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RationaleLung function in early adulthood is associated with subsequent adverse health outcomes.ObjectivesTo ascertain whether stable and reproducible lung function trajectories can be derived in different populations and investigate their association with objective measures of cardiovascular structure and function.MethodsUsing latent profile modelling, we studied three population-based birth cohorts with repeat spirometry data from childhood into early adulthood to identify trajectories of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). We used multinomial logistic regression models to investigate early-life predictors of the derived trajectories. We then ascertained the extent of the association between the derived FEV1/FVC trajectories and blood pressure and echocardiographic markers of increased cardiovascular risk and stroke in ~3200 participants at age 24 years in one of our cohorts.ResultsWe identified four FEV1/FVC trajectories with strikingly similar latent profiles across cohorts (pooled N=6377): above average (49.5%); average (38.3%); below average (10.6%); and persistently low (1.7%). Male sex, wheeze, asthma diagnosis/medication and allergic sensitisation were associated with trajectories with diminished lung function in all cohorts. We found evidence of an increase in cardiovascular risk markers ascertained by echocardiography (including left ventricular mass indexed to height and carotid intima-media thickness) with decreasing FEV1/FVC (with p values for the mean crude effects per-trajectory ranging from 0.10 to p<0.001). In this analysis, we considered trajectories as a pseudo-continuous variable; we confirmed the assumption of linearity in all the regression models.ConclusionsChildhood lung function trajectories may serve as predictors in the development of not only future lung disease, but also the cardiovascular disease and multimorbidity in adulthood.

Identifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding “second hits” in transwith these is unknown.

The COVID-19 vaccination service is a key component in the UK approach to reducing disease morbidity and mortality. Groups within the population at increased risk of severe outcomes from COVID-19 overlap with groups that are less likely to take up the offer of vaccination. This article outlines some learning from approaches within a large vaccination centre in the UK to reduce inequalities.

Objective: Food additives can exacerbate ADHD symptoms and cause non-immunoglobulin E-dependent histamine release from circulating basophils. However, children vary in the extent to which their ADHD symptoms are exacerbated by the ingestion of food additives. The authors hypothesized that genetic polymorphisms affecting histamine degradation would explain the diversity of responses to additives. Method: In a double-blind, placebo-controlled crossover trial, challenges involving two food color additive and sodium benzoate (preservative) mixtures in a fruit drink were administered to a general community sample of 3-year-old children (N=153) and 8/9-year-old children (N=144). An aggregate ADHD symptom measure (based on teacher and parent blind ratings of behavior, blind direct observation of behavior in the classroom, and--for 8/9-year-old children only--a computerized measure of attention) was the main outcome variable. Results: The adverse effect of food additives on ADHD symptoms was moderated by histamine degradation gene polymorphisms HNMT T939C and HNMT Thr105lle in 3- and 8/9-year-old children and by a DAT1 polymorphism (short versus long) in 8/9-year-old children only. There was no evidence that polymorphisms in catecholamine genes COMT Vall08Met, ADRA2A C1291G, and DRD4-rs7403703 moderated the effect on ADHD symptoms. Conclusions: Histamine may mediate the effects of food additives on ADHD symptoms, and variations in genes influencing the action of histamine may explain the inconsistency between previous studies. Genes influencing a range of neurotransmitter systems and their interplay with environmental factors, such as diet, need to be examined to understand genetic influences on ADHD symptoms.

The quickest way to lose money in online futures trading is to have your computer crash in the middle of a trade. A common horror story goes like this: 'I [...]

