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1.
Int J Epidemiol ; 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33899104

RESUMO

BACKGROUND: With genome-wide association data for many exposures and outcomes now available from large biobanks, one-sample Mendelian randomization (MR) is increasingly used to investigate causal relationships. Many robust MR methods are available to address pleiotropy, but these assume independence between the gene-exposure and gene-outcome association estimates. Unlike in two-sample MR, in one-sample MR the two estimates are obtained from the same individuals, and the assumption of independence does not hold in the presence of confounding. METHODS: With simulations mimicking a typical study in UK Biobank, we assessed the performance, in terms of bias and precision of the MR estimate, of the fixed-effect and (multiplicative) random-effects meta-analysis method, weighted median estimator, weighted mode estimator and MR-Egger regression, used in both one-sample and two-sample data. We considered scenarios differing by the: presence/absence of a true causal effect; amount of confounding; and presence and type of pleiotropy (none, balanced or directional). RESULTS: Even in the presence of substantial correlation due to confounding, all two-sample methods used in one-sample MR performed similarly to when used in two-sample MR, except for MR-Egger which resulted in bias reflecting direction and magnitude of the confounding. Such bias was much reduced in the presence of very high variability in instrument strength across variants (IGX2 of 97%). CONCLUSIONS: Two-sample MR methods can be safely used for one-sample MR performed within large biobanks, expect for MR-Egger. MR-Egger is not recommended for one-sample MR unless the correlation between the gene-exposure and gene-outcome estimates due to confounding can be kept low, or the variability in instrument strength is very high.

2.
Clin Transl Allergy ; 10(1): 60, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33303027

RESUMO

BACKGROUND: Asthma is a chronic respiratory disease which is not curable, yet some patients experience spontaneous remission. We hypothesized that epigenetic mechanisms may be involved in asthma remission. METHODS: Clinical remission (ClinR) was defined as the absence of asthma symptoms and medication for at least 12 months, and complete remission (ComR) was defined as ClinR with normal lung function and absence of airway hyperresponsiveness. We analyzed differential DNA methylation of ClinR and ComR comparing to persistent asthma (PersA) in whole blood samples (n = 72) and nasal brushing samples (n = 97) in a longitudinal cohort of well characterized asthma patients. Significant findings of whole blood DNA methylation were tested for replication in two independent cohorts, Lifelines and Epidemiological study on the Genetics and Environment of Asthma (EGEA). RESULTS: We identified differentially methylated CpG sites associated with ClinR (7 CpG sites) and ComR (129 CpG sites) in whole blood. One CpG (cg13378519, Chr1) associated with ClinR was replicated and annotated to PEX11 (Peroxisomal Biogenesis Factor 11 Beta). The whole blood DNA methylation levels of this CpG were also different between ClinR and healthy subjects. One ComR-associated CpG (cg24788483, Chr10) that annotated to TCF7L2 (Transcription Factor 7 Like 2) was replicated and associated with expression of TCF7L2 gene. One out of seven ClinR-associated CpG sites and 8 out of 129 ComR-associated CpG sites identified from whole blood samples showed nominal significance (P < 0.05) and the same direction of effect in nasal brushes. CONCLUSION: We identified DNA methylation markers possibly associated with clinical and complete asthma remission in nasal brushes and whole blood, and two CpG sites identified from whole blood can be replicated in independent cohorts and may play a role in peroxisome proliferation and Wnt signaling pathway.

3.
ERJ Open Res ; 6(3)2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33015143

RESUMO

Higher levels of testosterone have been associated with better lung function in cross-sectional population-based studies. The role of testosterone in lung function in women and in lung function decline in men or women is unclear. We studied 5114 men and 5467 women in the UK Biobank with high-quality spirometry at baseline (2006-2010) and 8.4 years later. We studied cross-sectional associations of total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI) and sex hormone-binding globulin (SHBG) with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC using linear regression and associations of baseline markers with lung function decline using linear mixed-effects regression. Men with higher levels of TT had higher FEV1 (27.56 mL per interquartile range increase TT, 95% CI 5.43-49.68) and FVC (48.06 mL, 95% CI 22.07-74.06) at baseline. Higher cFT levels were associated with higher FEV1 and FVC among physically active men only. In women, higher FAI and cFT levels were associated with lower lung function at baseline and higher levels of TT, cFT and FAI were associated with slightly attenuated FEV1 and FVC decline. Higher levels of SHBG were associated with better lung function in both sexes but slightly accelerated decline in men. In this population-based sample, higher levels of TT were associated with better lung function in men and higher levels of cFT with better lung function in physically active men. A small attenuation of lung function decline with higher levels of TT, cFT and FAI was seen in women only.

