Genetics Of Asthma Research Articles

Hypospadias and Genes Related to Genital Tubercle and Early Urethral Development

We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans. We examined 293 relatively common tag single nucleotide polymorphisms in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2 and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population based nonmalformed male controls born in California from 1990 to 2003. There were 28 single nucleotide polymorphisms for which any of the comparisons (ie overall or for a specific severity) had a p value of less than 0.01. The homozygous variant genotypes for 4 single nucleotide polymorphisms in BMP7 were associated with at least a twofold increased risk of hypospadias regardless of severity. Five single nucleotide polymorphisms for FGF10 were associated with threefold to fourfold increased risks, regardless of severity. For 4 of them the results were restricted to whites. For GLI1, GLI2 and GLI3 there were 12 associated single nucleotide polymorphisms but results were inconsistent by severity and race/ethnicity. For SHH 1 single nucleotide polymorphism was associated with a 2.4-fold increased risk of moderate hypospadias. For WT1 6 single nucleotide polymorphisms were associated with approximately a twofold increased risk, primarily for severe hypospadias. This study provides evidence that single nucleotide polymorphisms in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk.

Replication and fine mapping of asthma-associated loci in individuals of African ancestry.

Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RL1/IL18R1, and 10p14, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.

Investigating highly replicated asthma genes as candidate genes for allergic rhinitis

BackgroundAsthma genetics has been extensively studied and many genes have been associated with the development or severity of this disease. In contrast, the genetic basis of allergic rhinitis (AR) has not been evaluated as extensively. It is well known that asthma is closely related with AR since a large proportion of individuals with asthma also present symptoms of AR, and patients with AR have a 5–6 fold increased risk of developing asthma. Thus, the relevance of asthma candidate genes as predisposing factors for AR is worth investigating. The present study was designed to investigate if SNPs in highly replicated asthma genes are associated with the occurrence of AR.MethodsA total of 192 SNPs from 21 asthma candidate genes reported to be associated with asthma in 6 or more unrelated studies were genotyped in a Swedish population with 246 AR patients and 431 controls. Genotypes for 429 SNPs from the same set of genes were also extracted from a Singapore Chinese genome-wide dataset which consisted of 456 AR cases and 486 controls. All SNPs were subsequently analyzed for association with AR and their influence on allergic sensitization to common allergens.ResultsA limited number of potential associations were observed and the overall pattern of P-values corresponds well to the expectations in the absence of an effect. However, in the tests of allele effects in the Chinese population the number of significant P-values exceeds the expectations. The strongest signals were found for SNPs in NPSR1 and CTLA4. In these genes, a total of nine SNPs showed P-values <0.001 with corresponding Q-values <0.05. In the NPSR1 gene some P-values were lower than the Bonferroni correction level. Reanalysis after elimination of all patients with asthmatic symptoms excluded asthma as a confounding factor in our results. Weaker indications were found for IL13 and GSTP1 with respect to sensitization to birch pollen in the Swedish population.ConclusionsGenetic variation in the majority of the highly replicated asthma genes were not associated to AR in our populations which suggest that asthma and AR could have less in common than previously anticipated. However, NPSR1 and CTLA4 can be genetic links between AR and asthma and associations of polymorphisms in NPSR1 with AR have not been reported previously.

The Editor takes a closer look at some of this month's articles

The Editor takes a closer look at some of this month's articles

Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene.

Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.

Ten-Year Follow-up of Cluster-based Asthma Phenotypes in Adults. A Pooled Analysis of Three Cohorts

The temporal stability of adult asthma phenotypes identified using clustering methods has never been addressed. Longitudinal cluster-based methods may provide novel insights in the study of the natural history of asthma. To compare the stability of cluster-based asthma phenotype structures a decade apart in adults and to address the individuals' phenotypic transition across these asthma phenotypes. The latent transition analysis was applied on longitudinal data (twice, 10 yr apart) from 3,320 adults with asthma who took part in the European Community Respiratory Health Survey, the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, or the Epidemiological Study on Genetics and Environment of Asthma. Nine variables covering personal and phenotypic characteristics measured twice, 10 years apart, were simultaneously considered. Latent transition analysis identifies seven asthma phenotypes (prevalence range, 8.4-20.8%), mainly characterized by the level of asthma symptoms (low, moderate, high), the allergic status, and pulmonary function. Phenotypes observed 10 years apart showed strong similarities. The probability of membership in the same asthma phenotype at both times varied across phenotypes from 54 to 88%. Different transition patterns were observed across phenotypes. Transitions toward increased asthma symptoms were more frequently observed among nonallergic phenotypes as compared with allergic phenotypes. Results showed a strong stability of the allergic status over time. Adult asthma phenotypes identified by a clustering approach, 10 years apart, were highly consistent. This study is the first to model the probabilities of transitioning over time between comprehensive asthma phenotypes.