Emerging evidence suggests that exposures in prepuberty, particularly in fathers-to-be, may impact the phenotype of future offspring. Analyses of the RHINESSA cohort find that offspring of father’s exposed to tobacco smoking or overweight that started in prepuberty demonstrate poorer respiratory health in terms of more asthma and lower lung function. A role of prepuberty onset smoking for offspring fat mass is suggested in the RHINESSA and ALSPAC cohorts, and historic studies suggest that ancestral nutrition during prepuberty plays a role for grand-offspring’s health and morbidity. Support for causal relationships between ancestral exposures and (grand-)offspring’s health in humans has been enhanced by advancements in statistical analyses that optimize the gain while accounting for the many complexities and deficiencies in human multigeneration data. The biological mechanisms underlying such observations have been explored in experimental models. A role of sperm small RNA in the transmission of paternal exposures to offspring phenotypes has been established, and chemical exposures and overweight have been shown to influence epigenetic programming in germ cells. For example, exposure of adolescent male mice to smoking led to differences in offspring weight and alterations in small RNAs in the spermatozoa of the exposed fathers. It is plausible that male prepuberty may be a time window of particular susceptibility, given the extensive epigenetic reprogramming taking place in the spermatocyte precursors at this age. In conclusion, epidemiological studies in humans, mechanistic research, and biological plausibility, all support the notion that exposures in the prepuberty of males may influence the phenotype of future offspring.Emerging research from human multigeneration cohorts, historic studies, and mechanistic research indicates that prepuberty is an important window of susceptibility with regard to health and disease of future offspring.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.

Single-cell RNA sequencing (scRNA-seq) of the bronchial epithelium enables examination of cellular subtypes and their responses to viral infections. Here, an optimized method for the isolation of virally infected primary bronchial epithelial cells using a commercially available microfluidic device is presented. Using this method single cells can be rapidly isolated with minimal equipment available in most laboratories. Isolation can be carried out inside biological safety cabinets, permitting the use of virally infected cells. Both cell-line and primary cells isolated using the device retained sufficient RNA integrity for the generation of short-read sequencing-compatible cDNA libraries to facilitate scRNA-seq.

Background: Active smoking has been reported among 7% of teenagers worldwide, with ages ranging from 13 to 15 years. An epidemiological study suggested that preconceptional paternal smoking is associated with adolescent obesity in boys. We developed a murine adolescent smoking model before conception to investigate the paternal molecular causes of changes in offspring’s phenotype. Method: Male and female C57BL/6J mice were exposed to increasing doses of mainstream cigarette smoke (CS) from onset of puberty for 6 weeks and mated with room air (RA) controls. Results: Thirteen miRNAs were upregulated and 32 downregulated in the spermatozoa of CS-exposed fathers, while there were no significant differences in the count and morphological integrity of spermatozoa, as well as the proliferation of spermatogonia between CS- and RA-exposed fathers. Offspring from preconceptional CS-exposed mothers had lower body weights (p= 0.007). Moreover, data from offspring from CS-exposed fathers suggested a potential increase in body weight (p= 0.062). Conclusion: We showed that preconceptional paternal CS exposure regulates spermatozoal miRNAs, and possibly influences the body weight of F1 progeny in early life. The regulated miRNAs may modulate transmittable epigenetic changes to offspring, thus influence the development of respiratory- and metabolic-related diseases such as obesity, a mechanism that warrants further studies for elaborate explanations.

Because advances in broadband capabilities will soon allow first responders to access and use many forms of data when responding to emergencies, it is becoming critically important to design heads-up displays to present first responders with information in a manner that does not induce extraneous mental workload or cause undue interaction errors. Virtual reality offers a unique medium for envisioning and testing user interface concepts in a realistic and controlled environment. In this paper, we describe a virtual reality-based emergency response scenario that was designed to support user experience research for evaluating the efficacy of intelligent user interfaces for firefighters. We describe the results of a usability test that captured firefighters’ feedback and reactions to the VR scenario and the prototype intelligent user interface that presented them with task critical information through the VR headset. The paper concludes with lessons learned from our development process and a discussion of plans for future research.

Diet diversity (DD) during infancy may prevent food allergies (FA), possibly by exposing the gastrointestinal microbiota to diverse foods and nutrients.

