This largest study to date of genetic variation in TGFB1 and asthma and atopy adds to increasing evidence for a role in these disorders.
TGFB1; asthma; allergy; polymorphism; genetic; SNP
Occupational factors contribute to a significant fraction of respiratory disease and symptoms. We evaluated the role of occupational exposures on asthma, chronic bronchitis, and respiratory symptoms in a population-based cohort, the Singapore Chinese Health Study. History of occupations, occupational exposures, and respiratory conditions were collected by interviews with 52,325 Singaporeans born 1918–1953. Exposure to dusts, from cotton, wood, metal, mineral and/or asbestos, was associated with non-chronic cough and/or phlegm (OR = 1.19, 95% CI = 1.08, 1.30), chronic bronchitis (OR = 1.26, 95% CI = 1.01, 1.57) and adult-onset asthma (OR = 1.14, 95% CI = 1.00, 1.30). Cotton dust was the major component contributing to respiratory symptoms. Vapor exposure, from chemical solvents, dyes, cooling oils, paints, wood preservatives and/or pesticides, was associated with non-chronic cough or phlegm (OR = 1.14, 95% CI = 1.03, 1.27), chronic dry cough (OR = 1.55, 95% CI = 1.19, 2.01) and adult-onset asthma (OR = 1.34, 95% CI = 1.15, 1.56). Chemical solvents, cooling oils and pesticides were the major sources contributing to respiratory symptoms. These data support the role of occupational exposures in the etiology of respiratory illness in a population-based cohort in Singapore with a low prevalence of atopic illness.
Asthma; Chronic Bronchitis; Occupational Disease; Occupational exposure; Chronic obstructive pulmonary disease; OR - odds ratio; CI - confidence interval; COPD - chronic obstructive pulmonary disease
S-nitrosothiols are potent endogenous bronchodilators depleted in asthmatic airway lining fluid. S-nitrosoglutathione reductase (GSNOR, also known as ADH5 or FDH) catalyzes the metabolism of S-nitrosoglutathione (GSNO) and controls intracellular levels of S-nitrosothiols. GSNOR knockout mice have increased lung S-nitrosothiols and are therefore protected from airway hyperresponsiveness after methacholine or allergen challenge.
To investigate whether genetic variation in GSNOR is associated with childhood asthma and atopy.
We genotyped 5 tagging and two additional single nucleotide polymorphisms (SNPs) in GSNOR, in 532 nuclear families consisting of asthmatic children aged 4 to 17 years and both parents in Mexico City. Atopy was determined by skin prick tests.
Carrying one or two copies of the minor allele of SNP rs1154404 was associated with decreased risk of asthma [relative risk (RR) = 0.77, 95% confidence interval (CI), 0.61–0.97, P = 0.028 for one copy; RR = 0.66, 95% CI, 0.44–0.99, P = 0.046 for two copies]. Homozygosity for the minor allele of SNP rs28730619 was associated with increased risk of asthma (RR = 1.60, 95% CI, 1.13–2.26, P = 0.0077). Haplotype analyses supported the single SNP findings. GSNOR SNPs were not associated with the degree of atopy.
This is the first study of genetic polymorphisms in GSNOR and asthma. These data suggest that genetic variation in GSNOR may play a role in asthma susceptibility.
The association of GSNOR polymorphisms with asthma suggests a potential therapeutic target.
Findings from this study suggest that genetic variation in S-nitrosoglutathione reductase (GSNOR) may play a role in asthma susceptibility.
alcohol dehydrogenase 5 (ADH5); allergy; asthma; formaldehyde dehydrogenase (FDH); genetic predisposition to disease; nitric oxide (NO); single nucleotide polymorphism (SNP); S-nitrosoglutathione (GSNO); S-nitrosoglutathione reductase (GSNOR); S-nitrosothiol (SNO)
Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”).
We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses.
Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression.
Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution.
Studies suggest that prenatal vitamin D status may be inversely associated with lower respiratory tract infections (LRTIs) early in life. Studies of prenatal vitamin D status and development of asthma have inconsistent findings.
