We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

A genomewide association study has shown an association between variants at chromosome 17q21 and an increased risk of asthma. To elucidate the relationship between this locus and disease, we examined a large, family-based data set that included extensive phenotypic and environmental data from the Epidemiological Study on the Genetics and Environment of Asthma. We tested 36 single-nucleotide polymorphisms (SNPs) in the 17q21 region in 1511 subjects from 372 families for an association with asthma. We also tested for genetic heterogeneity according to the age at the onset of asthma and exposure to environmental tobacco smoke in early life. Eleven SNPs were significantly associated with asthma (P<0.01), of which three (rs8069176, rs2305480, and rs4795400) were strongly associated (P<0.001). Ordered-subset regression analysis led us to select an onset at 4 years of age or younger to classify patients as having early-onset asthma. Association with early-onset asthma was highly significant (P<10⁻⁵ for four SNPs), whereas no association was found with late-onset asthma. With respect to exposure to environmental tobacco smoke in early life, we observed a significant association with early-onset asthma only in exposed subjects (P<5×10⁻⁵ for six SNPs). Under the best-fitting recessive model, homozygous status (GG) at the most strongly associated SNP (rs8069176) conferred an increase in risk by a factor of 2.9, as compared with other genotypes (AG and AA) in the group exposed to environmental tobacco smoke (P=2.8×10⁻⁶; P=0.006 for the test for heterogeneity of the SNP effect on early-onset asthma between groups with tobacco exposure and those without such exposure). This study shows that the increased risk of asthma conferred by 17q21 genetic variants is restricted to early-onset asthma and that the risk is further increased by early-life exposure to environmental tobacco smoke. These findings provide a greater understanding of the functional role of the 17q21 variants in the pathophysiology of asthma.

Background: Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure–health effect relationships. The “exposome” concept encompasses the totality of exposures from conception onward, complementing the genome. Objectives: The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the “early-life exposome.” Here we describe the general design of the project. Methods: In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother–child pairs, and biomarkers will be measured in a subset of 1,200 mother–child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure–response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures. Conclusions: HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome. Citation: Vrijheid M, Slama R, Robinson O, Chatzi L, Coen M, van den Hazel P, Thomsen C, Wright J, Athersuch TJ, Avellana N, Basagaña X, Brochot C, Bucchini L, Bustamante M, Carracedo A, Casas M, Estivill X, Fairley L, van Gent D, Gonzalez JR, Granum B, Gražulevičienė R, Gutzkow KB, Julvez J, Keun HC, Kogevinas M, McEachan RR, Meltzer HM, Sabidó E, Schwarze PE, Siroux V, Sunyer J, Want EJ, Zeman F, Nieuwenhuijsen MJ. 2014. The Human Early-Life Exposome (HELIX): project rationale and design. Environ Health Perspect 122:535–544; http://dx.doi.org/10.1289/ehp.1307204

The chronic impact of ambient air pollutants on lung function in adults is not fully understood. The objective of this study was to investigate the association of long-term exposure to ambient air pollution with lung function in adult participants from five cohorts in the European Study of Cohorts for Air Pollution Effects (ESCAPE).Residential exposure to nitrogen oxides (NO₂, NO_x) and particulate matter (PM) was modelled and traffic indicators were assessed in a standardised manner. The spirometric parameters forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC) from 7613 subjects were considered as outcomes. Cohort-specific results were combined using meta-analysis.We did not observe an association of air pollution with longitudinal change in lung function, but we observed that a 10 μg·m⁻³increase in NO₂exposure was associated with lower levels of FEV₁(−14.0 mL, 95% CI −25.8 to −2.1) and FVC (−14.9 mL, 95% CI −28.7 to −1.1). An increase of 10 μg·m⁻³in PM₁₀, but not other PM metrics (PM_2.5, coarse fraction of PM, PM absorbance), was associated with a lower level of FEV₁(−44.6 mL, 95% CI −85.4 to −3.8) and FVC (−59.0 mL, 95% CI −112.3 to −5.6). The associations were particularly strong in obese persons.This study adds to the evidence for an adverse association of ambient air pollution with lung function in adults at very low levels in Europe.

Purpose Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations. Participants The HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31 472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6–11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level). Findings to date Cohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6–11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder. Future plans HELIX study results will inform on the early life exposome and its association with molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project.

There is a need to improve asthma characterisation by integrating multiple aspects of the disease. The aim of the present study was to identify distinct asthma phenotypes by applying latent class analysis (LCA), a model-based clustering method, to two large epidemiological studies.Adults with asthma who participated in the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA2) (n = 641) and the European Community Respiratory Health Survey (ECRHSII) (n = 1,895) were included. 19 variables covering personal characteristics, asthma symptoms, exacerbations and treatment, age of asthma onset, allergic characteristics, lung function and airway hyperresponsiveness were considered in the LCA.Four asthma phenotypes were distinguished by the LCA in each sample. Two phenotypes were similar in EGEA2 and ECRHSII: active treated allergic childhood-onset asthma and active treated adult-onset asthma. The other two phenotypes were composed of subjects with inactive or mild untreated asthma, who differed by atopy status and age of asthma onset (childhood or adulthood). The phenotypes clearly discriminated populations in terms of quality of life, and blood eosinophil and neutrophil counts.The LCAs revealed four distinct asthma phenotypes in each sample. Considering these more homogeneous phenotypes in future studies may lead to a better identification of risk factors for asthma.