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1.  Expression analysis of asthma candidate genes during human and murine lung development 
Respiratory Research  2011;12(1):86.
Background
Little is known about the role of most asthma susceptibility genes during human lung development. Genetic determinants for normal lung development are not only important early in life, but also for later lung function.
Objective
To investigate the role of expression patterns of well-defined asthma susceptibility genes during human and murine lung development. We hypothesized that genes influencing normal airways development would be over-represented by genes associated with asthma.
Methods
Asthma genes were first identified via comprehensive search of the current literature. Next, we analyzed their expression patterns in the developing human lung during the pseudoglandular (gestational age, 7-16 weeks) and canalicular (17-26 weeks) stages of development, and in the complete developing lung time series of 3 mouse strains: A/J, SW, C57BL6.
Results
In total, 96 genes with association to asthma in at least two human populations were identified in the literature. Overall, there was no significant over-representation of the asthma genes among genes differentially expressed during lung development, although trends were seen in the human (Odds ratio, OR 1.22, confidence interval, CI 0.90-1.62) and C57BL6 mouse (OR 1.41, CI 0.92-2.11) data. However, differential expression of some asthma genes was consistent in both developing human and murine lung, e.g. NOD1, EDN1, CCL5, RORA and HLA-G. Among the asthma genes identified in genome wide association studies, ROBO1, RORA, HLA-DQB1, IL2RB and PDE10A were differentially expressed during human lung development.
Conclusions
Our data provide insight about the role of asthma susceptibility genes during lung development and suggest common mechanisms underlying lung morphogenesis and pathogenesis of respiratory diseases.
doi:10.1186/1465-9921-12-86
PMCID: PMC3141421  PMID: 21699702
Asthma; Development; Expression; Genetics; Lung
2.  A Genome-Wide Association Study of Pulmonary Function Measures in the Framingham Heart Study 
PLoS Genetics  2009;5(3):e1000429.
The ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV1/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09). One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV1/FVC (p-value = 2.0e-04). The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV1/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV1 and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.
Author Summary
Cigarette smoking is the primary risk factor for impaired lung function, yet only 20% of smokers develop chronic obstructive pulmonary disease (COPD). This observation, along with family studies of lung function and COPD, suggests that genetic factors influence susceptibility to cigarette smoke. We examined the relationship between common genetic variants and measures of lung function in a sample of 7,691 participants from the Framingham Heart Study and confirmed our observations in 835 participants from the Family Heart Study selected to include cases of airflow obstruction. We identified a variant on chromosome 4 that was strongly associated with FEV1/FVC in the Framingham Study and confirmed the association in the Family Heart Study. The accompanying manuscript identified the same region to be associated with COPD. Several interesting genes are present in the region that we identified, including a gene (HHIP) interacting with a biological pathway involved in lung development, but it is not yet clear which gene in the region explains the association. Our results identified a region of chromosome 4 that warrants further study to understand the genetic effects influencing lung function.
doi:10.1371/journal.pgen.1000429
PMCID: PMC2652834  PMID: 19300500
3.  123 Serum IL6 and Soluble IL6R Are Correlated With Lung Function in Non-Hispanic Whites with Asthma 
Background
Interleukin 6 (IL6) belongs to a family of cytokines with both pro- and anti-inflammatory properties. The functional relationship between IL6 signaling and airway disease has not be well characterized; however, IL6 expression is increased during lung inflammation and injury. In this study, serum IL6 and soluble IL6R levels were assessed in non-Hispanic whites with asthma from the Severe Asthma Research Program. Correlations between serum IL6 and IL6R levels, lung function, phenotypic asthma clusters, and asthma severity were evaluated.
Methods
Serum IL6 and soluble IL6R was measured in 149 subjects with mild to severe asthma. Serum sIL6R levels were measured using the sIL-6R DuoSet (R&D Systems, Minneapolis, MN) ELISA kit and reported as ng/ml. Serum IL6 measurements were determined using the IL-6 ELISA kit (R&D Systems, Minneapolis, MN) and reported as pg/ml. Serum IL6 and sIL6R measurements were transformed to normalize distribution. The continuous variables analyzed included: % predicted FEV1 [ppFEV1], % predicted FVC [ppFVC], and FEV1/FVC. Serum samples were collected at Wake Forest. Phenotypic asthma clusters were derived as previously described (Am J Respir Crit Care Med. 2010;181:315–323).
Results
Elevated serum IL6 was associated with lower ppFEV1 (P = 0.02) and lower ppFVC (P = 0.003), while elevated serum soluble IL6R was associated with lower ppFEV1 (P = 0.02) and lower ppFVC (P = 0.008). Increasing trends in serum IL6 were observed in atopic asthma Clusters 2 and 4 and the later onset fixed airways obstruction Cluster 5. The highest IL6 serum levels were observed in Cluster 3 characterized has having late onset asthma and elevated BMI. Serum IL6 levels were elevated in subjects with severe asthma (log IL6 = 0.33; N = 25) compared to subjects with mild/moderate asthma (log IL6 = 0.16; N = 69).
Conclusions
Serum IL6 and sIL6R levels are elevated in non-Hispanic white asthma subjects with lower lung function. Serum IL6 and sIL6R are potentially important biomarkers that may distinguish between non-severe and severe asthma and between atopic asthma Clusters.
doi:10.1097/01.WOX.0000411868.89373.49
PMCID: PMC3513110
4.  IL6R Variation Asp358Ala Is a Potential Modifier of Lung Function in Asthma 
Background
The IL6R 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 (r2=1) with the IL6R coding SNP rs2228145 (Asp358Ala). This IL6R coding change increases IL6 receptor shedding and promotes IL6 transsignaling.