4.
BMC Pulm Med ; 20(1): 193, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32677943

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. METHODS: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. RESULTS: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20). CONCLUSIONS: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.

5.
EClinicalMedicine ; 23: 100389, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32529179

RESUMO

Background: Emerging evidence suggests that androgens and estrogens have a role in respiratory health, but it is largely unknown whether levels of these hormones can affect lung function in adults from the general population. This study investigated whether serum dehydroepiandrosterone sulfate (DHEA-S), a key precursor of both androgens and estrogens in peripheral tissues, was related to lung function in adult women participating in the European Community Respiratory Health Survey (ECRHS). Methods: Lung function and serum DHEA-S concentrations were measured in n = 2,045 and n = 1,725 women in 1999-2002 and in 2010-2013, respectively. Cross-sectional associations of DHEA-S levels (expressed as age-adjusted z-score) with spirometric outcomes were investigated, adjusting for smoking habits, body mass index, menopausal status, and use of corticosteroids. Longitudinal associations of DHEA-S levels in 1999-2002 with incidence of restrictive pattern and airflow limitation in 2010-2013 were also assessed. Findings: Women with low DHEA-S (z-score<-1) had lower FEV1 (% of predicted, adjusted difference: -2.2; 95%CI: -3.5 to -0.9) and FVC (-1.7; 95%CI: -2.9 to -0.5) and were at a greater risk of having airflow limitation and restrictive pattern on spirometry than women with higher DHEA-S levels. In longitudinal analyses, low DHEA-S at baseline was associated with a greater incidence of airflow limitation after an 11-years follow-up (incidence rate ratio, 3.43; 95%CI: 1.91 to 6.14). Interpretation: Low DHEA-S levels in women were associated with impaired lung function and a greater risk of developing airflow limitation later in adult life. Our findings provide new evidence supporting a role of DHEA-S in respiratory health. Funding: EU H2020, grant agreement no.633212.

6.
Sci Justice ; 60(3): 243-252, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32381241

RESUMO

Typing short tandem repeats (STRs) is the basis for human identification in current forensic testing. The standard method uses capillary electrophoresis (CE) to separate amplicons by length and fluorescent labeling. In recent years new methods, including massively parallel sequencing (MPS), have been developed which increased the discriminative power of STRs through sequencing. MPS also offers the opportunity to test more genetic markers in a run than is possible with standard CE technology. Verogen's ForenSeq™ DNA Signature Prep kit includes over 150 genetic markers [STRs and single nucleotide polymorphisms (SNPs)]. Further, MPS separation depends on sequences rather than lengths; therefore, amplicons can be small or even of the same lengths. These improvements are advantageous when testing challenging forensic samples that could be severely degraded. This study tested the ForenSeq™ DNA Signature Prep kit in repeated experimental runs on series of degraded DNA samples, ranging from mild to severe degradation, as well as 24 mock case-type samples, derived from bones, blood cards, and teeth. Despite passing the quality metrics, positive controls (2800 M) showed drop-outs at some loci, mostly SNPs. Sequencing DNA samples repeatedly in two experimental runs as well as sequencing one pooled library in triplicate led to the assumption that spurious alleles of the Y-STRs in this study were not a result of sequencing artifacts but could be due to sequence structures (e.g. duplications, palindromes) of the Y-chromosome and/or might be accumulated during library preparation. Two sets of serially degraded DNA samples revealed that dropped-out loci were primarily loci with long amplicons as well as low read numbers (coverage), e.g. PentaE, DXS8378, and rs1736442. STRs started to drop out at degradation indices (DIs) > 4. However, severely degraded DNA (DI: 44) still resulted in 90% of the 20 CODIS loci, while only 35% were obtained using Promega's PowerPlex® Fusion kit, a current standard CE kit. Mock case-type samples confirmed these results. ForenSeq™ DNA Signature Prep kit demonstrated that it can be successfully used on degraded DNA samples. This study may be helpful for other laboratories assessing and validating MPS technologies.

