17q12-21 variants are associated with asthma and interact with active smoking in an adult population from the United Kingdom

BackgroundAlthough an association between 17q12-21 and asthma has been replicated across different populations, some inconsistencies have been found between different studies.ObjectiveWe investigated the association between genetic variation in this region with asthma, lung function, airway inflammation, hyperresponsiveness (AHR), and atopy in a case-control study of United Kingdom adults. The interaction between genotype and smoking was also evaluated.MethodsStudy subjects (n = 983) were carefully phenotyped using questionnaires, measurement of lung function, AHR (methacholine challenge), exhaled nitric oxide (eNO), and assessment of atopic status. Blood/saliva/buccal swabs were collected, and 47 single nucleotide polymorphisms (SNPs) in 17q12-21 were genotyped using MALDI-TOF (Matrix-assisted LASER desorption/ionisation-time of flight) mass spectrometry. We conducted a comprehensive investigation of 28 common SNPs within 6 genes of interest (IKZF3, ZPBP2, ORMDL3, GSDMA, GSDMB, TOP2A).ResultsSixteen SNPs were significantly associated with asthma after multiple testing correction (P ≤ .01), of which 5 (rs2290400, rs8079416, rs3894194, rs7212938, and rs3859192) were strongly associated (FDR P ≤ .0002), and one was novel (IKZF3-rs1453559). For 3 of these SNPs, we found significant interaction with smoking and asthma (rs12936231, rs2290400, and rs8079416). Smoking modified the associations between 8 SNPs and lung function (rs9911688, rs9900538, rs1054609, rs8076131, rs3902025, rs3859192, rs11540720, and rs11650680). We observed significant interaction between 5 SNPs and smoking on AHR, and 3 interacted with smoking in relation to asthma with AHR (rs4795404, rs4795408, rs3859192).ConclusionWe found 1 novel association and replicated several previously reported associations between 17q12-21 polymorphisms and asthma. We demonstrated significant interactions between active smoking and polymorphisms in 17q12-21 with asthma, lung function, and AHR in adults. Our data confirm that 17q12-21 is an important asthma susceptibility locus.     

Polymorphisms and haplotypes of the chromosome locus 17q12-17q21.1 contribute to adult asthma susceptibility in Slovenian patients

One of the major asthma susceptibility loci is 17q12-17q21.1, but the relationship between this locus and adult asthma is unclear. Association analysis of 13 single nucleotide polymorphisms (SNPs) and haplotypes from 17q12-17q21.1 was performed in 418 adult patients with asthma and 288 controls from Slovenia. Single SNP analysis revealed only marginal associations with adult asthma for SNPs located in GSDMA, GSDMB, ORMDL3 and ZPBP2 genes, and rs7219080 was the most highly associated. Analyses of asthma phenotypes found no association with atopy or lung function, but rs2305480 and rs8066582 were associated with childhood asthma and rs9916279 was associated with asthma in smokers. Notably, haplotypes consisting of rs9916279, rs8066582, rs1042658, and rs2302777 harbouring PSMD3, CSF3 and MED24 genes were highly associated with asthma. The four most common haplotypes, TCCG, TTTA, CCCA and TTCA, were more frequent in patients with asthma, whereas TTCG, TCCA, TCTA and TTTG were more frequent in controls. Only 3% of asthma patients belonged to haplotypes TTCG, TCCA, TCTA and TTTG compared with nearly one-third (31%) of controls. Associations confirmed that the 17q12-17q21.1 locus harbours a genetic determinant for asthma risk in adults and suggest that in addition to the previously known ORMDL3-GSDM locus, CSF3-PSMD3-MED24 also plays a role in asthma pathogenesis.     

GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness

In 2007, a genome-wide association study identified associations between variants involved in the regulation of ORMDL3 expression and asthma. These observations were subsequently replicated in case-control studies in several ethnic groups. We investigated the possible contribution of GSDMB/ORMDL3 variants to asthma susceptibility and intermediate asthma phenotypes in Korean children. The polymorphisms rs7216389, rs4794820, rs4065275, and rs11650680 were genotyped using the TaqMan assay in 931 asthmatics and 480 normal controls in a case-control study, and in 1907 elementary school children in a general population study. Each subject also underwent peripheral blood analysis of immunoglobulin E levels, eosinophil cationic protein (ECP) levels, and eosinophil percentage. Pulmonary function testing (FEV₁ and MMEF) and a methacholine provocation test (PC₂₀) were also performed. The case-control study revealed a significant association between a linkage disequilibrium block, including rs7216389, rs4794820, and rs4065275, and susceptibility to asthma and atopic asthma. The CT and TT genotypes of rs11650680 were associated with lower log ECP levels than the CC genotype in asthmatics, while the GA and AA genotypes of rs4794820 were associated with higher log PC₂₀ values than the GG genotype in atopic asthmatics. The haplotype (CAA) of rs7216389, rs4794820 and rs4065275 was associated with a lower risk of asthma susceptibility and a higher log PC₂₀. In the general population study, rs11650680 was significantly associated with a diagnosis of asthma. Moreover, the GA and AA genotypes of rs4794820 were associated with higher log PC₂₀ values and lower eosinophil percentages than the GG genotype in subjects who had been diagnosed with asthma, or showed bronchial hyperresponsiveness (PC₂₀ ? 16). The GSDMB/ORMDL3 gene block, which includes rs7216389, rs4065275, rs4794820, and rs11650680, may be associated with asthma susceptibility in Korean children because it promotes eosinophilic inflammation, which induces bronchial hyperresponsiveness.     

The Association of GSDMB and ORMDL3 Gene Polymorphisms With Asthma: A Meta-Analysis

PurposeORM1-like 3 (ORMDL3) belongs to a highly conserved protein family which is anchored as transmembrane protein in the endoplasmic reticulum. Gasdermin B (GSDMB) is adjacent to ORMDL3 on chromosome 17q21.2 and belongs to the gasdermin-domain containing the protein family (GSDM family). Recent reports suggest that GSDMB and ORMDL3 are associated with asthma in several populations. However, genetic association studies that examined the association of GSDMB and ORMDL3 gene variants with asthma showed conflicting results. To assess whether combined evidence shows the association between GSDMB/ORMDL3 polymorphism and asthma.MethodsA bibliographic search from MEDLINE identified 13 original articles using the search keywords ''GSDMB'', ''ORMDL3'', and ''asthma''. An updated literature-based meta-analysis involving 6,691 subjects with asthma, 9,281 control individuals, and 1,360 families were conducted. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on the fixed effects model or the random effects model depended on Cochran''s Q-statistic and I² values. Data from case-control and TDT studies were analyzed in an allelic model using the Catmap software.ResultsWe selected and identified 3 SNPs of ORMDL3 associated with asthma (rs8076131: OR=1.10; 95% CI, 1.02-1.20; P=0.012. rs12603332: OR=1.15; 95% CI, 1.05-1.25; P=0.002. rs3744246: OR=1.10; 95% CI, 1.02-1.17; P=0.008) and 1 SNP of GSDMB associated with asthma (rs7216389: OR=1.37; 95% CI, 1.27-1.47; P<0.01). Publication bias was estimated using modified Egger''s linear regression test proposed by Harbordetal and revealed no evidence of biases. Furthermore, cumulative meta-analysis in chronological order showed the inclination toward significant association for rs7216389 and rs12603332 with continually adding studies, and the inclination toward null-significant association for rs3744246 and rs8076131.ConclusionsModerate evidence exists for associations of the ORMDL3 rs8076131, rs12603332, and rs3744246 and GSDMB rs7216389 variants with asthma. Large sample size and representative population-based studies and TDT studies with homogeneous asthmatic patients and well-matched controls are warranted to confirm this finding.     

Exposure to furry pets and the risk of asthma and allergic rhinitis: a meta-analysis

Background:  Exposure to pets has been implicated as a risk factor for asthma. However, this relation has been difficult to assess in individual studies because of the large potential of selection bias. We sought to examine the association between exposure to furry pets and asthma and allergic rhinitis by means of a meta-analysis.
Methods:  We retrieved studies published in any language by searching systematically Medline (1966–March 2007), Embase, LILACS and ISI Proceedings computerized databases, and by examining manually the references of the original articles and reviews retrieved. We included cohort and case–control studies reporting relative risk estimates and confidence intervals of exposure to cats, dogs and unspecified furry animals and subsequent asthma and allergic rhinitis. We excluded cross-sectional studies and those studies that did not measure exposure but rather sensitization to pets.
Results:  Thirty-two studies were included. For asthma, the pooled relative risk related to dog exposure was 1.14 (95% CI 1.01–1.29), that related to exposure to any furry pet was 1.39 (95% CI 1.00–1.95). Among cohort studies, exposure to cats yielded a relative risk of 0.72 (95% CI 0.55–0.93). For rhinitis, the pooled relative risk of exposure to any furry pet was 0.79 (95% CI 0.68–0.93).
Conclusions:  Exposure to cats exerts a slight preventive effect on asthma, an effect that is more pronounced in cohort studies. On the contrary, exposure to dogs increases slightly the risk of asthma. Exposure to furry pets of undermined type is not conclusive. More studies with exact measurement of exposure are needed to elucidate the role of pet exposures in atopic diseases.     

Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma

Background:  A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3 ) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans.
Objective:  We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like ( GSDML ) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population.
Methods:  We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4–17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens.
Results:  Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19–2.53, P  = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12–2.38, P  = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high ( r ² = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35–1.54, P  < 0.00001).
Conclusions:  Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma.     

Relationship between the 17q21 locus and adult asthma in a Czech population

Several whole-genome association studies have shown a significant link between childhood asthma and the 17q12 chromosome region. We selected tagging single nucleotide polymorphisms (SNPs) in the ORMDL3 gene (17q12) to investigate gene variability in relation to adult allergic asthma and asthma/atopy traits in a Czech Caucasian population of adults. We conducted a case-control association study comprising 668 unrelated subjects (337 asthmatic and 331 control subjects). Four selected SNPs (rs17608925, rs12603332, rs8076131, and rs3169572) were genotyped using the TaqMan SNP Genotyping Assays. The single locus analysis showed only a borderline association between rs3169572 variant and asthma (p = 0.030, p(corr) > 0.05). However, seven different haplotypes were identified; among them, the TTAA haplotype was marginally associated with asthma (p = 0.045, p(corr) > 0.05) and TCAG haplotype was significantly associated with asthma in males (p = 0.009, p(corr) < 0.05, odds ratio = 1.48, 95% confidence interval = 1.10-2.00). In addition, associations between the ORMDL3 genotypes and the total IgE level (p = 0.05, p(corr) > 0.05) and hypersensitivity to the pollen (p = 0.007, p(corr) < 0.05) were established. However, no relationship between ORMDL3 SNPs and the pulmonary functions was found (p > 0.05). These findings suggest that the genetic variability in the 17q21 region may be one of the risk factors also for adult asthma, especially in male individuals.     

Replicated association of 17q12-21 with susceptibility of primary biliary cirrhosis in a Japanese cohort

To examine the genetics of susceptibility to primary biliary cirrhosis (PBC), genome-wide association studies GWAS have been performed in patients of European ancestry and have shown the significant associations of IL12-related pathways, SPIB, IRF5-TNPO3, and 17q12-21. We tested whether these findings could be extended to a Japanese cohort, 303 Japanese PBC and 298 controls. We failed to detect significant associations at IL12A (rs574808, rs1075498) and IL12RB2 (rs3790567). There was no genetic variance at IRF5-TNPO3 (rs10488631) in Japanese. A single nucleotide polymorphism (SNP) at SPIB (rs3745516) reached nominal significance, but the corrected P value did not reach significance. For the 17q12-21 region, two SNPs had nominally significant associations [GSDMB (rs2305480, P = 0.022) and ZPBP2 (rs11557467, P = 0.021)] and we noted a significant P value at a SNP in IKZF3 (rs939327, P = 0.0024, P(c) = 0.017) after correction for multiple comparisons. Thus, these results indicate a haplotype on 17q12-21 with a similar association in Japanese and European PBC.     

Asthma and atopy are associated with chromosome 17q21 markers in Chinese children

Background:  Single-nucleotide polymorphism (SNP)-based genome-wide association study revealed that markers on chromosome 17q21 were linked to childhood asthma but not atopy in Caucasians, with the strongest signal being detected for the SNP rs7216389 in the ORMDL3 gene. Such association was unknown in Chinese. This study delineated the allele and genotype frequencies of 10 SNPs at chromosome 17q21, and investigated the relationship between these SNPs and asthma and plasma IgE in southern Chinese children.
Methods:  Asthmatic children and non-allergic controls were recruited from pediatric clinics. Their plasma total and aeroallergen-specific IgE concentrations were measured by immunoassay. Ten SNPs on 17q21 region were genotyped by multiplex SNaPshot™, and their genotype associations with asthma traits analyzed using multivariate regression.
Results:  315 patients and 192 controls were enrolled. The allele frequency for C allele of rs7216389 varied significantly from 0.232 in our controls, 0.389 in Han Chinese to 0.536 in Caucasians. Asthma diagnosis was associated with rs11650680 and five other SNPs including rs7216389 ( P  =   0.019–0.034), whereas atopy was associated only with rs11650680 ( P  =   0.0004). Linear regression revealed the covariates for plasma total IgE to be significant for rs11650680 ( P  =   0.008–0.0002). Haplotypic associations were found with atopy and increased plasma total IgE, with the respective odds ratios and 95% confidence intervals for TTTCCGTT haplotype to be 0.21 and 0.09–0.52 ( P  =   0.0002) and 0.41 and 0.18–0.90 ( P  =   0.025).
Conclusion:  Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region.     