Objectives
To evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes.
Methods
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 IL6 receptor (sIL6R) levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL6R protein expression in BAL cells and endobronchial biopsies.
Results
The minor C allele of IL6R SNP rs2228145 was associated with lower ppFEV1 in the SARP cohort (p=0.005), the CSGA cohort (0.008), and in combined cohort analysis (p=0.003). Additional associations with ppFVC, FEV1/FVC, and PC20 were observed. The rs2228145 C allele (Ala358) was more frequent in severe asthma phenotypic clusters. Elevated serum sIL6R was associated with lower ppFEV1 (p=0.02) and lower ppFVC (p=0.008) (N=146). IL6R protein expression was observed in BAL macrophages, airway epithelium, vascular endothelium, and airway smooth muscle.
Conclusions
The IL6R coding SNP rs2228145 (Asp358Ala) is a potential modifier of lung function in asthma and may identify subjects at risk for more severe asthma. IL6 transsignaling may have a pathogenic role in the lung.
doi:10.1016/j.jaci.2012.03.018
PMCID: PMC3409329  PMID: 22554704
soluble interleukin 6 receptor; sIL6R; interleukin 6; IL6; asthma; pulmonary lung function; severe asthma; IL6 transsignaling; genetic variation; SNP rs2228145
5.  Association of VEGF polymorphisms with childhood asthma, lung function and airway responsiveness 
The European respiratory journal  2009;33(6):1287-1294.
Vascular endothelial growth factor (VEGF) is an angiogenic factor implicated in asthma severity. The objective of the present study was to determine whether VEGF single nucleotide polymorphisms (SNPs) are associated with asthma, lung function and airway responsiveness.
The present authors analysed 10 SNPs in 458 white families in the Childhood Asthma Management Program (CAMP). Tests of association with asthma, lung function and airway responsiveness were performed using PBAT software (Golden Helix, Inc. Bozeman, MT, USA; available at www.goldenhelix.com). Family and population-based, revpeated measures analysis of airflow obstruction were conducted. Replication studies were performed in 412 asthmatic children and their parents from Costa Rica.
Associations with asthma, lung function and airway responsiveness were observed in both cohorts. SNP rs833058 was associated with asthma in both cohorts. This SNP was also associated with increased airway responsiveness in both populations. An association of rs4711750 and its haplotype with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio in both cohorts was observed. Longitudinal analysis in CAMP confirmed an association of rs4711750 with FEV1/FVC decline over ~4.5 yrs of observation.
VEGF polymorphisms are associated with childhood asthma, lung function and airway responsiveness in two populations, suggesting that VEGF polymorphisms influence asthma susceptibility, airflow obstruction and airways responsiveness.
doi:10.1183/09031936.00113008
PMCID: PMC3725278  PMID: 19196819
Airflow obstruction; asthma; single nucleotide polymorphisms; vascular endothelial growth factor
6.  Genome-wide association study of lung function decline in adults with and without asthma 
Background
Genome-wide association studies (GWAS) have identified determinants of chronic obstructive pulmonary disease, asthma and lung function level, however none addressed decline in lung function.
Aim
We conducted the first GWAS on age-related decline in forced expiratory volume in the first second (FEV1) and in its ratio to forced vital capacity (FVC) stratified a priori by asthma status.
Methods
Discovery cohorts included adults of European ancestry (1441 asthmatics, 2677 non-asthmatics; Epidemiological Study on the Genetics and Environment of Asthma (EGEA); Swiss Cohort Study on Air Pollution And Lung And Heart Disease In Adults (SAPALDIA); European Community Respiratory Health Survey (ECRHS)). The associations of FEV1 and FEV1/FVC decline with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed-up by in silico replication (1160 asthmatics, 10858 non-asthmatics: Atherosclerosis Risk in Communities (ARIC); Framingham Heart Study (FHS); British 1958 Birth Cohort (B58C); Dutch asthma study).
Results
Main signals identified differed between asthmatics and non-asthmatics. None of the SNPs reached genome-wide significance. The association between the height related gene DLEU7 and FEV1 decline suggested for non-asthmatics in the discovery phase was replicated (discovery P=4.8×10−6; replication P=0.03) and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, associated with FEV1/FVC decline in asthmatics (P=5.3×10−8) did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline.
Conclusions
Genetic heterogeneity of lung function may be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status.
doi:10.1016/j.jaci.2012.01.074
PMCID: PMC3340499  PMID: 22424883
Asthma; cohort studies; genome-wide association; lung function decline; heterogeneity
7.  Decreased response to inhaled steroids in overweight and obese asthmatic children 
Background
The mechanisms and consequences of the observed association between obesity and childhood asthma are unclear.
Objectives
To determine the effect of obesity on treatment responses to inhaled corticosteroids in asthmatic children.
Methods
We performed a post hoc analysis to evaluate the interaction between body mass index (BMI) and treatment with inhaled budesonide on lung function in the Childhood Asthma Management Program (CAMP) trial. Participants were then stratified into overweight/obese and non-overweight, and their response to inhaled budesonide was analyzed longitudinally over the 4 years of the trial.
Results
There was a significant interaction between BMI and budesonide for pre-BD FEV1/FVC (P=0.0007) and bronchodilator response (BDR) (P=0.049), and a non-significant trend for an interaction between BMI and budesonide on pre-BD FEV1 (P=0.15). Non-overweight children showed significant improvement with inhaled budesonide in lung function (FEV1, FEV1/FVC, and BDR) during the early (years 1–2) and late stages (years 3–4) of the trial. Overweight/obese children had improved FEV1 and BDR during the early but not the late stage of the trial, and showed no improvement in FEV1/FVC. When comparing time points where both groups showed significant response, the degree of improvement among non-overweight children was significantly greater than in overweight/obese children at most visits. Non-overweight children had a 44% reduction in the risk of ER visits or hospitalizations throughout the trial (P=0.001); there was no reduction in risk among overweight/obese (P=0.97).
