| 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. |
- 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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| 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. |
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| 5. |
- Cerveri, Isa, et al.
(författare)
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Underestimation of airflow obstruction among young adults using FEV1/FVC<70% as a fixed cut-off : a longitudinal evaluation of clinical and functional outcomes
- 2008
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Ingår i: Thorax. - : BMJ. - 0040-6376 .- 1468-3296. ; 63:12, s. 1040-1045
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Tidskriftsartikel (refereegranskat)abstract
- Background: Early detection of airflow obstruction is particularly important among young adults because they are more likely to benefit from intervention. Using the forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) (FEV1/FVC) <70% fixed ratio, airflow obstruction may be underdiagnosed. The lower limit of normal (LLN), which is statistically defined by the lower fifth percentile of a reference population, is physiologically appropriate but it still needs a clinical validation.Methods: To evaluate the characteristics and longitudinal outcomes of subjects misidentified as normal by the fixed ratio with respect to the LLN, 6249 participants (aged 20-44 years) in the European Community Respiratory Health Survey were examined and divided into three groups (absence of airflow obstruction by the LLN and the fixed ratio; presence of airflow obstruction only by the LLN; presence of airflow obstruction by the two criteria) for 1991-1993. LLN equations were obtained from normal non-smoking participants. A set of clinical and functional outcomes was evaluated in 1999-2002.Results: The misidentified subjects were 318 (5.1%); only 45.6% of the subjects with airflow obstruction by the LLN were also identified by the fixed cut-off. At baseline, FEV1 (107%, 97%, 85%) progressively decreased and bronchial hyperresponsiveness (slope 7.84, 6.32, 5.57) progressively increased across the three groups. During follow-up, misidentified subjects had a significantly higher risk of developing chronic obstructive pulmonary disease and a significantly higher use of health resources (medicines, emergency department visits/hospital admissions) because of breathing problems than subjects without airflow obstruction (p<0.001).Conclusions: Our findings show the importance of using statistically derived spirometric criteria to identify airflow obstruction.
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| 6. |
- Chinn, Susan, et al.
(författare)
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Bronchial responsiveness in atopic adults increases with exposure to cat allergen
- 2007
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 176:1, s. 20-26
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: The association of asthma with sensitization and allergen exposure is known to be complex. There have been few studies of bronchial responsiveness in relation to both risk factors in adults. Objectives: To determine the relation of bronchial responsiveness to allergen exposure and IgE sensitization in a community study taking into account the major determinants of bronchial responsiveness in adulthood. Methods: Cross-sectional data were drawn from 1,884 participants in 20 centers in the European Community Respiratory Health Survey follow-up, which included measurement of house dust mite and cat allergen in mattress dust samples, and IgE sensitization to four allergens. Bronchial responsiveness to methacholine was expressed as a continuous variable, and analyzed by multiple regression. Measurements and Main Results: The trend toward greater bronchial responsiveness with increasing exposure to cat allergen was greater in those sensitized to any of the four allergens than those not sensitized (p = 0.001); there was no significant interaction between cat sensitization and Fel d 1 exposure. No trend was found with house dust mite allergen exposure. The difference in bronchial responsiveness between those exposed to the highest levels compared with the lowest was approximately –2.02 doubling doses of PD20 (95% confidence interval, –3.06 to –0.97), and nearly as great in those exposed to more moderate levels. Conclusions: Cat allergen exposure at moderate levels may be harmful to all atopic adults. The clinical implication is that it is insufficient to test patients with asthma for cat sensitization; all atopic individuals may benefit from reduced cat exposure.
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| 7. |
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| 8. |
- de Marco, Roberto, et al.
(författare)
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Asthma, COPD and overlap syndrome : a longitudinal study in young European adults
- 2015
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 46:3, s. 671-679
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Tidskriftsartikel (refereegranskat)abstract
- We compared risk factors and clinical characteristics, 9-year lung function change and hospitalisation risk across subjects with the asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), asthma or COPD alone, or none of these diseases. Participants in the European Community Respiratory Health Survey in 1991-1993 (aged 20-44 years) and 1999-2001 were included. Chronic airflow obstruction was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity
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| 9. |
- de Marco, Roberto, et al.
