Associations between Nitric Oxide Synthase Genes and Exhaled NO-Related Phenotypes according to Asthma Status

International audienceBACKGROUND: The nitric oxide (NO) pathway is involved in asthma, and eosinophils participate in the regulation of the NO pool in pulmonary tissues. We investigated associations between single nucleotide polymorphisms (SNPs) of NO synthase genes (NOS) and biological NO-related phenotypes measured in two compartments (exhaled breath condensate and plasma) and blood eosinophil counts. METHODOLOGY: SNPs (N = 121) belonging to NOS1, NOS2 and NOS3 genes were genotyped in 1277 adults from the French Epidemiological study on the Genetics and Environment of Asthma (EGEA). Association analyses were conducted on four quantitative phenotypes: the exhaled fraction of NO (Fe(NO)), plasma and exhaled breath condensate (EBC) nitrite-nitrate levels (NO2-NO3) and blood eosinophils in asthmatics and non-asthmatics separately. Genetic heterogeneity of these phenotypes between asthmatics and non-asthmatics was also investigated. PRINCIPAL FINDINGS: In non-asthmatics, after correction for multiple comparisons, we found significant associations of Fe(NO) levels with three SNPs in NOS3 and NOS2 (P ≤ 0.002), and of EBC NO2-NO3 level with NOS2 (P = 0.002). In asthmatics, a single significant association was detected between Fe(NO) levels and one SNP in NOS3 (P = 0.004). Moreover, there was significant heterogeneity of NOS3 SNP effect on Fe(NO) between asthmatics and non-asthmatics (P = 0.0002 to 0.005). No significant association was found between any SNP and NO2-NO3 plasma levels or blood eosinophil counts. CONCLUSIONS: Variants in NO synthase genes influence Fe(NO) and EBC NO2-NO3 levels in adults. These genetic determinants differ according to asthma status. Significant associations were only detected for exhaled phenotypes, highlighting the critical relevance to have access to specific phenotypes measured in relevant biological fluid

Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study.

BACKGROUND: Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. METHODS AND FINDINGS: We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. CONCLUSIONS: In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease

Meta-analysis identifies seven susceptibility loci involved in the atopic March

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified

Association of Forced Vital Capacity with the Developmental Gene <i>NCOR2</i>

Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 chi

Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy

Asthma is caused by a heterogeneous combination of environmental and genetic factors. In the context of GA2LEN (Global Allergy and Asthma European Network), we carried out meta-analyses of almost all genome-wide linkage screens conducted to date in 20 independent populations from different ethnic origins (≥3024 families with ≥10 027 subjects) for asthma, atopic asthma, bronchial hyper-responsiveness and five atopy-related traits (total immunoglobulin E level, positive skin test response (SPT) to at least one allergen or to House Dust Mite, quantitative score of SPT (SPTQ) and eosinophils (EOS)). We used the genome scan meta-analysis method to assess evidence for linkage within bins of traditionally 30-cM width, and explored the manner in which these results were affected by bin definition. Meta-analyses were conducted in all studies and repeated in families of European ancestry. Genome-wide evidence for linkage was detected for asthma in two regions (2p21–p14 and 6p21) in European families ascertained through two asthmatic sibs. With regard to atopy phenotypes, four regions reached genome-wide significance: 3p25.3–q24 in all families for SPT and three other regions in European families (2q32–q34 for EOS, 5q23–q33 for SPTQ and 17q12–q24 for SPT). Tests of heterogeneity showed consistent evidence of linkage of SPTQ to 3p11–3q21, whereas between-study heterogeneity was detected for asthma in 2p22–p13 and 6p21, and for atopic asthma in 1q23–q25. This large-scale meta-analysis provides an important resource of information that can be used to prioritize further fine-mapping studies and also be integrated with genome-wide association studies to increase power and better interpret the outcomes of these studies

Evidence for gene x smoking exposure interactions in a genome-wide linkage screen of asthma and bronchial hyper-responsiveness in EGEA families.: Gene-smoking exposure interaction in EGEA study

Asthma and bronchial hyper-responsiveness (BHR), an asthma-related phenotype, result from many genetic (G) and environmental (E) factors. Passive exposure to tobacco smoke (ETS) in early life is one of these risk factors. Following a genome scan for asthma and associated phenotypes conducted in 295 French Epidemiological study on the Genetics and Environment of Asthma, our present aim was to investigate interactions between genetic susceptibility to asthma and to BHR with passive ETS using two different methods: the predivided sample test (PST) and the mean interaction test (MIT). PST and MIT consider the identical by descent (identity by descent) distribution at all markers in affected sib-pairs with 2, 1 or 0 sib(s) exposed to ETS. While the PST allows detection of both linkage and G x E interaction, the MIT tests for linkage by taking into account a possible interaction. Among the six regions detected at

Genome-wide association study of lung function decline in adults with and without asthma

Background: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function. Objective: We conducted the first genome-wide association study on the age-related decrease in FEV1 and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. Methods: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV1 and FEV1/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study). Results: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 x 10(-6); replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV1/FVC ratio decrease in asthmatic participants (P = 5.3 x 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. Conclusions: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status. (J Allergy Clin Immunol 2012;129:1218-28.