Conclusions
Compared to children of normal weight, overweight/obese children in CAMP showed a decreased response to inhaled budesonide on measures of lung function and ER visits/hospitalizations for asthma.
doi:10.1016/j.jaci.2010.12.010
PMCID: PMC3056233  PMID: 21377042
Asthma; obesity; pediatric asthma; childhood obesity; budesonide
8.  Genome-Wide Association Study Implicates Chromosome 9q21.31 as a Susceptibility Locus for Asthma in Mexican Children 
PLoS Genetics  2009;5(8):e1000623.
Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case–parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10×10−6 in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79×10−7). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.
Author Summary
Asthma is a leading chronic childhood disease with a presumed strong genetic component, but no genes have been definitely shown to influence asthma development. Few genetic studies of asthma have included Hispanic populations. Here, we conducted a genome-wide association study of asthma in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents to identify novel genetic variation for childhood asthma. We implicated several polymorphisms in or near TLE4 on chromosome 9q21.31 (a novel candidate region for childhood asthma) and replicated one polymorphism in an independent study of childhood-onset asthmatics with atopy and their parents of Mexican ethnicity. Hispanics have differing proportions of Native American, European, and African ancestries, and we found less Native American ancestry than expected at chromosome 9q21.31. This suggests that chromosome 9q21.31 may underlie ethnic differences in childhood asthma and that future replication would be most effective in populations with Native American ancestry. Analysis of publicly available genome-wide expression data revealed that association signals in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of the overall GWAS findings and the multigenic etiology of asthma.
doi:10.1371/journal.pgen.1000623
PMCID: PMC2722731  PMID: 19714205
9.  Variants in TGFB1, Dust Mite Exposure, and Disease Severity in Children with Asthma 
Rationale: Polymorphisms in the gene for transforming growth factor-β1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma.
Objectives: To test for association between single nucleotide polymorphisms (SNPs) in TGFB1 and markers of asthma severity in childhood.
Methods: We tested for the association between nine SNPs in TGFB1 and indicators of asthma severity (lung function, airway responsiveness, and disease exacerbations) in two cohorts: 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the Childhood Asthma Management Program (CAMP). We also tested for the interaction between these polymorphisms and exposure to dust mite allergen on asthma severity.
Measurements and Main Results: The A allele of promoter SNP rs2241712 was associated with increased airway responsiveness in Costa Rica (P = 0.0006) and CAMP (P = 0.005), and the C allele of an SNP in the promoter region (rs1800469) was associated with increased airway responsiveness in both cohorts (P ≤ 0.01). Dust mite exposure modified the effect of the C allele of exonic SNP rs1800471 on airway responsiveness (P = 0.03 for interactions in both cohorts). The T allele of a coding SNP (rs1982073) was associated with a reduced risk of asthma exacerbations in Costa Rica (P = 0.009) and CAMP (P = 0.005). Dust mite exposure also significantly modified the effect of the A allele of the promoter SNP rs2241712 on asthma exacerbations in both cohorts.
Conclusions: SNPs in TGFB1 are associated with airway responsiveness and disease exacerbations in children with asthma. Moreover, dust mite exposure may modify the effect of TGFB1 SNPs on airway responsiveness and asthma exacerbations.
doi:10.1164/rccm.200808-1268OC
PMCID: PMC2648908  PMID: 19096005
airway responsiveness; asthma; dust mite allergen; single nucleotide polymorphisms; transforming growth factor-β1
10.  GSTCD and INTS12 Regulation and Expression in the Human Lung 
PLoS ONE  2013;8(9):e74630.
Genome-Wide Association Study (GWAS) meta-analyses have identified a strong association signal for lung function, which maps to a region on 4q24 containing two oppositely transcribed genes: glutathione S-transferase, C-terminal domain containing (GSTCD) and integrator complex subunit 12 (INTS12). Both genes were found to be expressed in a range of human airway cell types. The promoter regions and transcription start sites were determined in mRNA from human lung and a novel splice variant was identified for each gene. We obtained the following evidence for GSTCD and INTS12 co-regulation and expression: (i) correlated mRNA expression was observed both via Q-PCR and in a lung expression quantitative trait loci (eQTL) study, (ii) induction of both GSTCD and INTS12 mRNA expression in human airway smooth muscle cells was seen in response to TGFβ1, (iii) a lung eQTL study revealed that both GSTCD and INTS12 mRNA levels positively correlate with percent predicted FEV1, and (iv) FEV1 GWAS associated SNPs in 4q24 were found to act as an eQTL for INTS12 in a number of tissues. In fixed sections of human lung tissue, GSTCD protein expression was ubiquitous, whereas INTS12 expression was predominantly in epithelial cells and pneumocytes. During human fetal lung development, GSTCD protein expression was observed to be highest at the earlier pseudoglandular stage (10-12 weeks) compared with the later canalicular stage (17-19 weeks), whereas INTS12 expression levels did not alter throughout these stages. Knowledge of the transcriptional and translational regulation and expression of GSTCD and INTS12 provides important insights into the potential role of these genes in determining lung function. Future work is warranted to fully define the functions of INTS12 and GSTCD.
doi:10.1371/journal.pone.0074630
PMCID: PMC3776747  PMID: 24058608
11.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Conclusions
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001669.
