Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook ...an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10
) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV
), forced vital capacity (FVC) and their ratio (FEV
/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (
(aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV
/FVC: p
=3.96×10
and p
=7.22×10
). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV
/FVC: p=2.65×10
).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.
Exposure to particulate matter with diameter ≤2.5 μm (PM2.5) is associated with an elevated risk of adverse health effects and cooking is a primary source of PM2.5 in non-smoking households. ...Therefore, it is important to investigate PM2.5 concentrations that might be found in domestic kitchens, and the appropriate ventilation mechanisms to reduce them.
Uncertainty in daily mean PM2.5 concentrations in English kitchens is predicted using a statistical model and stochastic simulation. A worst-case heating season scenario is considered where 3 meals are cooked per day and fresh air is provided by infiltration and fans.
The model predicts that >98% of English houses are too airtight to dilute PM2.5 emissions solely by infiltration so that daily mean concentrations in kitchens are below the WHO guideline of 25 μg/m3. Therefore, controlled ventilation is required in all kitchens. Ventilation strategies prescribed by English Building Regulations and ASHRAE 62.2 are found to be adequate for <12% and 75% of houses, respectively, when applied during cooking. Continuing to ventilate for a further 10 minutes has a significant effect when using an intermittent strategy, increasing the centiles of compliant houses to 46% and >98%, respectively. A cooker hood is the most effective ventilation strategy when used during cooking plus 10 minutes. Standards should be amended to incorporate required combinations of airflow rates and capture efficiencies. A hood with a capture efficiency of 50% requires airflow rates of 52 l/s and 90 l/s for PM2.5 concentrations to remain below WHO guidelines in 75% and 98% of houses, respectively.
•Houses are too airtight to dilute PM2.5 emissions from cooking by infiltration.•Controlled ventilation is required in all domestic kitchens.•Ventilate during cooking plus 10 minutes has a significant effect.•A cooker hood is the most effective method of pollutant control.•Existing regulations of domestic kitchen ventilation require revision.
GPR126 is an adhesion G protein‐coupled receptor which lies on chromosome 6q24. Genetic variants in this region are reproducibly associated with lung function and COPD in genome wide association ...studies (GWAS). The aims of this study were to define the role of GPR126 in the human lung and in pulmonary disease and identify possible casual variants. Online tools (GTEx and LDlink) identified SNPs which may have effects on GPR126 function/ expression, including missense variant Ser123Gly and an intronic variant that shows eQTL effects on GPR126 expression. GPR126 signaling via cAMP‐mediated pathways was identified in human structural airway cells when activated with the tethered agonist, stachel. RNA‐seq was used to identify downstream genes/ pathways affected by stachel‐mediated GPR126 activation in human airway smooth muscle cells. We identified ~350 differentially expressed genes at 4 and 24 hours post stimulation with ~20% overlap. We identified that genes regulated by GPR126 activation include IL33, CTGF, and SERPINE1, which already have known roles in lung biology. Pathways altered by GPR126 included those involved in cell cycle progression and cell proliferation. Here, we suggest a role for GPR126 in airway remodeling.
•A probabilistic model and modelling framework to evaluate a housing stock is presented.•Uncertainties are predicted for exposures to PM2.5, ventilation rates, and energy losses.•PM2.5 emission rates ...and envelope leakage affect exposures the most.
The housing stock of Chile is responsible for 15% of its total final energy consumption and so its Government is regulating the construction of dwellings. However, there is a need to establish models to help governments determine sensible guidance. This paper presents the Chilean Housing Archetypes AiR quality Model (CHAARM) and a stochastic framework for predicting uncertainties in indoor pollutant concentrations, ventilation and infiltration rates, and associated energy demand during the heating season. Pollutant sources are PM2.5 emitted by cooking and unflued heaters present in 80% of houses.
