Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.

Genome-wide association study of lung function and clinical implication in heavy smokers.

BACKGROUND: The aim of this study is to identify genetic loci associated with post-bronchodilator FEV1/FVC and FEV1, and develop a multi-gene predictive model for lung function in COPD. METHODS: Genome-wide association study (GWAS) of post-bronchodilator FEV1/FVC and FEV1 was performed in 1645 non-Hispanic White European descent smokers. RESULTS: A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV1/FVC (p = 1.2 × 10- 8) and FEV1 (p = 2.1 × 10- 9). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10- 4) and severity (OR = 4.1; p = 0.0036). Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype. 8.6% of the variance of post-bronchodilator FEV1/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P <  2.2 × 10- 16). CONCLUSIONS: This study is the first to show genome-wide significant association of rs28929474 in SERPINA1 with lung function. Of clinical importance, heterozygotes of rs28929474 (4.7% of subjects) have significantly reduced pulmonary function, demonstrating a major impact in smokers. The multi-gene model is significantly associated with CT-based emphysema and clinical outcome measures of severity. Combining genetic information with demographic and environmental factors will further increase the predictive power for assessing reduced lung function and COPD severity.

Expression of asthma susceptibility genes in bronchial epithelial cells and bronchial alveolar lavage in the Severe Asthma Research Program (SARP) cohort.

OBJECTIVE: Genome-wide association studies (GWASs) have identified genes associated with asthma, however expression of these genes in asthma-relevant tissues has not been studied. This study tested expression and correlation between GWAS-identified asthma genes and asthma or asthma severity. METHODS: Correlation analyses of expression levels of GWAS-identified asthma genes and asthma-related biomarkers were performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and bronchial alveolar lavage (BAL, n = 94). RESULTS: Expression levels of asthma genes between BEC and BAL and with asthma or asthma severity were weakly correlated. The expression levels of IL18R1 were consistently higher in asthma than controls or in severe asthma than mild/moderate asthma in BEC and BAL (p < 0.05). In RAD50-IL13 region, the expression levels of RAD50, not IL4, IL5, or IL13, were positively correlated between BEC and BAL (ρ = 0.53, P = 4.5 × 10(-6)). The expression levels of IL13 were positively correlated with IL5 in BEC (ρ = 0.35, P = 1.9 × 10(-4)) and IL4 in BAL (ρ = 0.42, P = 2.5 × 10(-5)), respectively. rs3798134 in RAD50, a GWAS-identified SNP, was correlated with IL13 expression and the expression levels of IL13 were correlated with asthma (P = 0.03). rs17772583 in RAD50 was significantly correlated with RAD50 expression in BAL and BEC (P = 7.4 × 10(-7) and 0.04) but was not associated with asthma. CONCLUSIONS: This is the first report studying the expression of GWAS-identified asthma genes in BEC and BAL. IL13, rather than RAD50, IL4, or IL5, is more likely to be the asthma susceptibility gene. Our study illustrates tissue-specific expression of asthma-related genes. Therefore, whenever possible, disease-relevant tissues should be used for transcription analysis.

Detrimental effects of environmental tobacco smoke in relation to asthma severity.

BACKGROUND: Environmental tobacco smoke (ETS) has adverse effects on the health of asthmatics, however the harmful consequences of ETS in relation to asthma severity are unknown. METHODS: In a multicenter study of severe asthma, we assessed the impact of ETS exposure on morbidity, health care utilization and lung functions; and activity of systemic superoxide dismutase (SOD), a potential oxidative target of ETS that is negatively associated with asthma severity. FINDINGS: From 2002-2006, 654 asthmatics (non-severe 366, severe 288) were enrolled, among whom 109 non-severe and 67 severe asthmatics were routinely exposed to ETS as ascertained by history and validated by urine cotinine levels. ETS-exposure was associated with lower quality of life scores; greater rescue inhaler use; lower lung function; greater bronchodilator responsiveness; and greater risk for emergency room visits, hospitalization and intensive care unit admission. ETS-exposure was associated with lower levels of serum SOD activity, particularly in asthmatic women of African heritage. INTERPRETATION: ETS-exposure of asthmatic individuals is associated with worse lung function, higher acuity of exacerbations, more health care utilization, and greater bronchial hyperreactivity. The association of diminished systemic SOD activity to ETS exposure provides for the first time a specific oxidant mechanism by which ETS may adversely affect patients with asthma.

Importance of hedgehog interacting protein and other lung function genes in asthma.

BACKGROUND: Two recent large meta-analyses of genome-wide association studies of lung function in general populations of European descent identified 11 candidate genes/regions. The importance of these genes in lung function in white and African American subjects with asthma is unknown. OBJECTIVES: To determine whether genes that regulate lung function in general populations are associated with lung function abnormalities in subjects with asthma from different racial groups. METHODS: Single nucleotide polymorphisms (SNPs) were tested in 5 asthma populations (N = 1441) for association with pulmonary function, and meta-analysis was performed across populations. The SNPs with the highest significance were then tested for association with bronchodilator reversibility and bronchial hyperresponsiveness to methacholine. A joint analysis of consistently replicated SNPs was performed to predict lung function in asthma. RESULTS: Hedgehog interacting protein (HHIP) on chromosome 4q31 was associated with lung function in all 5 populations (rs1512288: P(meta) = 9.62E-05 and 3.23E-05 for percent predicted FEV(1) [ppFEV(1)] and percent predicted forced vital capacity [ppFVC], respectively). The SNPs in HHIP were also associated with reversibility (P < .05) but not bronchial hyperresponsiveness to methacholine. Because of differences in linkage disequilibrium in the African American subjects, the most relevant SNPs in HHIP were identified. A subset of normal lung function genes, including HHIP, family with sequence similarity 13, member A (FAM13A), and patched homolog 1 (PTCH1), together predict lung function abnormalities, a measure of severity in white and African American subjects with asthma. CONCLUSION: A subset of the genes, including HHIP, that regulate lung function in general populations are associated with abnormal lung function in asthma in non-Hispanic white and African American subjects.