Environmental tobacco smoke exposure and nocturnal symptoms among inner-city children with asthma

BACKGROUND: Environmental tobacco smoke (ETS) is a frequent exposure and is linked to asthma among inner-city children. OBJECTIVE: We sought to examine the relationship among ETS exposure, select asthma symptoms, and consequences among inner-city children with asthma. METHODS: Data from interviews with primary caregivers of inner-city elementary school children with asthma were evaluated (n = 590). Caregiver reports of child asthma symptoms, exercise limitations, asthma management, health care use, and ETS exposure were examined. RESULTS: Smoking in the home was reported by 29.4% of primary caregivers. ETS exposure (yes/no) was not related to frequency of child nocturnal symptoms or other select asthma morbidity markers. However, among children exposed to ETS, the frequency and severity of child nocturnal symptoms were highest among children exposed to moderate-to-heavy levels of ETS. After controlling for child age, anti-inflammatory medication use, asthma primary care, and caregiver's education, exposure to higher levels of ETS was associated with nearly a 3-fold increase in nocturnal symptoms in children (odds ratio, 2.83; 95% CI, 1.22-6.55). CONCLUSION: Among elementary school inner-city children with asthma, exposure to higher levels of ETS was associated with increased frequency of nocturnal symptoms. Reducing the exposure of children with asthma to ETS should be a clear priority in developing effective asthma management plans for inner-city families.     

Smoking, environmental tobacco smoke, and aspirin-exacerbated respiratory disease

BackgroundTobacco smoke is a widely recognized environmental pollutant and is a major public health hazard worldwide. Although environmental tobacco smoke (ETS) has a clear link with many conditions, including asthma, ear infections, and sinus cancer, evidence related to aspirin-exacerbated respiratory disease (AERD) requires further investigation.ObjectiveTo investigate whether active smoke or ETS exposures are associated with an increased risk of developing AERD.MethodsA total of 260 patients with AERD were enrolled in a case-control study with their respective asymptomatic spouses serving as matched controls. Multiple logistic regression analysis was used to examine the association of AERD with active smoking and ETS, adjusted for age, sex, and location of childhood residence.ResultsThe AERD case patients were more likely to have ever smoked actively when compared with controls (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.04-2.28). A significant association (OR, 3.46; 95% CI, 2.22-5.39) was found between childhood ETS exposure and AERD. If a patient was exposed to ETS during both childhood and adulthood, results showed an OR of 5.09 for developing AERD (95% CI, 2.75-9.43). However, no statistically significant association between AERD and ETS only during adulthood was found (OR, 1.60; 95% CI, 0.75-3.40), suggesting that the combined effect of childhood and adulthood ETS may be augmented by the prior childhood exposure.ConclusionsActive smoking and childhood ETS exposure are associated with increased odds of developing AERD. In particular, combined childhood and adulthood exposure had major effects. This study suggests that ETS is at least one contributor to the syndrome of AERD.     

Smoking, atopy and certain furry pets are major determinants of respiratory symptoms in children: the International Study of Asthma and Allergies in Childhood Study (Ireland)