Advances in adult asthma diagnosis and treatment in 2012: Potential therapeutics and gene-environment interactions

In the Journal of Allergy and Clinical Immunology in 2012, research reports related to asthma in adults clustered around mechanisms of disease, with a special focus on their potential for informing new therapies. There was also consideration of the effect of the environment on health from pollution, climate change, and epigenetic influences, underlining the importance of understanding gene-environment interactions in the pathogenesis of asthma and response to treatment.

A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations

IgE is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino subjects have not been well represented in genetic studies of total IgE. We sought to identify the genetic predictors of serum total IgE levels. We used genome-wide association data from 4292 subjects (2469 African Americans, 1564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (ie, African American, Latino, and European American) and asthma status. The resulting P values were meta-analyzed, accounting for sample size and direction of effect. Top single nucleotide polymorphism associations from the meta-analysis were reassessed in 6 additional cohorts comprising 5767 subjects. We identified 10 unique regions in which the combined association statistic was associated with total serum IgE levels (P<5.0×10(-6)) and the minor allele frequency was 5% or greater in 2 or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the single nucleotide polymorphism most significantly associated with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P=.007 and 2.45×10(-7), respectively). In addition, findings from earlier genome-wide association studies were also validated in the current meta-analysis. This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE levels in multiple race-ethnic groups. This study also extends and confirms the findings of earlier genome-wide association analyses in African American and Latino subjects.

Occupational exposure to cleaning products and asthma in hospital workers

ObjectiveCleaning products may cause work-related asthma, but information regarding the specific exposures involved is scarce. We aimed to determine the associations between asthma and occupational exposure to cleaning agents in...

Asthma Research for All of the United States

Asthma disproportionally affects different ethnic/racial groups, with Puerto Ricans and African Americans suffering the highest asthma prevalence and morbidity, Mexicans the lowest, and non-Hispanic whites in between. Genome-wide association studies of asthma have found both shared and race/ethnic-specific genetic risks factors for asthma. However, the majority of genetic asthma research is performed in populations of European descent, which limits the benefits of genetic research to European populations. It is important to biomedical and clinical research to include more diverse and underrepresented populations. The rich genetic diversity of all populations can be leveraged to scientific advantage. For example, admixture mapping provides a more powerful approach than traditional genome-wide allelic association studies in discovering genetic associations for complex diseases. By being more inclusive we can achieve a better understanding of the genetics of asthma, address health disparities, and ensure that scientific advances will benefit populations worldwide.

Plasma and exhaled breath condensate nitrite–nitrate level in relation to environmental exposures in adults in the EGEA study

This study evaluated the associations between biological markers in the nitrate–nitrite–NO pathway and four environmental exposures among subjects examined in the second survey (2003–2007) of the French Epidemiological study on Genetics and Environment of Asthma (EGEA). Total nitrite and nitrate (NO2- /NO3-) levels were measured both in plasma and in exhaled breath condensate (EBC) in 949 adults. Smoking, diet and exposure to chlorine products were assessed using standardized questionnaires. Exposure to air pollutants was estimated by using geostatistical models. All estimates were obtained with generalized estimating equations for linear regression models. Median levels of NO2-/NO3- were 36.3μM (1st–3rd quartile: 25.7, 51.1) in plasma and 2.0μmol/mg proteins (1st–3rd quartile 0.9, 3.9) in EBC. After adjustment for asthma, age, sex and menopausal status, plasma NO2-/NO3- level increased with leafy vegetable consumption (above versus below median=0.04 (95%CI: 0.001, 0.07)) and decreased in smokers (versus non/ex-smokers=−0.08 (95%CI: −0.11, −0.04). EBC NO2-/NO3- level decreased in smokers (−0.08 (95%CI: −0.16, −0.001)) and with exposure to ambient O3 concentration (above versus below median=−0.10 (95%CI: −0.17, −0.03)). Cured meat, chlorine products, PM10 and NO2 concentrations were not associated with NO2-/NO3- levels. Results suggest that potential modifiable environmental and behavioral risk factors may modify NO2-/NO3- levels in plasma and EBC according to the route of exposure.

Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases

Genome-wide association studies (GWASs) of asthma have consistently implicated the ORM1-like 3 and gasdermin B (ORMDL3-GSDMB), IL33, IL-1 receptor-like 1 and IL-18 receptor 1 (IL1RL1-IL18R1), RAD50-IL13, thymic stromal lymphopoietin and WD repeat domain 36 region (TSLP-WDR36), and HLA-DR/DQ regions. A GWAS of asthma was performed in a non-Hispanic white population. A GWAS was performed in 813 Severe Asthma Research Program/Collaborative Studies on the Genetics of Asthma/Chicago Asthma Genetics Study cases and 1564 control subjects. The GWAS results were compared with those of the published GWASs of autoimmune diseases. Multiple single nucleotide polymorphisms in the TNFAIP3 interacting protein 1 (TNIP1) gene, which interacts with TNFAIP3 and inhibits the TNF-α-induced nuclear factor κB inflammation pathway, were associated with asthma: rs1422673 (P = 3.44 × 10(-7)) and rs10036748 (P = 1.41 × 10(-6), r(2) = 0.67). rs1422673 was also associated with asthma in the published GABRIEL (P = .018) and EVE (P = 1.31 × 10(-5)) studies. The minor allele T of rs20541 in IL13 is the risk allele for asthma but the protective allele for psoriasis. The minor allele T of rs2395185 in HLA-DRA is the risk allele for asthma but the protective allele for ulcerative colitis. The minor allele A of rs2872507 in GSDMB is the protective allele for asthma but the risk allele for rheumatoid arthritis, Crohn disease, and ulcerative colitis. The T allele of rs10036748 in the TNIP1 gene is the minor protective allele for asthma but the minor or major risk allele for systemic lupus erythematosus and systemic sclerosis in non-Hispanic white or Chinese subjects, respectively. Our study suggests that single nucleotide polymorphisms associated with both asthma and autoimmune diseases might have opposite effects on immunopathogenesis.

Understanding asthma genetics: the road to primary prevention

Understanding asthma genetics: the road to primary prevention

The ANO3/MUC15 locus is associated with eczema in families ascertained through asthma

A previous genome-wide linkage scan in 295 families of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) reported strong evidence of linkage of 11p14 to eczema. Our purpose was to conduct fine-scale mapping of the 11p14 region to identify the genetic variants associated with eczema. Association analyses were first conducted in the family sample from the French EGEA by using 2 methods: the family-based association method and logistic regression. Replication of the EGEA findings was sought in French Canadian and United Kingdom family samples, which, similarly to EGEA samples, were ascertained through asthma. We also tested for association in 2 German samples ascertained through eczema. We found significant association of eczema with 11p14 genetic variants in the vicinity of the linkage peak in EGEA (P= 10(-4) for rs1050153 by using the family-based association method, which reached the multiple testing-corrected threshold of 10(-4); P= .003 with logistic regression). Pooled analysis of the 3 asthma-ascertained samples showed strong improvement in the evidence for association (P= 6 × 10(-6) for rs293974, P= 3 × 10(-5) for rs1050153, and P= 8 × 10(-5) for rs15783). No association was observed in the eczema-ascertained samples. The significant single nucleotide polymorphisms are located within the overlapping anoctamin 3 (ANO3) and mucin 15 (MUC15) genes. Several lines of evidence suggest that MUC15 is a strong candidate for eczema. Further investigation is needed to confirm our findings and to better understand the role of the ANO3/MUC15 locus in eczema and its relationship with respect to asthma.

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

BackgroundThe 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.MethodologySNPs (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 FindingsIn non-asthmatics, after correction for multiple comparisons, we found significant associations of FeNO 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 FeNO 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.ConclusionsVariants in NO synthase genes influence FeNO 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.

