| 1. |
- Artigas Soler, María, et al.
(författare)
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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| 2. |
- de Marco, Roberto, et al.
(författare)
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Risk Factors for Chronic Obstructive Pulmonary Disease in a European Cohort of Young Adults
- 2011
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 183:7, s. 891-897
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Few studies have investigated the factors associated with the early inception of chronic obstructive pulmonary disease (COPD). Objectives: We investigated COPD risk factors in an international cohort of young adults using different spirometric definitions of the disease. Methods. We studied 4,636 subjects without asthma who had prebronchodilator FEV1/FVC measured in the European Community Respiratory Health Survey both in 1991 to 1993 (when they were 20-44 yr old) and in 1999 to 2002. COPD was defined according to the Global Initiative for Chronic Obstructive Lung Disease fixed cut-off criterion (FEV1/FVC < 0.70), and two criteria based on the Quanjer and LuftiBus reference equations (FEV1/FVC less than lower limit of normal). COPD determinants were studied using two-level Poisson regression models. Measurements and Main Results: COPD incidence ranged from 1.85 (lower limit of normal [Quanjer]) to 2.88 (Global Initiative for Chronic Obstructive Lung Disease) cases/1,000/yr. Although about half of the cases had smoked less than 20 pack-years, smoking was the main risk factor for COPD, and it accounted for 29 to 39% of the new cases during the follow-up. Airway hyperresponsiveness was the second strongest risk factor (15-17% of new cases). Other determinants were respiratory infections in childhood and a family history of asthma, whereas the role of sex, age, and of being underweight largely depended on the definition of COPD used. Conclusions: COPD may start early in life. Smoking prevention should be given the highest priority to reduce COPD occurrence. Airway hyperresponsiveness, a family history of asthma, and respiratory infections in childhood are other important determinants of COPD. We suggest the need for a definition of COPD that is not exclusively based on spirometry.
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| 3. |
- Hancock, Dana B, et al.
(författare)
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Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
- 2012
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:12, s. e1003098-
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Krauss-Etschmann, Susanne, et al.
(författare)
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Of flies, mice and men : a systematic approach to understanding the early life origins of chronic lung disease
- 2013
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 68:4, s. 380-384
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Forskningsöversikt (refereegranskat)abstract
- Despite intensive research efforts, the aetiology of the majority of chronic lung diseases (CLD) in both, children and adults, remains elusive. Current therapeutic options are limited, providing only symptomatic relief, rather than treating the underlying condition, or preventing its development in the first place. Thus, there is a strong and unmet clinical need for the development of both, novel effective therapies and preventative strategies for CLD. Many studies suggest that modifications of prenatal and/or early postnatal lung development will have important implications for future lung function and risk of CLD throughout life. This view represents a fundamental change of current pathophysiological concepts and treatment paradigms, and holds the potential to develop novel preventative and/or therapeutic strategies. However, for the successful development of such approaches, key questions, such as a clear understanding of underlying mechanisms of impaired lung development, the identification and validation of relevant preclinical models to facilitate translational research, and the development of concepts for correction of aberrant development, all need to be solved. Accordingly, a European Science Foundation Exploratory Workshop was held where clinical, translational and basic research scientists from different disciplines met to discuss potential mechanisms of developmental origins of CLD, and to identify major knowledge gaps in order to delineate a roadmap for future integrative research.
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| 5. |
- Leynaert, Benedicte, et al.
(författare)
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Gender differences in prevalence, diagnosis and incidence of allergic and non-allergic asthma : a population-based cohort
- 2012
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 67:7, s. 625-631
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Tidskriftsartikel (refereegranskat)abstract
- Background Although women with severe non-allergic asthma may represent a substantial proportion of adults with asthma in clinical practice, gender differences in the incidence of allergic and non-allergic asthma have been little investigated in the general population. Methods Gender differences in asthma prevalence, reported diagnosis and incidence were investigated in 9091 men and women randomly selected from the general population and followed up after 8-10 years as part of the European Community Respiratory Health Survey. The protocol included assessment of bronchial responsiveness, IgE specific to four common allergens and skin tests to nine allergens. Results Asthma was 20% more frequent in women than in men over the age of 35 years. Possible under-diagnosis of asthma appeared to be particularly frequent among non-atopic individuals, but was as frequent in women as in men. The follow-up of subjects without asthma at baseline showed a higher incidence of asthma in women than in men (HR 1.94; 95% CI 1.40 to 2.68), which was not explained by differences in smoking, obesity or lung function. More than 60% of women and 30% of men with new-onset asthma were non-atopic. The incidence of non-allergic asthma was higher in women than in men throughout all the reproductive years (HR 3.51; 95% CI 2.21 to 5.58), whereas no gender difference was observed for the incidence of allergic asthma. Conclusions This study shows that female sex is an independent risk factor for non-allergic asthma, and stresses the need for more careful assessment of possible non-allergic asthma in clinical practice, in men and women.
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| 6. |
- Loth, Daan W, et al.
(författare)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Tidskriftsartikel (refereegranskat)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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| 7. |
- Macsali, Ferenc, et al.