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001669
PMCID: PMC4077660  PMID: 24983943
12.  Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction 
Wilk, Jemma B. | Shrine, Nick R. G. | Loehr, Laura R. | Zhao, Jing Hua | Manichaikul, Ani | Lopez, Lorna M. | Smith, Albert Vernon | Heckbert, Susan R. | Smolonska, Joanna | Tang, Wenbo | Loth, Daan W. | Curjuric, Ivan | Hui, Jennie | Cho, Michael H. | Latourelle, Jeanne C. | Henry, Amanda P. | Aldrich, Melinda | Bakke, Per | Beaty, Terri H. | Bentley, Amy R. | Borecki, Ingrid B. | Brusselle, Guy G. | Burkart, Kristin M. | Chen, Ting-hsu | Couper, David | Crapo, James D. | Davies, Gail | Dupuis, Josée | Franceschini, Nora | Gulsvik, Amund | Hancock, Dana B. | Harris, Tamara B. | Hofman, Albert | Imboden, Medea | James, Alan L. | Khaw, Kay-Tee | Lahousse, Lies | Launer, Lenore J. | Litonjua, Augusto | Liu, Yongmei | Lohman, Kurt K. | Lomas, David A. | Lumley, Thomas | Marciante, Kristin D. | McArdle, Wendy L. | Meibohm, Bernd | Morrison, Alanna C. | Musk, Arthur W. | Myers, Richard H. | North, Kari E. | Postma, Dirkje S. | Psaty, Bruce M. | Rich, Stephen S. | Rivadeneira, Fernando | Rochat, Thierry | Rotter, Jerome I. | Artigas, María Soler | Starr, John M. | Uitterlinden, André G. | Wareham, Nicholas J. | Wijmenga, Cisca | Zanen, Pieter | Province, Michael A. | Silverman, Edwin K. | Deary, Ian J. | Palmer, Lyle J. | Cassano, Patricia A. | Gudnason, Vilmundur | Barr, R. Graham | Loos, Ruth J. F. | Strachan, David P. | London, Stephanie J. | Boezen, H. Marike | Probst-Hensch, Nicole | Gharib, Sina A. | Hall, Ian P. | O’Connor, George T. | Tobin, Martin D. | Stricker, Bruno H.
Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations.
Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
doi:10.1164/rccm.201202-0366OC
PMCID: PMC3480517  PMID: 22837378
chronic obstructive pulmonary disease; single-nucleotide polymorphism; genes
13.  African Ancestry and Lung Function in Puerto Rican Children 
Background
Puerto Ricans and African Americans share a significant proportion of African ancestry. Recent findings suggest that African ancestry influences lung function in African American adults.
Objective
To examine whether a greater proportion of African ancestry is associated with lower FEV1 and FVC in Puerto Rican children, independently of socioeconomic status (SES), healthcare access or key environmental/lifestyle (EL) factors.
Methods
Cross-sectional case-control study of 943 Puerto Rican children ages 6 to 14 years with (n=520) and without (n=423) asthma (defined as physician-diagnosed asthma and wheeze in the prior year) living in Hartford (CT, n=383) and San Juan (PR, n=560). We estimated the percentage of African racial ancestry in study participants using genome-wide genotypic data. We tested whether African ancestry is associated with FEV1 and FVC using linear regression. Multivariate models were adjusted for indicators of SES and healthcare, and selected EL exposures.
Results
After adjustment for household income and other covariates, each 20% increment in African ancestry was significantly associated with lower pre-bronchodilator(BD) FEV1 (−105 ml, 95% confidence interval [CI] = −159 ml to −51 ml, P <0.001) and FVC (−133 ml, 95% CI −197 ml to −69 ml, P <0.001), and post-BD FEV1 (−152 ml, 95% CI=−210 ml to −94 ml, P <0.001) and FVC (−145 ml, 95% CI= −211 to −79 ml, P <0.001) in children with asthma. Similar but weaker associations were found for pre- and post-BD FEV1 (change for each 20% increment in African ancestry= −78 ml, 95% CI= −131 to −25 ml, P=0.004), and for post-BD FVC among children without asthma.
Conclusions
Genetic and/or EL factors correlated with African ancestry may influence childhood lung function in Puerto Ricans.
doi:10.1016/j.jaci.2012.03.035
PMCID: PMC3367038  PMID: 22560959
ancestry; FEV1; FVC; Puerto Ricans; childhood
14.  Lung function and respiratory health in adolescents of very low birth weight 
Archives of Disease in Childhood  2003;88(2):135-138.
Aims: To determine if very low birth weight (VLBW; birth weight <1500 g) is associated with reduced lung function and respiratory health in adolescence and, if it is, whether this impairment is associated with prematurity or intrauterine growth restriction.
Methods: A geographically defined cohort of 128 VLBW infants and an age, sex, and school matched comparison group born in 1980/81 were studied. The cohort and comparison group were assessed at 15 years of age. The birth weight ratio of the index cases (observed birth weight/expected birth weight for the gestation) was determined to assess the degree of growth restriction. Respiratory support received during the neonatal period was obtained from hospital records. Smoking habits and respiratory morbidity were obtained through questionnaires. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and forced expiratory flow when 25–75% of FVC is expired (FEF25–75%) were measured using a portable spirometer. The values are expressed as percentage predicted for height, age, and gender using standard reference values. Adjustments were made for smoking habits of mother and children.
Results: The differences in means between index and comparison groups for FEF25–75% (-12.42%; p < 0.001) and FEV1/FVC (-3.53%; p < 0.001) ratio were statistically significant. The differences in FVC and FEV1 were not significant. No correlation was found between the birth weight ratio and lung function among the index cohort. Chronic cough, wheezing, and asthma were more common among the index cohort than in the comparison group. Within the index group, there was no difference in lung function between those who received and those who did not receive respiratory support.