The IL6R variation Asp358Ala is a potential modifier of lung function in subjects with asthma

The IL6R single nucleotide polymorphism (SNP) rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r(2) = 1) with the IL6R coding SNP rs2228145 (Asp(358)Ala). This IL6R coding change increases IL-6 receptor (IL-6R) shedding and promotes IL-6 transsignaling. We sought to evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes. The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL-6R levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL-6R protein expression in bronchoalveolar lavage cells and endobronchial biopsies. The minor C allele of IL6R SNP rs2228145 was associated with a lower percent predicted FEV(1) in the SARP cohort (P= .005), the CSGA cohort (P= .008), and in a combined cohort analysis (P= .003). Additional associations with percent predicted forced vital capacity (FVC), FEV(1)/FVC ratio, and PC(20) were observed. The rs2228145 C allele (Ala(358)) was more frequent in severe asthma phenotypic clusters. Elevated serum soluble IL-6R levels were associated with lower percent predicted FEV(1) (P= .02) and lower percent predicted FVC (P= .008) (n= 146). IL-6R protein expression was observed in bronchoalveolar lavage macrophages, airway epithelium, vascular endothelium, and airway smooth muscle. The IL6R coding SNP rs2228145 (Asp(358)Ala) is a potential modifier of lung function in subjects with asthma and might identify subjects at risk for more severe asthma. IL-6 transsignaling might have a pathogenic role in the lung.

STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children

STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children

Domestic use of cleaning sprays and asthma activity in females

We aimed to study the associations between the household use of cleaning sprays and asthma symptoms and control of asthma, in females from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). Data were available for 683 females (mean age 44 yrs, 55% never smokers, 439 without asthma and 244 with current asthma). Both domestic exposures and asthma phenotypes (asthma symptom score, current asthma, poorly-controlled asthma (56%)) were evaluated as previously described in the European Community Respiratory Health Survey. Associations between the use of sprays and asthma phenotypes were evaluated using logistic and nominal regressions, adjusted for age, smoking, body mass index and occupational exposures. Significant associations were observed between the weekly use of at least two types of sprays and a high asthma symptom score (OR (95% CI) 2.50 (1.54-4.03)) compared with a null score. Consistent results were observed for current asthma (1.67 (1.08-2.56)) and poorly-controlled asthma (2.05 (1.25-3.35)) compared with females without asthma. The association for current asthma was higher in females not reporting avoidance of polluted places (2.12 (1.27-3.54)) than in those reporting such avoidance (0.99 (0.53-1.85)). The common use of household cleaning sprays is positively associated with a high asthma symptom score, current asthma and poorly-controlled asthma in females.

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

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. We conducted the first genome-wide association study on the age-related decrease in FEV(1) and its ratio to forced vital capacity (FVC) stratified a priori by asthma status. 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 FEV(1) and FEV(1)/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). 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 FEV(1) decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P= 4.8 × 10(-6); replication, P= .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV(1)/FVC ratio decrease in asthmatic participants (P= 5.3 × 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline. 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.

Asthma control assessed in the EGEA epidemiological survey and health-related quality of life

The aims were to assess 1) the relationship of asthma control assessed by combining epidemiological survey questions and lung function to Health-Related Quality of Life (HRQL) and 2) whether individuals with controlled asthma reach similar generic HRQL levels as individuals without asthma. The analysis included 584 individuals without asthma and 498 with asthma who participated in the follow-up of the Epidemiological study on Genetics and Environment of Asthma (EGEA). Asthma control was assessed from survey questions and lung function, closely adapted from the 2006-2009 Global Initiative for Asthma guidelines. The Asthma Quality of Life Questionnaire (AQLQ, scores range:1-7) and the generic SF-36 (scores range: 0-100) were used. Adjusted mean total AQLQ score decreased by 0.5 points for each asthma control steps (6.4, 5.9 and 5.4 for controlled, partly-controlled and uncontrolled asthma respectively, p < 0.0001). The differences in SF-36 scores between individuals with controlled asthma and those without asthma were minor and not significant for the PCS (-1, p = 0.09), borderline significant for the MCS (-1.6, p = 0.05) and small for the 8 domains (<5.1) although statistically significant for 4 domains. These results support the discriminative properties of the proposed asthma control grading system and its use in epidemiology.