(författare)
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Early Age at Menarche, Lung Function, and Adult Asthma
- 2011
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 183:1, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Hormonal and metabolic status appears to influence lung health in women, and there are findings suggesting that early menarche may be related to asthma, cardiovascular disease, diabetes, and breast cancer. Objectives: This study investigates whether age at menarche is related to adult lung function and asthma. Methods: Among participants in the European Community Respiratory Health Survey II, 3,354 women aged 27-57 years from random population samples in 21 centers responded to a questionnaire concerning women's health (1998-2002). Of these women, 2,873 had lung function measurements, 2,136 had measurements of bronchial hyperreactivity, and 2,743 had IgE measurements. Logistic, linear, and negative binomial regression analyses included adjustment for age, height, body mass index, education, smoking, family size, and center. Measurements and Main Results: FEV1 and FVC were lower and asthma was more common in women with early menarche. Women reporting menarche at age 10 years or less, as compared with women with menarche at age 13 years (reference category), had lower FEV1 (adjusted difference, -113 ml; 95% confidence interval [CI], -196 to -33 ml) and FVC (-126 ml; 95% CI, -223 to -28 ml); also lower FEV1 expressed as a percentage of the predicted value (-3.28%; 95% CI, -6.25 to -0.30%) and FVC expressed as a percentage of the predicted value (-3.63%; 95% CI, -6.64 to -0.62%). Women with early menarche more often had asthma symptoms (odds ratio, 1.80; 95% CI, 1.09-2.97), asthma with bronchial hyperreactivity (odds ratio, 2.79; 95% CI, 1.06-7.34), and higher asthma symptom score (mean ratio, 1.58; 95% CI, 1.12-2.21). Conclusions: Women with early menarche had lower lung function and more asthma in adulthood. This supports a role for metabolic and hormonal factors in women's respiratory health.
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| 8. |
- Matheson, Melanie Claire, et al.
(författare)
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Early-life risk factors and incidence of rhinitis : Results from the European Community Respiratory Health Study - an international population-based cohort study
- 2011
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 128:4, s. 816-823.e5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rhinitis is an increasingly common condition with a heavy health care burden, but relatively little is known about its risk factors. Objective: To examine the association between early-life factors and the development of rhinitis in the European Community Respiratory Health Study (ECRHS). Methods: In 1992-1994, community-based samples of 20-44-year-old people were recruited from 48 centers in 22 countries. On average, 8.9 years later, 28 centers reinvestigated their samples. Onset of rhinitis was reported by 8486 participants in interviewer-led questionnaires. Cox regression was used to assess independent predictors of rhinitis at ages <= 5, 6-10, 11-20, and >= 21 years. Results: The crude lifelong incidence of rhinitis was 7.00/1000/year (men) and 7.95/1000/year (women) (P = .002). Women developed less rhinitis in later childhood (hazard ratios [HR], 0.63; 95% CI, 0.47-0.85) and more rhinitis in adulthood (HR, 1.36; 95% CI, 1.11-1.66) than did men. In atopic subjects, siblings were associated with lower risk of rhinitis throughout life (pooled HR, 0.94; 95% CI, 0.91-0.98 per 1 sibling). Early contact with children in the family or day care was associated with less incidence of rhinitis, predominantly before age 5 years (HR, 0.84; 95% CI, 0.72-0.99). Early childhood pets or growing up on a farm was associated with less incidence of rhinitis in adolescence (HR, 0.50; 95% CI, 0.37-0.68). Combining these factors showed evidence of a dose-response relationship (trend P = .0001). Conclusions: Gender is a strong risk factor for rhinitis, with age patterns varying according to atopic status. Protective effects of early contact with children and animals were suggested for incident rhinitis, with risk patterns varying by age window and atopic status.
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| 9. |
- Ramasamy, Adaikalavan, et al.
(författare)
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Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:9, s. e44008-
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P < 5x10(-8)) and three variants reported as suggestive (P < 5 x 10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4x10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
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| 10. |
- Ziegler-Heitbrock, Loems, et al.
(författare)
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The EvA study : aims and strategy
- 2012
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 40:4, s. 823-829
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Tidskriftsartikel (refereegranskat)abstract
- The EvA study is a European Union-funded project under the Seventh Framework Programme (FP7), which aims at defining new markers for chronic obstructive pulmonary disease (COPD) and its subtypes. The acronym is derived from emphysema versus airway disease, indicating that the project targets these two main phenotypes of the disease. The EvA study is based on the concept that emphysema and airway disease are governed by different pathophysiological processes, are driven by different genes and have differential gene expression in the lung. To define these genes, patients and non-COPD controls are recruited for clinical examination, lung function analysis and computed tomography (CT) of the lung. CT scans are used to define the phenotypes based on lung density and airway wall thickness. This is followed by bronchoscopy in order to obtain samples from the airways and the alveoli. These tissue samples, along with blood samples, are then subjected to genome-wide expression and association analysis and markers linked to the phenotypes are identified. The population of the EvA study is different from other COPD study populations, since patients with current oral glucocorticoids, antibiotics and exacerbations or current smokers are excluded, such that the signals detected in the molecular analysis are due to the distinct inflammatory process of emphysema and airway disease in COPD.
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