Conclusion: Adolescents who were VLBW compared with matched controls showed medium and small airways obstruction. This was associated with prematurity rather than intrauterine growth restriction or having received respiratory support during the neonatal period. The index VLBW cohort compared with their controls were also more prone to chronic cough, wheezing, and asthma.
doi:10.1136/adc.88.2.135
PMCID: PMC1719454  PMID: 12538315
15.  Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function 
Hancock, Dana B. | Artigas, María Soler | Gharib, Sina A. | Henry, Amanda | Manichaikul, Ani | Ramasamy, Adaikalavan | Loth, Daan W. | Imboden, Medea | Koch, Beate | McArdle, Wendy L. | Smith, Albert V. | Smolonska, Joanna | Sood, Akshay | Tang, Wenbo | Wilk, Jemma B. | Zhai, Guangju | Zhao, Jing Hua | Aschard, Hugues | Burkart, Kristin M. | Curjuric, Ivan | Eijgelsheim, Mark | Elliott, Paul | Gu, Xiangjun | Harris, Tamara B. | Janson, Christer | Homuth, Georg | Hysi, Pirro G. | Liu, Jason Z. | Loehr, Laura R. | Lohman, Kurt | Loos, Ruth J. F. | Manning, Alisa K. | Marciante, Kristin D. | Obeidat, Ma'en | Postma, Dirkje S. | Aldrich, Melinda C. | Brusselle, Guy G. | Chen, Ting-hsu | Eiriksdottir, Gudny | Franceschini, Nora | Heinrich, Joachim | Rotter, Jerome I. | Wijmenga, Cisca | Williams, O. Dale | Bentley, Amy R. | Hofman, Albert | Laurie, Cathy C. | Lumley, Thomas | Morrison, Alanna C. | Joubert, Bonnie R. | Rivadeneira, Fernando | Couper, David J. | Kritchevsky, Stephen B. | Liu, Yongmei | Wjst, Matthias | Wain, Louise V. | Vonk, Judith M. | Uitterlinden, André G. | Rochat, Thierry | Rich, Stephen S. | Psaty, Bruce M. | O'Connor, George T. | North, Kari E. | Mirel, Daniel B. | Meibohm, Bernd | Launer, Lenore J. | Khaw, Kay-Tee | Hartikainen, Anna-Liisa | Hammond, Christopher J. | Gläser, Sven | Marchini, Jonathan | Kraft, Peter | Wareham, Nicholas J. | Völzke, Henry | Stricker, Bruno H. C. | Spector, Timothy D. | Probst-Hensch, Nicole M. | Jarvis, Deborah | Jarvelin, Marjo-Riitta | Heckbert, Susan R. | Gudnason, Vilmundur | Boezen, H. Marike | Barr, R. Graham | Cassano, Patricia A. | Strachan, David P. | Fornage, Myriam | Hall, Ian P. | Dupuis, Josée | Tobin, Martin D. | London, Stephanie J.
PLoS Genetics  2012;8(12):e1003098.
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
Author Summary
Measures of pulmonary function provide important clinical tools for evaluating lung disease and its progression. Genome-wide association studies have identified numerous genetic risk factors for pulmonary function but have not considered interaction with cigarette smoking, which has consistently been shown to adversely impact pulmonary function. In over 50,000 study participants of European descent, we applied a recently developed joint meta-analysis method to simultaneously test associations of gene and gene-by-smoking interactions in relation to two major clinical measures of pulmonary function. Using this joint method to incorporate genetic main effects plus gene-by-smoking interaction, we identified three novel gene regions not previously related to pulmonary function: (1) DNER, (2) HLA-DQB1 and HLA-DQA2, and (3) KCNJ2 and SOX9. Expression analyses in human lung tissue from ours or prior studies indicate that these regions contain genes that are plausibly involved in pulmonary function. This work highlights the utility of employing novel methods for incorporating environmental interaction in genome-wide association studies to identify novel genetic regions.
doi:10.1371/journal.pgen.1003098
PMCID: PMC3527213  PMID: 23284291
16.  Adam33 polymorphisms are associated with COPD and lung function in long-term tobacco smokers 
Respiratory Research  2009;10(1):21.
Background
Variation in ADAM33 has been shown to be important in the development of asthma and altered lung function. This relationship however, has not been investigated in the population susceptible to COPD; long term tobacco smokers. We evaluated the association between polymorphisms in ADAM33 gene with COPD and lung function in long term tobacco smokers.
Methods
Caucasian subjects, at least 50 year old, who smoked ≥ 20 pack-years (n = 880) were genotyped for 25 single nucleotide polymorphisms (SNPs) in ADAM33. COPD was defined as an FEV1/FVC ratio < 70% and percent-predicted (pp)FEV1 < 75% (n = 287). The control group had an FEV1/FVC ratio ≥ 70% and ppFEV1 ≥ 80% (n = 311) despite ≥ 20 pack years of smoking. Logistic and linear regressions were used for the analysis. Age, sex, and smoking status were considered as potential confounders.
Results
Five SNPs in ADAM33 were associated with COPD (Q-1, intronic: p < 0.003; S1, Ile → Val: p < 0.003; S2, Gly → Gly: p < 0.04; V-1 intronic: p < 0.002; V4, in 3' untranslated region: p < 0.007). Q-1, S1 and V-1 were also associated with ppFEV1, FEV1/FVC ratio and ppFEF25–75 (p values 0.001 – 0.02). S2 was associated with FEV1/FVC ratio (p < 0.05). The association between S1 and residual volume revealed a trend toward significance (p value < 0.07). Linkage disequilibrium and haplotype analyses suggested that S1 had the strongest degree of association with COPD and pulmonary function abnormalities.