CHAARM predicts that 66% of dwellings have a daily mean PM2.5 concentration below the WHO 24-hour guideline value of 25 μg/m3, even if their windows are always closed. Houses are not found to be airtight and 60% have Q50>10 m3 h−1 m-2. Dwelling ventilation and infiltration heat loss is estimated to be 0.25–42.3 MWh with 90% confidence, and to account for at least 15% of the estimated total energy demand of the stock. Therefore, many houses require remediation measures to improve their airtightness and to reduce their annual space heating demand. However, to avoid negative health effects from exposure to PM2.5, kitchen ventilation, such as a cooker hood, should be installed and unflued heaters should be replaced.
Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 ...individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10
), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
Serum urate is the most abundant small molecule with antioxidant properties found in blood and the epithelial lining fluid of the respiratory system. Moderately raised serum urate is associated with ...lower rates of lung cancer and COPD in smokers but whether these relationships reflect antioxidant properties or residual confounding is unknown.
We investigated the observational and potentially causal associations of serum urate with lung cancer incidence and FEV
using one-sample Mendelian randomization (MR) and the UK Biobank resource. Incident lung cancer events were identified from national cancer registries as FEV
was measured at baseline. Observational and genetically instrumented incidence rate ratios (IRRs) and risk differences per 10,000 person-years (PYs) by smoking status were estimated.
The analysis included 359,192 participants and 1,924 lung cancer events. The associations between measured urate levels and lung cancer were broadly U-shaped but varied by sex at birth with the strongest associations in current smoking men. After adjustment for confounding variables, current smoking men with low serum urate (100 µmol/L) had the highest predicted lung cancer incidence at 125/10,000 PY (95%CI 56-170/10,000 PY) compared with 45/10,000 PY (95%CI 38-47/10,000 PY) for those with the median level (300 µmol/L). Raised measured urate was associated with a lower baseline FEV
. The MR results did not support a causal relationship between serum urate and lung cancer or FEV
.
We found no evidence that serum urate is a modifiable risk factor for respiratory health or lung cancer.
Summary
Background
Irritable bowel syndrome with diarrhoea (IBS‐D) is a common condition, greatly reducing the quality of life with few effective treatment options available.
Aim
To report the ...beneficial response shown in our trial with the 5‐hydroyxtryptamine (5‐HT) receptor 3 antagonist, ondansetron in IBS‐D
Methods
A randomised, placebo‐controlled, cross‐over trial of 5 weeks of ondansetron versus placebo in 125 patients meeting modified Rome III criteria for IBS‐D as previously described. Patients were compared to 21 healthy controls. 5‐HT and 5‐HIAA were measured in rectal biopsies. Whole gut transit time was assessed using a radio‐opaque marker technique. Whole blood DNA was genotyped for an insertion polymorphism in the promoter region of the serotonin transporter gene SLC6A4, as well as single nucleotide polymorphisms (SNPs) of the tryptophan hydroxylase gene TPH1 and 5‐HT3 receptor genes HTR3A, C and E.
Results
Patients’ biopsies showed significantly higher 5‐HIAA levels (2.1 (1.2‐4.2) pmol/mg protein vs 1.1 (0.4‐1.5) in controls, P < .0001). 39 patients used < 4 mg/d (“super‐responders”) while 55 required ≥ 4 mg/d. 5‐HT concentrations in rectal biopsies were significantly lower in super‐responders (21.3 (17.0‐31.8) vs 37.7 (21.4‐61.4), P = .0357) and the increase in transit time on ondansetron was significantly greater (15.6 (1.8‐31) hours vs 3.9 (−5.1‐17.9) hours). Stool consistency responders were more likely to carry the CC genotype of the SNP p.N163K rs6766410 of the HTR3C gene (33% vs 14%, P = .0066).
Conclusion
IBS‐D patients have significant abnormalities in mucosal 5‐HT metabolism. Those with the lowest concentration of 5‐HT in rectal biopsies showed the greatest responsiveness to ondansetron.
South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty ...acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures.
Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO2max (40.6±6.6 vs 52.4±5.7 ml x kg(-1) x min(-1), p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77±2.02 vs 6.55±2.60 mg x kg(-1) x min(-1) at 55% VO2max, p = 0.013), and absolute (3.46±2.20 vs 6.00±1.93 mg x kg(-1) x min(-1) at 25 ml O(2) x kg(-1) x min(-1), p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10-13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity.
These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes.
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