ABSTRACTDNA methylation (DNAm) in blood (umbilical cord blood and capillary blood collected after birth on Guthrie cards) during the perinatal period is being increasingly studied with the aim of identifying epigenetic markers of in utero environmental exposures or later disease development. However, the comparability in DNAm between these two sources is unknown. To this end, DNAm from the cord blood and capillary blood of 34 subjects in the Isle of Wight 3rdGeneration Birth Cohort (68 samples) were included to assess the comparability. Differences in average DNAm (overall agreement), correlations in DNAm, and intra-class correlation coefficients (ICC) in DNAm between the two sources, at each of the 430,742 CpG sites, were evaluated. The results showed that a high proportion (70.1%) of the CpGs DNAm agreed between cord blood and neonatal blood on Guthrie cards. A small portion of CpGs showed high correlation (correlation ≥0.5) or high ICC (ICC ≥0.5) in DNAm of the whole genome. This proportion increased dramatically in differentially methylated regions (DMRs) that are associated with exposure to maternal smoking, between the two sources.

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.

For linear systems in the observer canonical form, we introduce a state observer with time-varying gains that tend to infinity as time approaches a prescribed convergence time. The observer is shown to exhibit fixed-time stability with an arbitrary convergence time, which is prescribed by the user irrespective of initial conditions. The output estimation error injection terms are also shown to remain uniformly bounded and converge to zero at the prescribed time. [ABSTRACT FROM AUTHOR]

Sulfur dioxide (SO2) is emitted in large quantities from coal‐burning power plants and leads to various harmful health and environmental effects. In this study, we use plume intercepts from the Wintertime INvestigation of Transport, Emission and Reactivity (WINTER) campaign to estimate the oxidation rates of SO2under wintertime conditions and the factors that determine SO2removal. Observations suggest that OH governs the rate SO2oxidation in the eastern United States during winter. The range of mean oxidation rates during the day from power plants were 0.22–0.71%/hr, producing SO2lifetimes of 13–43 days, if SO2consumption is assumed to occur during 10.5 hr of daylight in cloudless conditions. Though most nighttime rate measurements were zero within uncertainty, there is some evidence of nighttime removal, which suggests alternate oxidation mechanisms. The fastest nighttime observed SO2oxidation rate was 0.25±0.07%/hr, producing a combined day/night SO2lifetime of 8.5–21 days. The upper limit of the oxidation rate (the mean+1σof the fastest day and night observations) is 16.5%/day, corresponding to a lifetime of 6.1 days. The analysis also quantifies the primary emission of sulfate from power plants. The median mole percentage of SO4‐2from observed plumes was 1.7% and the mean percentage sulfate was 2.8% for intercepts within 1 hr of transit to power plants. The largest value observed from close intercepts was over 7% sulfate, and the largest extrapolated value was 18%, based on intercepts further from their source and fastest observed oxidation rate. The daytime conversion rate of SO2to SO4‐2was 0.22‐0.71%/hr in winter under clear‐sky conditions, with lifetimes of 140‐450 hrFor 10.5 hr of daylight, the upper limit of the oxidation rate is 16.5%/day, corresponding to a lifetime of 6.1 daysDirect emissions of SO4‐2relative to total sulfur (SO2+ SO4‐2) had mean and median values of 1.7% and 2.8%, respectively

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n= 321,223) and offspring birth weight (n= 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming.