Conclusion
Five SNPs in ADAM33 were associated with COPD and lung function in long-term smokers. Functional studies will be needed to evaluate the biologic significance of these polymorphisms in the pathogenesis of COPD.
doi:10.1186/1465-9921-10-21
PMCID: PMC2664793  PMID: 19284602
17.  Lung Function Is Associated with Arterial Stiffness in Children 
PLoS ONE  2011;6(10):e26303.
Background
In older adults, an independent association exists between impaired lung function and cardiovascular disease. This interaction might be related to the effects of aging and/or smoking. In order to explore possible childhood antecedents to this association, we hypothesized that decreased lung function and vascular stiffness might be related, in early life.
Objective
To determine the relationship between lung function and carotid augmentation index (AIx), a measure of vascular stiffness, in 8-year old children.
Methods
Data on brachial blood pressure, lung function (FEV1, FVC, FEV1/FVC, obtained by spirometry) and carotid AIx75 (AIx standardised to an arbitrary heart rate of 75 beats per minute, obtained by applanation tonometry) was available in 249 community-based 8-year old children. These healthy children had been subjects in a randomised controlled trial of two interventions (omega-3 fatty acid supplementation and house-dust mite avoidance) to prevent asthma. Smoking in pregnancy and childhood environmental tobacco smoke (ETS) exposure was prospectively collected by questionnaire. The association between lung function and carotid AIx75 was assessed in multivariate models that included sex, height, smoking status during pregnancy, ETS exposure and randomisation groups (house dust mite avoidance and dietary intervention) as covariates.
Results
In the fully adjusted models, Carotid AIx75 was independently associated with FEV1 (standardised β = −0.17,b = −6.72, partial R2 = .02, p = 0.03), FVC (standardised β = −0.29, b = −9.31, partial R2 = 0.04, p<0.001) and FEV1/FVC (standardised β = .13, b = 18.4, partial R2 = 0.02, p = 0.04).
Conclusion
Lower lung volumes are associated with increased vascular stiffness at an early age. The interaction between lung function and vascular stiffness may thus represent more than just age-related alterations in both the pulmonary and vascular systems.
doi:10.1371/journal.pone.0026303
PMCID: PMC3201952  PMID: 22046271
18.  The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers 
BMC Medical Genetics  2011;12:173.
Background
We have previously shown evidence that polymorphisms within genes controlling leukotriene B4 (LTB4) production (ALOX5AP and LTA4H) are associated with asthma susceptibility in children. Evidence also suggests a potential role of LTB4 in COPD disease mechanisms including recruitment of neutrophils to the lung. The aim of the current study was to see if these SNPs and those spanning the receptor genes for LTB4 (LTB4R1 and LTB4R2) influence baseline lung function and COPD susceptibility/severity in smokers.
Methods
Eight ALOX5AP, six LTA4H and six LTB4R single nucleotide polymorphisms (SNPs) were genotyped in a UK Smoking Cohort (n = 992). Association with baseline lung function (FEV1 and FEV1/FVC ratio) was determined by linear regression. Logistic regression was used to compare smoking controls (n = 176) with spirometry-defined COPD cases (n = 599) and to more severe COPD cases (GOLD stage 3 and 4, n = 389).
Results
No association with ALOX5AP, LTA4H or LTB4R survived correction for multiple testing. However, we showed modest association with LTA4H rs1978331C (intron 11) with increased FEV1 (p = 0.029) and with increased FEV1/FVC ratio (p = 0.020).
Conclusions
These data suggest that polymorphisms spanning ALOX5AP, LTA4H and the LTB4R locus are not major determinants of baseline lung function in smokers, but provide tentative evidence for LTA4H rs1978331C (intron 11) in determining baseline FEV1 and FEV1/FVC ratio in Caucasian Smokers in addition to our previously identified role in asthma susceptibility.
doi:10.1186/1471-2350-12-173
PMCID: PMC3267686  PMID: 22206291
19.  SICKLE CELL DISEASE IN MALAWIAN CHILDREN IS ASSOCIATED WITH RESTRICTIVE SPIROMETRY: A CROSS SECTIONAL SURVEY 
SUMMARY
Background
A proportion of children with sickle cell disease (SCD) demonstrate clinical findings consistent with the diagnosis of asthma. These children are at increased risk of complications including acute chest syndrome.
Objective
To assess lung function and symptoms of asthma in children with SCD in Blantyre, Malawi.
Design
Twenty-five children aged seven to sixteen with electrophoretically confirmed SCD were recruited to undergo spirometry and questionnaire screening of asthma symptoms. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio, were compared with local and international reference ranges. Symptoms were assessed using the International Study of Asthma and Allergies in Childhood questionnaire.
Results
Mean spirometric indices represented as z-scores derived from international reference ranges were low: FEV1 −1.64 (95% CI −2.04 to −1.23), FVC −1.49 (95% CI −1.90 to −1.09), FEV1/FVC −0.39 (95% CI −0.76 to −0.03). Comparison with local reference ranges, represented as percentage of predicted value, revealed similar impairments: FEV1 86.9 (95% CI 81.1 to 92.7), FVC 89.0 (95% CI 83.5 to 94.4), FEV1/FVC ratio 97.7 (95% CI 95.4 to 99.9). The prevalence of wheeze was 16.7%.
Conclusion
We present spirometric abnormalities suggestive of restrictive lung disease with no evidence of obstructive defects or increased prevalence of wheeze.
doi:10.5588/ijtld.12.0965
PMCID: PMC3826120  PMID: 23827770
paediatric; lung function; wheeze; asthma
20.  Association between lung function and cognition among children in a prospective birth cohort study 
Psychosomatic medicine  2008;70(3):356-362.