Mesothelioma: you do not have to work for it.

Asbestos pollution is a global problem. Asbestos exposure induced mesothelioma does not require an 'occupational' type of exposure. Bystander exposures may result in earlier age of disease onset and more aggressive disease progression as described in the following 3 case reports.

Identification of a mesothelioma phenotype.

Despite the strong association of asbestos exposure to mesothelioma, only a fraction of persons exposed develop this neoplasm which is characterized by long latency and shortened survival. Familial clustering implicates both exposure and genetic predisposition as causative, but a biologically relevant mesothelioma phenotype essential to genetic analysis has not been defined. To identify a more extensive set of traits that would define a mesothelioma phenotype for the purpose of genetic analysis, we set to determine characteristics that distinguish mesothelioma patients from others exposed to asbestos and to identify factors that predict the presence of mesothelioma over other mesenchymal tumors of the peritoneum and carcinoma metastatic to the pleura. We compared demographics in four asbestos-exposed groups (controls n=347, bronchogenic cancer n=67, mesothelioma n=179 and benign asbestos-induced lung disease (BALD) n=3757). Within the mesothelioma group, we compared traits to identify characteristics associated with shortened survival. We found that compared to other asbestos-exposed groups, subjects with mesothelioma were younger at first asbestos exposure, had a greater risk of a second cancer diagnosis (odds ratio=3.29), had a longer disease latency, and had a greater risk of cancer among first-degree relatives (point estimate for risk 2.93; 95% CI 2.5-3.5). Thoracic tumor location, work exposure and male gender were consistently associated with shortened survival (1.9+/-1.3 years). We conclude that thoracic tumor location, work exposure, male gender, long latency, early age at first exposure, presence of a second cancer, and first-degree relative with cancer define a phenotype that sets mesothelioma patients with a short survival apart from other asbestos-exposed individuals. We propose that this phenotype be applied to candidate gene analysis.

Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma.

BACKGROUND: Sex hormones may contribute to the higher prevalence and severity of adult asthma in women compared with men. OBJECTIVE: Sequence variants in the estrogen receptor alpha gene (ESR1) may alter estrogen action in asthma. METHODS: Two hundred asthma probands and their families (n=1249) were genotyped for 5 single nucleotide polymorphisms (SNPs) in the ESR1 gene (intervening sequence 1 [IVS1]-1505A/G, IVS1-1415T/C, IVS1-397C/T, IVS1-351G/A and exon1+30T/C). Association with asthma and bronchial hyperresponsiveness (BHR) were tested. In the asthma probands, association of SNPs with BHR severity and annual FEV1 decline were determined. RESULTS: No SNP was associated with asthma. IVS1-397 was significantly associated with the presence of BHR (P=.02) and interacted with sex; female subjects with the CT or TT genotype were at risk (P=.01). In asthma probands, all SNPs were associated with FEV1 decline. Exon1+30 CT and TT group had an excess decline of 11.6 mL/y (P=.03) and 15.7 mL/y (P=.01), respectively, compared with the CC group. Of the IVS1 polymorphisms, IVS1-351G/A showed the strongest association, with the AA group having excess decline of 16.1 mL/y (P=.01) compared with the GG group. In subanalyses by sex, these associations were significant only in female subjects. CONCLUSION: ESR1 gene variants may affect development of BHR, particularly in female subjects. They may also lead to a more rapid lung function loss in patients with asthma, and in female subjects specifically. This may result from altered estrogen action, which affects lung development and/or airway remodeling. Further studies on ESR1 gene variations are important to understand better the origin of sex differences in asthma. CLINICAL IMPLICATIONS: Variations in the gene encoding estrogen receptor alpha are associated with BHR and a more rapid annual lung function decline, especially in female subjects. Even though this has no diagnostic or clinical implication, it may open avenues for future sex-specific treatment in asthma.

Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure.

BACKGROUND: Asthma is a common respiratory disease caused by the interaction of genetic susceptibility and exposure to various environmental factors. Passive smoke exposure, characterized by parental smoking, has been shown to be a risk factor for the development of atopy and asthma. OBJECTIVE: We sought to perform a genome-wide linkage screen for asthma and bronchial hyperresponsiveness (BHR) and to determine the influence of passive tobacco smoke exposure during childhood on the results of genetic linkage studies to investigate gene-environment interactions. METHODS: A genome-wide linkage screen for asthma and BHR was performed in 200 families ascertained through a parent with asthma. Analyses were performed separately for the entire sample and for the smoking-exposed and nonexposed families. RESULTS: For asthma and BHR, the strongest evidence for linkage was observed for chromosomes 3p and 5q. The families in which the children were exposed to passive smoking accounted for the evidence for linkage of BHR to 5q ( P < .001), but evidence for linkage to 3p was found in both sets of families. Similar results were observed for asthma. However, there was no observed difference in the frequency of asthma or BHR in the offspring from the smoke-exposed compared with the nonexposed families. CONCLUSION: The results from this study demonstrate that the influence of susceptibility genes for a common disease such as asthma might not be apparent unless there is the appropriate exposure to environmental stimuli, such as passive exposure to cigarette smoke. This approach should be useful for identification of asthma susceptibility genes.