United States Environmental Protection Agency guidance on the use of photochemical models for assessing the efficacy of an emissions control strategy for ozone requires that modeling be used in a relative sense. Consequently, testing a modeling system's ability to predict changes in ozone resulting from emission changes is critical. We evaluate model simulations for precursor species (NOx, CO, and volatile organic compounds [VOCs]), radicals (OH and HO2), a secondary pollutant (O3), and the model response of these compounds to weekend/weekday emission changes during California Nexus study in 2010. The modeling system correctly simulated the broad spatial and temporal variation of NOxand O3in California South Coast. Although the model generally underpredicted the daytime mixing ratios of NO2at the surface and overpredicted the NO2column, the simulated weekend to weekday ratios are consistent with each other and match the observed ratios well. The modeling system exhibited reasonable performance in simulating the VOC compounds with fossil fuel origins but has larger bias in simulating certain species associated with noncombustion sources. The modeling system successfully captured the weekend changes of the enhancement ratios for various VOC species to CO and the relative changes of HOx, which are indicators of faster chemical processing on weekends. This work demonstrates satisfactory model performances for O3and most relevant chemical compounds with more robust performance in simulating weekend versus weekday changes. Improved planetary boundary layer height simulations, a better understanding of OH‐HO2cycling, continued improvement of emissions, especially urban biogenic emissions and emissions of oxygenated VOCs, are important for future model improvement. We evaluate model simulations for O3, NOx, VOCs, and HOxas well as their response to weekend emission changes during CalNex 2010The model results show a robust ability to simulate the weekend effect, for a majority of the relevant chemical speciesFurther understanding is needed for urban biogenic emissions and emissions of oxygenated VOCs such as ethanol, methanol, and acetone

Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.

Recent studies suggest overestimates in current U.S. emission inventories of nitrogen oxides (NOx= NO + NO2). Here, we expand a previously developed fuel-based inventory of motor-vehicle emissions (FIVE) to the continental U.S. for the year 2013, and evaluate our estimates of mobile source emissions with the U.S. Environmental Protection Agency’s National Emissions Inventory (NEI) interpolated to 2013. We find that mobile source emissions of NOxand carbon monoxide (CO) in the NEI are higher than FIVE by 28% and 90%, respectively. Using a chemical transport model, we model mobile source emissions from FIVE, and find consistent levels of urban NOxand CO as measured during the Southeast Nexus (SENEX) Study in 2013. Lastly, we assess the sensitivity of ozone (O3) over the Eastern U.S. to uncertainties in mobile source NOxemissions and biogenic volatile organic compound (VOC) emissions. The ground-level O3is sensitive to reductions in mobile source NOxemissions, most notably in the Southeastern U.S. and during O3exceedance events, under the revised standard proposed in 2015 (>70 ppb, 8 h maximum). This suggests that decreasing mobile source NOxemissions could help in meeting more stringent O3standards in the future.

Nitric oxide (NO) is emitted in large quantities from coal‐burning power plants. During the day, the plumes from these sources are efficiently mixed into the boundary layer, while at night, they may remain concentrated due to limited vertical mixing during which they undergo horizontal fanning. At night, the degree to which NO is converted to HNO3and therefore unable to participate in next‐day ozone (O3) formation depends on the mixing rate of the plume, the composition of power plant emissions, and the composition of the background atmosphere. In this study, we use observed plume intercepts from the Wintertime INvestigation of Transport, Emissions and Reactivity campaign to test sensitivity of overnight NOxremoval to the N2O5loss rate constant, plume mixing rate, background O3, and background levels of volatile organic compounds using a 2‐D box model of power plant plume transport and chemistry. The factor that exerted the greatest control over NOxremoval was the loss rate constant of N2O5. At the lowest observed N2O5loss rate constant, no other combination of conditions converts more than 10% of the initial NOxto HNO3. The other factors did not influence NOxremoval to the same degree. N2O5loss rate is main factor controlling overnight NOxloss via conversion to HNO3in power plant plumesFate of organic nitrates is important factor in degree of overnight NOxremoval from power plant plumesExtremely low N2O5loss rate constant and uptake coefficients observed in plume are below most prior observations

Normal sun-exposed skin contains numerous epidermal patches that stain positive for p53 protein (p53 immunopositive patches, PIPs), which are considered potential early precursors of skin cancer. Although the TP53gene is mutated in many PIPs, it is unclear whether PIPs contain any other cancer-related mutations. Here we report that PIPs, predominantly <3,000 p53 immunopositive cells in size, within normal chronically exposed skin contain mutations in multiple genes that are mutated in cutaneous squamous cell cancers. These mutations in the PIPs were not detected within the non-PIP epidermis of corresponding normal chronically exposed skin. Although some of these genetic alterations are clonal in the PIPs, many of the mutations are subclonal within these lesions. Similar mutations are seen in later precancers (actinic keratoses and Bowen’s disease). Our results demonstrate that PIPs in chronically exposed skin contain multiple mutations in cancer-related genes. In addition, the results indicate that the clonal evolution of mutations that are seen within later precancerous lesions and in established malignancy can also occur in PIPs within normal human skin.

Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation.

Respiratory epithelium is a highly integrated structure that efficiently protects lungs from extrinsic irritants thanks to rapid repair of the wound. The repair is a complex process that requires coordinated expression of networks of genes. Plausible regulators of this process are microRNAs. We investigated whether global miRNA silencing influences the epithelial repair, and whether changes in miRNA expression profile during repair are similar between two bronchial epithelial cell cultures: differentiated and undifferentiated cells. Two bronchial cell types were used:16HBE14o- and NHBE. Transfection was performed with siRNAs against Drosha and Dicer. For miRNA profiling, non-transfected cells were cultured until confluent and harvested for RNA isolation at baseline (cells before wounding) and at different time post-wounding (8, 16, 24, and 48 h). MicroRNA expression profiling was performed using TaqMan Array Human MicroRNA Card A. Target prediction was done in miRNA body map, and pathway analysis using DAVID. Cells with downregulated Drosha and Dicer demonstrated a significantly delayed wound repair in comparison to control in both cell lines. MiRNA expression profiling revealed that ten miRNAs exhibited significant changes over time after cell injury. These genes showed a similar expression pattern in both cell lines. The predicted targets of these miRNAs were then clustered by pathway analysis into six biological groups related to wound repair. Silencing of global miRNA expression confirmed that miRNAs are crucial for airway epithelial repair. Moreover, epithelial cells of two different origins demonstrated some similarities in miRNA expression pattern during wound repair, independent of differentiation state.

Stratosphere-to-troposphere transport (STT) and biomass burning (BB) are two important natural sources for tropospheric ozone that can result in elevated ozone and air-quality episode events. High-resolution observations of multiple related species are critical for complex ozone source attribution. In this article, we present an analysis of coinciding ground-based and airborne observations, including ozone lidar, ozonesonde, high spectral resolution lidar (HSRL), and multiple airborne in situ measurements, made on 28 and 29 June 2013 during the Southeast Nexus field campaign. The ozone lidar and HSRL reveal detailed ozone and aerosol structures as well as the temporal evolution associated with a cold front passage. The observations also captured two enhanced (+30?ppbv) ozone layers in the free troposphere (FT), which were determined from this study to be caused by a mixture of BB and stratospheric sources. The mechanism for this STT is tropopause folding associated with a cutoff upper level low-pressure system according to the analysis of its potential vorticity structure. The depth of the tropopause fold appears to be shallow for this case compared to events observed in other seasons; however, the impact on lower tropospheric ozone was clearly observed. This event suggests that strong STT may occur in the southeast United States during the summer and can potentially impact lower troposphere during these times. Statistical analysis of the airborne observations of trace gases suggests a coincident influence of BB transport in the FT impacting the vertical structure of ozone during this case study. Ozone structures associated with a cold front passageSimultaneous ozone lidar, ozonesonde, aerosol lidar, and airborne in situ measurementsMixed influence of biomass burning and stratosphere-to-troposphere transport on tropospheric ozone