(författare)
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Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm
- 2007
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 175:1, s. 32-39
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: The few prospective studies aimed at assessing the incidence of chronic obstructive pulmonary disease (COPD) in relation to the presence of chronic cough/phlegm have produced contrasting results. Objectives: To assess the incidence of COPD in a cohort of young adults and to test whether chronic cough/phlegm and dyspnea are independent predictors of COPD. Methods: An international cohort of 5,002 subjects without asthma (ages 20-44 yr) with normal lung function (FEV1/FVC ratio ≥ 70%) from 12 countries was followed from 1991-2002 in the frame of the European Community Respiratory Health Survey II. Incident cases of COPD were those who had an FEV 1/FVC ratio less than 70% at the end of the follow-up, but did not report having had a doctor diagnose asthma during the follow-up. Main Results: The incidence rate of COPD was 2.8 cases/1,000/yr (95% confidence interval [CI], 2.3-3.3). Chronic cough/phlegm was an independent and statistically significant predictor of COPD (incidence rate ratio [IRR], 1.85; 95% CI, 1.17-2.93) after adjusting for smoking habits and other potential confounders, whereas dyspnea was not associated with the disease (IRR = 0.98; 95% CI, 0.64-1.50). Subjects who reported chronic cough/phlegm both at baseline and at the follow-up had a nearly threefold-increased risk of developing COPD with respect to asymptomatic subjects (IRR = 2.88; 95% CI, 1.44-5.79). Conclusions: The incidence of COPD is substantial even in young adults. The presence of chronic cough/phlegm identifies a subgroup of subjects with a high risk of developing COPD, independently of smoking habits.
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| 10. |
- de Marco, Roberto, et al.
(författare)
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Long-term outcomes in mild/moderate chronic obstructive pulmonary disease in the European community respiratory health survey
- 2009
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 180:10, s. 956-963
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Little is known about the long-term outcomes of individuals with mild/moderate chronic obstructive pulmonary disease (COPD) according to spirometric criteria. OBJECTIVES: To test whether nonsmokers and asymptomatic subjects with a spirometric diagnosis of COPD have a steeper decrease in lung function and higher hospitalization rates than subjects without airway obstruction. METHODS: A total of 5,205 subjects without asthma (20-44 years of age) from the general population, with FEV(1) >or= 50% predicted at baseline, were followed for 9 years in the frame of an international cohort study. Percent decrease in FEV(1) (DeltaFEV(1)%) and the annual hospitalization rate for respiratory causes during the follow-up were assessed for each subject. MEASUREMENTS AND MAIN RESULTS: At baseline, 324 (6.2%) subjects had the prebronchodilator FEV(1)/FVC ratio less than the lower limit of normal (LLN-COPD), and 105 (2.0%) subjects had the same ratio less than 0.70 (modified GOLD-COPD). At follow-up, smokers with LLN-COPD (n = 205) had a greater mean DeltaFEV(1)% (1.7%; 95% confidence interval [CI], 0.8-2.7) and a higher hospitalization rate (rate ratio [RR], 2.52; 95% CI, 1.65-3.86) than normal subjects. Similarly, symptomatic subjects with LLN-COPD (n = 104) had DeltaFEV(1)% (2.0%; 95% CI, 0.8-3.3) and the hospitalization rate (RR, 4.18; 95% CI, 2.43-7.21) higher than the reference group. By contrast, nonsmokers and asymptomatic subjects with LLN-COPD had outcomes that were similar or even better than normal subjects. Among subjects with LLN-COPD, the association of symptoms with DeltaFEV(1)% varied according to smoking habits (P = 0.007); it was particularly strong in symptomatic smokers and disappeared in symptomatic nonsmokers. Similar results were found with the modified GOLD classification. CONCLUSIONS: In relatively young populations, COPD is associated with poor long-term outcomes in smokers and in symptomatic subjects only.
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