Objectives
While a growing number of studies have demonstrated a relationship between lung function and cognition among adults, this relationship has not been studied among children. We examined the relationship between lung function and cognition among children in the Maternal-Infant Smoking Study of East Boston, a prospective cohort of women and children enrolled prior to 20 weeks of gestation.
METHODS
At 6 years of age, children completed lung function tests. At 9 years of age, the Wide Range Assessment of Memory and Learning (WRAML) and Kaufman Brief Intelligence Test (K-BIT) were administered. Linear regression was used to assess the relationship between cognition and lung function adjusting for race, maternal education, child's gender, age, height, birthweight, asthma, allergies, lower respiratory infections, blood lead level, in utero and second hand tobacco exposure.
RESULTS
The sample of 165 children included 53% girls and 52% Hispanic. Mean (± SD) forced expiratory volume in one second (FEV1) was 1.26L + 0.2; mean forced vital capacity (FVC) was 1.37L + 0.2. In multivariate regression, a one percent increase from expected FEV1 was associated with increases in the matrices and composite subscales of the KBIT (p < .05), and in the verbal and learning subscales of the WRAML (p <.10). FVC was associated with increases in the composite and matrices subscale of the KBIT and in the visual and learning subscales of the WRAML (all p < .05).
CONCLUSION
Increased lung function was associated with increased cognitive development among children after adjusting for tobacco exposure, birthweight and peak blood lead. Lung and cognitive function may operate under common regulatory processes and thus have shared vulnerabilities to a host of environmental factors during development.
doi:10.1097/PSY.0b013e3181656a5a
PMCID: PMC3086642  PMID: 18378869
cognitive function; lung function; children
21.  Canonical Wnt Signaling Activity in Early Stages of Chick Lung Development 
PLoS ONE  2014;9(12):e112388.
Wnt signaling pathway is an essential player during vertebrate embryonic development which has been associated with several developmental processes such as gastrulation, body axis formation and morphogenesis of numerous organs, namely the lung. Wnt proteins act through specific transmembrane receptors, which activate intracellular pathways that regulate cellular processes such as cell proliferation, differentiation and death. Morphogenesis of the fetal lung depends on epithelial-mesenchymal interactions that are governed by several growth and transcription factors that regulate cell proliferation, fate, migration and differentiation. This process is controlled by different signaling pathways such as FGF, Shh and Wnt among others. Wnt signaling is recognized as a key molecular player in mammalian pulmonary development but little is known about its function in avian lung development. The present work characterizes, for the first time, the expression pattern of several Wnt signaling members, such as wnt-1, wnt-2b, wnt-3a, wnt-5a, wnt-7b, wnt-8b, wnt-9a, lrp5, lrp6, sfrp1, dkk1, β-catenin and axin2 at early stages of chick lung development. In general, their expression is similar to their mammalian counterparts. By assessing protein expression levels of active/total β-catenin and phospho-LRP6/LRP6 it is revealed that canonical Wnt signaling is active in this embryonic tissue. In vitro inhibition studies were performed in order to evaluate the function of Wnt signaling pathway in lung branching. Lung explants treated with canonical Wnt signaling inhibitors (FH535 and PK115-584) presented an impairment of secondary branch formation after 48 h of culture along with a decrease in axin2 expression levels. Branching analysis confirmed this inhibition. Wnt-FGF crosstalk assessment revealed that this interaction is preserved in the chick lung. This study demonstrates that Wnt signaling is crucial for precise chick lung branching and further supports the avian lung as a good model for branching studies since it recapitulates early mammalian pulmonary development.
doi:10.1371/journal.pone.0112388
PMCID: PMC4251901  PMID: 25460002
22.  Lower FEV1 in non-COPD, nonasthmatic subjects: association with smoking, annual decline in FEV1, total IgE levels, and TSLP genotypes 
Few studies have investigated the significance of decreased FEV1 in non-COPD, nonasthmatic healthy subjects. We hypothesized that a lower FEV1 in these subjects is a potential marker of an increased susceptibility to obstructive lung disease such as asthma and COPD. This was a cross-sectional analysis of 1505 Japanese adults. We divided the population of healthy adults with no respiratory diseases whose FEV1/FVC ratio was ≥70% (n = 1369) into 2 groups according to their prebronchodilator FEV1 (% predicted) measurements: <80% (n = 217) and ≥80% (n = 1152). We compared clinical data – including gender, age, smoking habits, total IgE levels, and annual decline of FEV1 – between these 2 groups. In addition, as our group recently found that TSLP variants are associated with asthma and reduced lung function, we assessed whether TSLP single nucleotide polymorphisms (SNPs) were associated with baseline lung function in non-COPD, nonasthmatic healthy subjects (n = 1368). Although about half of the subjects with lower FEV1 had never smoked, smoking was the main risk factor for the decreased FEV1 in non-COPD, nonasthmatic subjects. However, the subjects with lower FEV1 had a significantly higher annual decline in FEV1 independent of smoking status. Airflow obstruction was associated with increased levels of total serum IgE (P = 0.029) and with 2 functional TSLP SNPs (corrected P = 0.027–0.058 for FEV1% predicted, corrected P = 0.015–0.033 for FEV1/FVC). This study highlights the importance of early recognition of a decreased FEV1 in healthy subjects without evident pulmonary diseases because it predicts a rapid decline in FEV1 irrespective of smoking status. Our series of studies identified TSLP variants as a potential susceptibility locus to asthma and to lower lung function in non-COPD, nonasthmatic healthy subjects, which may support the contention that genetic determinants of lung function influence susceptibility to asthma.
doi:10.2147/COPD.S16383
PMCID: PMC3064418  PMID: 21468164
airflow obstruction; asthma; chronic obstructive pulmonary disease; pulmonary function test; thymic stromal lymphopoietin
23.  Predictors of Remitting, Periodic, and Persistent Childhood Asthma 
Background
The course of mild to moderate persistent asthma in children is not clearly established.