BACKGROUND: Environmental, cultural and health care differences may account for variation among countries in the prevalence of asthma and respiratory symptoms in teenagers. OBJECTIVE: To examine the prevalence of respiratory symptoms and the level of diagnosis, and to compare determinants of asthma and severe wheeze in two countries. METHODS: Self-completion questionnaires based on the International Study of Asthma and Allergies in Childhood (ISAAC) protocol were provided to school children in Ireland (Republic and Northern Ireland). In the Republic of Ireland, all children in classes largely aged 13-14 years from 30 post-primary schools were selected by random sampling stratified by school size, composition and Health Board in Spring 1995. In Northern Ireland, all children largely aged 13-14 years of age from 26 post-primary schools were selected by random sampling stratified by school type, composition and Education and Library Board in Spring 1996. RESULTS: Questionnaires were completed by 2,364 children from Northern Ireland and 2,671 from the Republic, about 90% of those eligible to participate. The prevalences of wheeze at various levels of severity, of diagnosed asthma and of treated wheeze were very similar in Northern Ireland and the Republic of Ireland. A significant proportion of those reporting more severe symptomatology (four or more attacks of wheeze in the past 12 months and/or one or more nights disturbed and/or moderate or greater disruption of daily activities and/or speech restriction due to wheeze) had been neither diagnosed nor treated for asthma (20-37%). To investigate the determinants of the more severe symptomatology of asthma or treated wheeze a series of stepwise multiple regression analyses was performed. A history of atopy, cigarette smoking, the possession of a furry pet other than a dog or cat and age were each independently associated with severe wheeze, whilst atopy, a furry pet (as above) and gender were each independently associated with asthma or treated wheeze. CONCLUSIONS: Cigarette smoking is closely associated with the reporting of significant respiratory symptoms together with atopy and exposure to furry pets. Some 20-37% of severe symptoms were neither diagnosed nor treated as asthma.     

Pets, parental atopy, and asthma in adults

BACKGROUND: Studies of exposure to pets and the risk of asthma have provided conflicting results. OBJECTIVE: We conducted a population-based incident case-control study to assess the relationship of current and previous pet keeping with the risk of adult-onset asthma. We also investigated whether genetic propensity as a result of parental atopy modifies these relations. METHODS: From the source population of 441,000 inhabitants of a geographically defined area in South Finland, we systematically recruited, during a 2.5-year period, all new cases of asthma in 21- to 63-year-old adults and randomly selected control subjects. The clinically diagnosed case series consisted of 521 adults with newly diagnosed asthma and a control series of 932 control subjects. Information on current and past exposure to hairy pets was collected by using a self-administered questionnaire. RESULTS: In logistic regression analysis the risk of asthma was lower among subjects with pets during the past 12 months (adjusted odds ratio [OR], 0.74; 95% confidence interval [CI], 0.57-0.96) but higher among subjects with pets more than 12 months previously (adjusted OR, 1.39; 95% CI, 1.05-1.84). Parental atopy increased the risk of asthma (OR, 1.88; 95% CI, 1.47-2.41), but there was no interaction between parental atopy and pet exposure. CONCLUSIONS: The present results are consistent with the hypothesis that both keeping furry pets and parental atopy increase the risk of asthma development in adulthood. Parental atopy does not modify the effects of pet exposure. The negative association between current pets and the risk of asthma is consistent with selective avoidance of these pets by symptomatic individuals.     

Effects of air pollution on asthma hospitalization rates in different age groups in Hong Kong

AIMS: To assess the relationship between levels of ambient air pollutants and hospitalization rates for asthma in Hong Kong (HK). METHODS: This is a retrospective ecological study. Data of daily emergency hospital admissions to 15 major hospitals in HK for asthma and indices of air pollutants [sulphur dioxide (SO(2)), nitrogen dioxide (NO(2)), ozone (O(3)), particulates with an aerodynamic diameter of <10 microm particulate matter (PM(10)) and 2.5 microm (PM(2.5))] and meteorological variables from January 2000 to December 2005 were obtained from several government departments. Analysis was performed by the generalized additive models with Poisson distribution. The effects of time trend, season, other cyclical factors, temperature and humidity were adjusted. Autocorrelation and overdispersion were corrected. RESULTS: Altogether, 69 716 admissions were assessed. Significant associations were found between hospital admissions for asthma and levels of NO(2), O(3), PM(10) and PM(2.5). The relative risks (RR) for hospitalization for every 10 microg/m(3) increase in NO(2), O(3), PM(10) and PM(2.5) were 1.028, 1.034, 1.019 and 1.021, respectively, at a lag day that ranged from cumulative lag 0-4 to 0-5. In a multi-pollutant model, O(3) was significantly associated with increased admissions for asthma. The younger age group (0-14 years) tended to have a higher RR for each 10 microg/m(3) increase in pollutants than those aged 15-65 years. The elderly (aged >/=65 years) had a shorter 'best' lag time to develop asthma exacerbation following exposure to pollutants than those aged <65 years. CONCLUSION: Adverse effects of ambient concentrations of air pollutants on hospitalization rates for asthma are evident. Measures to improve air quality in HK are urgently needed.     