We examined associations of maternal mid-pregnancy 25-hydroxyvitamin D (25(OH)D) level with frequency of LRTIs by 36 months and with current asthma at 36 months using the Norwegian Mother and Child Cohort Study. Maternal plasma 25(OH)D level was measured using liquid chromatography-tandem mass spectrometry. Respiratory disorders were evaluated by maternal report through questionnaires. LRTIs were analyzed in a random sample of 1,248 children. Asthma was analyzed using a case-control design, including 489 cases and 1,183 controls. Multivariable generalized linear models calculated adjusted measures of association.
The median gestational week of sample collection was 18 weeks (range 9, 35). The mean 25(OH)D level was 73.7 nmol/L (standard deviation 23.7). Higher maternal mid-pregnancy 25(OH)D level was associated with reduced risk of 3 or more LRTIs by 36 months versus none, adjusted risk ratio (RR) 0.74 [95% confidence interval (CI): 0.58, 0.93] per 20 nmol/L increase. Associations were similar when examining frequency of LRTIs by 18 months and frequency of LRTIs between 18 and 36 months. Maternal mid-pregnancy 25(OH)D level was not significantly associated with current asthma at 36 months, adjusted odds ratio (OR) 0.91 [95% CI: 0.81, 1.02] per 20 nmol/L increase.
Higher maternal mid-pregnancy 25(OH)D level was associated with a modestly reduced risk of recurrent LRTIs by 36 months, but was not associated with current asthma at 36 months.
asthma; lower respiratory tract infection; pregnancy; vitamin D
Exacerbation is a critical event in asthma management. We investigated whether exacerbation of symptoms is associated with farming exposures among agricultural pesticide applicators with asthma.
Participants were pesticide applicators with active asthma (wheezing and breathing problems in past 12 months) who completed enrollment questionnaires for the Agricultural Health Study (AHS). Exacerbation of asthma was defined as having visited a hospital emergency room or doctor for an episode of wheezing or whistling in the past 12 months. Exposures of interest were using 36 specific pesticides in the past 12 months and conducting various agricultural activities. Adjusted odds ratios (ORs) were estimated by logistic regression while controlling for potential confounders.
The 926 AHS adult pesticide applicators with active asthma included 202 (22%) with exacerbation. Inverse associations with exacerbation were observed for two herbicides (glyphosate, odds ratio (OR) = 0.5, 95% confidence interval (CI) 0.3–0.8, and paraquat, OR=0.3, 95% CI 0.1–0.9) and several agricultural activities (repairing engines, grinding metal, driving diesel tractors, and performing veterinary procedures). Only asthma cases with allergies (i.e., doctor-diagnosed hay fever or eczema, 46%) had positive exacerbation-pesticide associations, with OR=2.1 (95% CI 1.1–4.1) for the herbicide pendimethalin and OR=10.2 (95% CI 1.9–55) for the insecticide aldicarb.
The inverse associations with two pesticides and specific farm activities are consistent with the possibility that asthma cases prone to exacerbation may avoid exposures that trigger symptoms. Although limited by small sample size and a cross-sectional design, our study suggests that use of specific pesticides may contribute to exacerbation of asthma among individuals with allergies.
Asthma; Asthma exacerbation; Work-related; Agriculture; Pesticides
Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RLML18R1, and 10pl4, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.
Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis.
We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS.
GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment, P-value 2.6 × 10−24) for allergic rhinitis-associated eSNPs (genetic variants associated with both gene expression and allergic rhinitis). The integrated GWAS, coexpression network, and eSNP results therefore supported this coexpression module as an allergic rhinitis module. Pathway analysis revealed that the module was enriched for mitochondrial pathways (8.6-fold enrichment, P-value 4.5 × 10−72).
Our results highlight mitochondrial pathways as a target for further investigation of allergic rhinitis mechanism and treatment. Our integrated approach can be applied to provide biologic context for GWAS of other diseases.
Genome-wide association study; Allergic rhinitis; Coexpression network; Expression single-nucleotide polymorphism; Coexpression module; Pathway; Mitochondria; Hay fever; Allergy