Objective
To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence.
Methods
The Childhood Asthma Management Program (CAMP) was a 4.3-year randomized, double-masked, multicenter trial in children with mild to moderate persistent asthma that compared continuous therapy with either budesonide or nedocromil, each to placebo, followed by 4 years observational follow-up period. Asthma activity during the observation period included remitting (no asthma activity in the last year), persistent (asthma activity in every quarter), and periodic asthma (neither remitting nor persistent).
Results
Asthma was identified as remitting in 6%, periodic in 39%, and persistent in 55% of the 909 participants, with no effect noted from earlier anti-inflammatory treatment during the CAMP trial. Within all three asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting vs. persistent asthma were lack of allergen sensitization and exposure to indoor allergens [OR=3.23, p<0.001], milder asthma [OR=2.01, p=0.03], older age [OR=1.23, p=0.01], less airway hyperresponsiveness (higher log methacholine FEV1 PC20 [OR=1.39, p=0.03]), higher pre-bronchodilator FEV1 % predicted [OR=1.05, p=0.02], and lower FVC % predicted [OR=0.96, p=0.04].
Conclusion
Remission of asthma in adolescence is infrequent and not impacted by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma.
doi:10.1016/j.jaci.2009.10.037
PMCID: PMC2844768  PMID: 20159245
Remission; Natural history; Persistent asthma
24.  Association of lung function decline with the heme oxygenase‐1 gene promoter microsatellite polymorphism in a general population sample. Results from the European Community Respiratory Health Survey (ECRHS), France 
Journal of Medical Genetics  2006;43(8):e43.
Inducible heme oxygenase (HO‐1) acts against oxidants that are thought to play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD), characterised by impaired lung function. A (GT)n repeat polymorphism in the HO‐1 gene promoter can modulate the gene transcription in response to oxidative stress. We hypothesised that this polymorphism could be associated with the level of lung function and decline in subjects exposed to oxidative agression (smokers). We genotyped 749 French subjects (20–44 years, 50% men, 40% never smokers) examined in both 1992 and 2000 as part of the ECRHS. Lung function was assessed by forced expiratory volume in 1 second (FEV1) and FEV1/forced ventilatory capacity (FVC) ratio. We compared long (L) allele carriers ((GT)n ⩾33 repeats for one or two alleles) to non‐carriers. Cross sectionally, in 2000, L allele carriers showed lower FEV1/FVC than non‐carriers. During the 8 year period, the mean annual FEV1 and FEV1/FVC declines were −30.9 (31.1) ml/year and −1.8 (6.1) U/year, respectively. FEV1/FVC decline was steeper in L allele carriers than in non‐carriers (−2.6 (5.5) v −1.5 (6.4), p = 0.07). There was a strong interaction between the L allele and smoking. In 2000, the L allele was associated with lower FEV1 and FEV1/FVC in heavy smokers (⩾20 cigarettes/day) only (p for interaction = 0.07 and 0.002 respectively). Baseline heavy smokers carrying the L allele showed the steepest FEV1 decline (−62.0 (29.5 ml/year) and the steepest FEV1/FVC decline (−8.8 (5.4 U/year) (p for interaction = 0.009 and 0.0006).These results suggest that a long (L) HO‐1 gene promoter in heavy smokers is associated with susceptibility to develop airway obstruction.
doi:10.1136/jmg.2005.039743
PMCID: PMC2564599  PMID: 16882737
lung function; decline; polymorphism; heme oxygenase; smoking
25.  The Association of Normal Range Glycated Hemoglobin with Restrictive Lung Pattern in the General Population 
PLoS ONE  2015;10(2):e0117725.
Glycated hemoglobin (HbA1c) is an important diagnostic indicator of diabetes mellitus, and some authors have argued that it is related to impaired lung function in the diabetic population. However, there was rare study for association between lung function and HbA1c in the non-diabetic population. We investigated whether HbA1c below the diagnostic threshold is related to deficits in lung function. We analyzed biochemical and spirometry data from a nation-wide, population-based, case-control study (the KNHANES IV and V). Eligible as cases were all native Koreans aged 40 years or more with no medical illness. A total of 3670 participants were divided into 4 groups according to HbA1c (%) as follows: Group I (n = 842), ≥ 4.0 and ≤ 5.3; Group II (n = 833), > 5.3 and ≤ 5.5; Group III (n = 898), > 5.5 and ≤ 5.7; and Group IV (n = 1097), > 5.7 and ≤ 6.4. Group I had the greatest forced vital capacity (FVC, 96.3 ± 0.5% pred, P < 0.0001), forced expiratory volume per second (FEV1, 93.8 ± 0.5% pred, P < 0.0001) and FEV1/FVC (0.792 ± 0.003, P < 0.0001) compared with the other groups. Linear regression showed that HbA1c was closely related to FVC (β = -6.972154, P < 0.0001) and FEV1 (β = -5.591589, P < 0.0001), but not to FEV1/FVC. Logistic regression analysis revealed a significant association between HbA1c and a restrictive spirometric pattern (FVC < 80% pred., FEV1/FVC ≥ 0.70; OR = 3.772, 95% CI = 1.234-11.53), indicating that elevated HbA1c is closely associated with lung impairment in the non-diabetic population. In the healthy population, relatively high HbA1c level is associated with decrements of FVC and FEV1 and may be a reliable predictor of poor lung function, especially the restrictive pattern.
doi:10.1371/journal.pone.0117725
PMCID: PMC4319889  PMID: 25658743

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