Sex-associated TSLP-induced immune alterations following early-life RSV infection leads to enhanced allergic disease

Many studies have linked severe RSV infection during early-life with an enhanced likelihood of developing childhood asthma, showing a greater susceptibility in boys. Our studies show that early-life RSV infection leads to differential long-term effects based upon the sex of the neonate; leaving male mice prone to exacerbation upon secondary allergen exposure while overall protecting female mice. During initial viral infection, we observed better viral control in the female mice with correlative expression of interferon-β that was not observed in male mice. Additionally, we observed persistent immune alterations in male mice at 4 weeks post infection. These alterations include Th2 and Th17-skewing, innate cytokine expression (Tslp and Il33), and infiltration of innate immune cells (DC and ILC2). Upon exposure to allergen, beginning at 4 weeks following early-life RSV-infection, male mice show severe allergic exacerbation while female mice appear to be protected. Due to persistent expression of TSLP following early-life RSV infection in male mice, genetically modified TSLPR−/− mice were evaluated and demonstrated an abrogation of allergen exacerbation in male mice. These data indicate that TSLP is involved in the altered immune environment following neonatal RSV-infection that leads to more severe responses in males during allergy exposure, later in life. Thus, TSLP may be a clinically relevant therapeutic target early in life.     

Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze

The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure.     

Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations

Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.     

Seasonal Patterns of Asthma in Children and Adolescents Presenting at Emergency Departments in Korea

PurposeSeasonal variations in asthma-related hospitalizations and emergency department visits have long been recognized. This study aimed to investigate the seasonal patterns of asthma in children and adolescents who presented at emergency departments in Korea.MethodsWe analyzed the National Emergency Department Information System records from 117 emergency departments in Korea that comprised all of the patients with asthma who were aged 3-18 years and who presented at the emergency departments from 2007 to 2012. The children and adolescents were divided into 3 groups based on their ages, namely, 3-6 years, 7-12 years, and 13-18 years. The data were tabulated, and graphs were created to show the seasonal trends in the monthly numbers of emergency department visits as a consequence of asthma.ResultsA total of 41,128 subjects were identified, and the male-to-female ratio was 1:0.5. General ward admissions comprised 42.6% (n=17,524 patients) of the emergency department visits, and intensive care unit admissions comprised 0.8% (n=335 patients) of the emergency department visits. The monthly numbers of emergency department visits for asthma varied according to the season, with high peaks during fall, which was from September to November, and low levels in summer, which was from June to August.ConclusionsImportant differences in the seasonal patterns of emergency department visits for asthma were evident in children and adolescents. Identifying seasonal trends in asthma-related emergency department visits may help determine the causes and reduce the likelihood of asthma exacerbation.     

The impact of asthma medication guidelines on asthma controller use and on asthma exacerbation rates comparing 1997-1998 and 2004-2005

BackgroundThe relationship between asthma controller medication use and exacerbation rates over time is unclear at the population level.ObjectiveTo estimate the change in asthma controller medication use between 2 time periods as measured by the controller-to-total asthma medication ratio and its association with changes in asthma exacerbation rates between 1997–1998 and 2004–2005.MethodsThe study design was a cross-sectional population-level comparison between individuals from 1997–1998 and 2004–2005. Study participants were individuals aged 5 to 56 years identified as having asthma in the Medical Expenditure Panel Survey (MEPS). The main outcome measures were a controller-to-total asthma medication ratio greater than 0.5 and asthma exacerbation rates (dispensing of systemic corticosteroid or emergency department visit/hospitalization for asthma) in 1997–1998 compared with 2004–2005.ResultsThe proportion of individuals with a controller-to-total asthma medication ratio greater than 0.5, when adjusted for other demographic factors, has improved by 16.1% (95% CI: 10.8%, 21.3%) for all individuals from 1997–1998 to 2004–2005. Annual asthma exacerbation rates did not change significantly in any group from 1997–1998 to 2004–2005 (0.27/year to 0.23/year). African American and Hispanic individuals with asthma had higher asthma exacerbation rates and a lower proportion with a controller-to-total asthma medication ratio greater than 0.5 than whites in both 1997–1998 and 2004–2005; however, these differences were not statistically significant.ConclusionsAn increase in asthma controller-to-total medication ratio in a sample reflective of the US population was not associated with a decreased asthma exacerbation rate comparing 1997–1998 and 2004–2005.