Tropospheric O3has been decreasing across much of the eastern U.S. but has remained steady or even increased in some western regions. Recent increases in VOC and NOxemissions associated with the production of oil and natural gas (O&NG) may contribute to this trend in some areas. The Northern Front Range of Colorado has regularly exceeded O3air quality standards during summertime in recent years. This region has VOC emissions from a rapidly developing O&NG basin and low concentrations of biogenic VOC in close proximity to urban‐Denver NOxemissions. Here VOC OH reactivity (OHR), O3production efficiency (OPE), and an observationally constrained box model are used to quantify the influence of O&NG emissions on regional summertime O3production. Analyses are based on measurements acquired over two summers at a central location within the Northern Front Range that lies between major regional O&NG and urban emission sectors. Observational analyses suggest that mixing obscures any OPE differences in air primarily influenced by O&NG or urban emission sector. The box model confirms relatively modest OPE differences that are within the uncertainties of the field observations. Box model results also indicate that maximum O3at the measurement location is sensitive to changes in NOxmixing ratio but also responsive to O&NG VOC reductions. Combined, these analyses show that O&NG alkanes contribute over 80% to the observed carbon mixing ratio, roughly 50% to the regional VOC OHR, and approximately 20% to regional photochemical O3production. Modeled photochemical O3production is Nox‐sensitive at a central location in the Colorado Northern Front RangeOil and natural gas VOC emissions contribute over 80% to the observed carbon mixing ratio and 17.4% to maximum modeled photochemical O3Observed O3production efficiencies are variable but show an influence of less than 1.8 ppbv/ppbv from oil and natural gas VOC emissions

Physiological adaptation to high altitude hypoxia may be impaired in Andeans with significant European ancestry. The respiratory 'burden' of sleep may challenge adaptation, leading to relative nocturnal hypoxia. Developmental aspects of sleep-related breathing in high-altitude native children have not previously been reported. We aimed to determine the influence of development on diurnal-nocturnal oxyhemoglobin differences in children living at high altitude.

In this work, we employ a classical predictor observer for linear feedback systems to stabilize a well-known missile guidance law degraded by an optical seeker measurement delay in the near-collision course of a missile-target intercept engagement. In the framework of a canonical, planar intercept missile guidance problem, coupled with a delay in the measurement of the missile-to-target line-of-sight angle, we tailor the general formula for the predictor observer to the guidance law. We then use numerical simulations to evaluate the performance of the delaycompensated guidance law. The results indicate that for the scenario considered, the predictor observer is able to stabilize the guidance kinematics for realistic values of the measurement delay, thus encouraging further feasibility studies for using this approach in practice.

Anne Dingus's article about Jell-O, "Going for the Jiggler," brought back some fond memories (and some not so fond) of Jell-O salads my mother concocted back in the fifties [June […]

The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.

Unbiased genetic approaches, especially genome-wide association studies, have identified novel genetic targets in the pathogenesis of asthma, but so far these targets account for only a small proportion of the heritability of asthma. Recognition of the importance of disease heterogeneity, the need for improved disease phenotyping, and the fact that genes involved in the inception of asthma are likely to be different from those involved in severity widens the scope of asthma genetics. The identification of genes implicated in several causal pathways suggests that genetic scores could be used to capture the effect of genetic variations on individuals. Gene–environment interaction adds another layer of complexity, which is being successfully explored by epigenetic approaches. Pharmacogenetics is one example of how gene–environment interactions are already being taken into account in the identification of drug responders and non-responders, and patients most susceptible to adverse effects. Such applications represent one component of personalised medicine, an approach that places the individual at the centre of health care.

A large number of genetic loci contribute towards an individual's susceptibility to asthma and other complex diseases. Genome-wide association studies (GWASs) have provided us with a wealth of loci associated with asthma susceptibility, asthma endotypes and responsiveness to asthma medications. The reproducibility of these genetic loci across different studies highlights the interplay of general and population-specific risk alleles in asthma. Although GWASs have been successful in identifying disease-associated loci, there is still large potential for such studies to provide further insights into asthma pathogenesis.

Epigenetic mechanisms have the ability to alter the phenotype without changing the genetic code. The science of epigenetics has grown considerably in recent years, and future epigenetically based treatments or prevention strategies are likely. Epigenetic associations with asthma have received growing interest because genetic and environmental factors have been unable to independently explain the cause of asthma.