Raquel Granell

Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood

Background: Patterns of wheezing during early childhood may indicate differences in aetiology and prognosis of respiratory illnesses. Improved characterisation of wheezing phenotypes could lead to the identification of environmental influences on the development of asthma and airway diseases in predisposed individuals. Methods: Data collected on wheezing at seven time points from birth to 7 years from 6265 children in a longitudinal birth cohort (the ALSPAC study) were analysed. Latent class analysis was used to assign phenotypes based on patterns of wheezing. Measures of atopy, airway function (forced expiratory volume in 1 s (FEV1), mid forced expiratory flow (FEF25-75)) and bronchial responsiveness were made at 7–9 years of age. Results: Six phenotypes were identified. The strongest associations with atopy and airway responsiveness were found for intermediate onset (18 months) wheezing (OR for atopy 8.36, 95% CI 5.2 to 13.4; mean difference in dose response to methacholine 1.76, 95% CI 1.41 to 2.12 %FEV1 per μmol, compared with infrequent/never wheeze phenotype). Late onset wheezing (after 42 months) was also associated with atopy (OR 6.6, 95% CI 4.7 to 9.4) and airway responsiveness (mean difference 1.61, 95% CI 1.37 to 1.85 %FEV1 per μmol). Transient and prolonged early wheeze were not associated with atopy but were weakly associated with increased airway responsiveness and persistent wheeze had intermediate associations with these outcomes. Conclusions: The wheezing phenotypes most strongly associated with atopy and airway responsiveness were characterised by onset after age 18 months. This has potential implications for the timing of environmental influences on the initiation of atopic wheezing in early childhood.

A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample

Rationale Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). Objectives To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. Methods We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. Results The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers. Conclusions Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.

Mothers' anxiety during pregnancy is associated with asthma in their children.

Background Maternal stress in early life has been associated with the development of asthma in children, although it is unclear whether there are any critical periods of exposure. The association of asthma with prenatal exposure to maternal stress has not been reported. Objective We tested whether prenatal and postnatal anxiety and/or depression in pregnant women predicted the risk of their offspring developing asthma in childhood. Methods The Avon Longitudinal Study of Parents and Children is a population-based birth cohort recruited during pregnancy. Data were available on maternal anxiety scores and asthma at age 7½ years in 5810 children. Anxiety was assessed at 18 and 32 weeks of gestation by using the validated Crown-Crisp Experiential Index. Asthma was defined at age 7½ years as doctor-diagnosed asthma with current symptoms or treatment in the previous 12 months. Multivariable logistic regression was used to determine the association of prenatal anxiety with asthma (odds ratio; 95% CI). Results Independent of postnatal anxiety and adjusted for a number of likely confounders, there was a higher likelihood of asthma at age 7½ years (odds ratio, 1.64; 95% CI, 1.25-2.17) in children of mothers in the highest compared with lowest quartile of anxiety scores at 32 weeks of gestation, with evidence for a dose-response (P value for trend <0.001). Conclusions Maternal anxiety symptoms as an indicator of stress during fetal life may program the development of asthma during childhood.

Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts.

RATIONALE Although epidemiological studies suggest that exposure to maternal smoking during fetal and early life increases the risk of childhood wheezing and asthma, previous studies were not able to differentiate the effects of prenatal from postnatal exposure. OBJECTIVES To assess the effect of exposure to maternal smoking only during pregnancy on wheeze and asthma among preschool-age children. METHODS A pooled analysis was performed based on individual participant data from eight European birth cohorts. Cohort-specific effects of maternal smoking during pregnancy, but not during the first year, on wheeze and asthma at 4 to 6 years of age were estimated using logistic regression and then combined using a random effects model. Adjustments were made for sex, parental education, parental asthma, birth weight, and siblings. MEASUREMENTS AND MAIN RESULTS Among the 21,600 children included in the analysis, 735 children (3.4%) were exposed to maternal smoking exclusively during pregnancy but not in the first year after birth. In the pooled analysis, maternal smoking only during pregnancy was associated with wheeze and asthma at 4 to 6 years of age, with adjusted odds ratios of 1.39 (95% confidence interval, 1.08-1.77) and 1.65 (95% confidence interval, 1.18-2.31), respectively. The likelihood to develop wheeze and asthma increased statistically significantly in a linear dose-dependent manner in relation to maternal daily cigarette consumption during the first trimester of pregnancy. CONCLUSIONS Maternal smoking during pregnancy appears to increase the risk of wheeze and asthma among children who are not exposed to maternal smoking after birth.

Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses.

In this paper, the authors describe different instrumental variable (IV) estimators of causal risk ratios and odds ratios with particular attention to methods that can handle continuously measured exposures. The authors present this discussion in the context of a Mendelian randomization analysis of the effect of body mass index (BMI; weight (kg)/height (m)(2)) on the risk of asthma at age 7 years (Avon Longitudinal Study of Parents and Children, 1991-1992). The authors show that the multiplicative structural mean model (MSMM) and the multiplicative generalized method of moments (MGMM) estimator produce identical estimates of the causal risk ratio. In the example, MSMM and MGMM estimates suggested an inverse relation between BMI and asthma but other IV estimates suggested a positive relation, although all estimates had wide confidence intervals. An interaction between the associations of BMI and fat mass and obesity-associated (FTO) genotype with asthma explained the different directions of the different estimates, and a simulation study supported the observation that MSMM/MGMM estimators are negatively correlated with the other estimators when such an interaction is present. The authors conclude that point estimates from various IV methods can differ in practical applications. Based on the theoretical properties of the estimators, structural mean models make weaker assumptions than other IV estimators and can therefore be expected to be consistent in a wider range of situations.

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Meta-analysis of mould and dampness exposure on asthma and allergy in eight European birth cohorts: an ENRIECO initiative

To cite this article: Tischer CG, Hohmann C, Thiering E, Herbarth O, Müller A, Henderson J, Granell R, Fantini MP, Luciano L, Bergström A, Kull I, Link E, von Berg A, Kuehni CE, Strippoli M‐PF, Gehring U, Wijga A, Eller E, Bindslev‐Jensen C, Keil T, Heinrich J & as part of the ENRIECO consortium. Meta‐analysis of mould and dampness exposure on asthma and allergy in eight European birth cohorts: an ENRIECO initiative. Allergy 2011; 66: 1570–1579.

Glutathione-S-transferase genes and asthma phenotypes: a Human Genome Epidemiology (HuGE) systematic review and meta-analysis including unpublished data

Background Oxidative stress is thought to be involved in the pathogenesis of asthma. Glutathione-S-transferase (GST) enzymes, which play an important role in antioxidant defences, may therefore influence asthma risk. Two common deletion polymorphisms of GSTM1 and GSTT1 genes and the GSTP1 Ile105Val polymorphism have been associated with asthma in children and adults, but results are inconsistent across studies. Methods Systematic review and meta-analysis of the effects of GST genes on asthma, wheezing and bronchial hyper-responsiveness (BHR), with inclusion of unpublished data from three studies, including the large Avon Longitudinal Study of Parents and Children (ALSPAC). Random effect or fixed effect models were used as appropriate, and sensitivity analyses were performed to assess the impact of study characteristics and quality on pooled results. Results The meta-analyses of GSTM1 (n = 22 studies) and GSTT1 (n = 19) showed increased asthma risk associated with the null genotype, but there was extreme between-study heterogeneity and publication bias and the association disappeared when meta-analysis was restricted to the largest studies. Meta-analysis of GSTP1 Ile105Val (n = 17) and asthma suggested a possible protective effect of the Val allele, but heterogeneity was extreme. Few studies evaluated wheezing and BHR and most reported no associations, although weak evidence was found for positive associations of GSTM1 null and GSTP1 Val allele with wheezing and a negative association of GSTP1 Val allele with BHR. Conclusions Our findings do not support a substantial role of GST genes alone in the development of asthma. Future studies of large size should focus on interactions of GST genes with environmental oxidative exposures and with other genes involved in antioxidant pathways. Quality of study conduct and reporting needs to be improved to increase credibility of the evidence accumulating over time.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.

BACKGROUND To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. OBJECTIVE We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. METHODS We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). RESULTS At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6)). CONCLUSION By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Association of IL33–IL-1 receptor–like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood

BACKGROUND Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. OBJECTIVE In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. METHODS Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. RESULTS Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. CONCLUSIONS IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.