9.
Free Radic Biol Med ; 151: 88-98, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007521

RESUMO

Oxidative stress occurs when antioxidant defences, which are regulated by a complex network of genes, are insufficient to maintain the level of reactive oxygen species below a toxic threshold. Outdoor air pollution has long been known to adversely affect health and one prominent mechanism of action common to all pollutants is the induction of oxidative stress. An individual's susceptibility to the effects of air pollution partly depends on variation in their antioxidant genes. Thus, understanding antioxidant gene-pollution interactions has significant potential clinical and public health impacts, including the development of targeted and cost-effective preventive measures, such as setting appropriate standards which protect all members of the population. In this review, we aimed to summarize the latest epidemiological evidence on interactions between antioxidant genes and outdoor air pollution, in the context of respiratory and cardiovascular health. The evidence supporting the existence of interactions between antioxidant genes and outdoor air pollution is strongest for childhood asthma and wheeze, especially for interactions with GSTT1, GSTM1 and GSTP1, for lung function in both children and adults for several antioxidant genes (GSTT1, GSTM1, GSTP1, HMOX1, NQO1, and SOD2) and, to a more limited extent, for heart rate variability in adults for GSTM1 and HMOX1. Methodological challenges hampering a clear interpretation of these findings and understanding of true potential heterogeneity are discussed.

12.
Respir Res ; 20(1): 268, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791327

RESUMO

BACKGROUND: Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers. METHODS: We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results to identify differentially methylated CpG-sites with FEV1/FVC. Expression Quantitative Trait Methylation (eQTM) analysis was performed in the Biobank-based Integrative Omics Studies (BIOS). RESULTS: A total of 36 CpG-sites were associated with FEV1/FVC in never smokers at p-value< 0.0001, but the meta-analysis did not reveal any epigenome-wide significant CpG-sites. Of interest, 35 of these 36 CpG-sites have not been associated with lung function before in studies including subjects irrespective of smoking history. Among the top hits were cg10012512, cg02885771, annotated to the gene LTV1 Ribosome Biogenesis factor (LTV1), and cg25105536, annotated to Kelch Like Family Member 32 (KLHL32). Moreover, a total of 11 eQTMS were identified. CONCLUSIONS: With the identification of 35 CpG-sites that are unique for never smokers, our study shows that DNA methylation is also associated with FEV1/FVC in subjects that never smoked and therefore not merely related to smoking.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Estudo de Associação Genômica Ampla/métodos , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Estudos de Coortes , Ilhas de CpG/genética , Feminino , Volume Expiratório Forçado/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Valores de Referência , Fumantes , Fumar/genética
13.
Eur Respir J ; 54(4)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31439684

RESUMO

In observational studies, early menopause is associated with lower forced vital capacity (FVC) and a higher risk of spirometric restriction, but not airflow obstruction. It is, however, unclear if this association is causal. We therefore used a Mendelian randomisation (MR) approach, which is not affected by classical confounding, to assess the effect of age at natural menopause on lung function.We included 94 742 naturally post-menopausal women from the UK Biobank and performed MR analyses on the effect of age at menopause on forced expiratory volume in 1 s (FEV1), FVC, FEV1/FVC, spirometric restriction (FVC

Assuntos
Pulmão/fisiopatologia , Menopausa Precoce/genética , Idoso , Feminino , Volume Expiratório Forçado , Humanos , Análise da Randomização Mendeliana , Menopausa/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Proteção , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Capacidade Vital
14.
Hum Mol Genet ; 28(15): 2477-2485, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152171

RESUMO

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted.

15.
Eur Respir J ; 54(1)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31073081

RESUMO

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute ß-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.


Assuntos
Metilação de DNA , Epigênese Genética , Estudo de Associação Genômica Ampla , Fumar/genética , Adulto , Idoso , Ilhas de CpG , Feminino , Volume Expiratório Forçado , Humanos , Modelos Lineares , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Valores de Referência , Fumar/fisiopatologia , Espirometria
16.
Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461

RESUMO

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.


Assuntos
Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
17.
BMC Pulm Med ; 19(1): 58, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845926

RESUMO

BACKGROUND: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking. METHODS: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10- 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087). RESULTS: In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and ever-smokers, respectively. At p < 10- 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effect in the validation cohorts and the NFYC SNP was an eQTL for NFYC-AS1. NFYC is a transcription factor that binds to several known COPD genes, and FABP7 may be involved in abnormal pulmonary development. CONCLUSIONS: The definition of airflow obstruction and the population under study may be important determinants of which SNPs are associated with airflow obstruction. The genes FABP7 and NFYC(-AS1) could play a role in airflow obstruction in never-smokers specifically.


Assuntos
Fator de Ligação a CCAAT/genética , Proteína 7 de Ligação a Ácidos Graxos/genética , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Volume Expiratório Forçado , Homologia de Genes/genética , Predisposição Genética para Doença , Humanos , Modelos Lineares , Modelos Logísticos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Fumar/efeitos adversos , Espirometria , Capacidade Vital , Adulto Jovem
18.
Environ Int ; 122: 263-269, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30449631

RESUMO

Respiratory symptoms are important indicators of respiratory diseases. Both genetic and environmental factors contribute to respiratory symptoms development but less is known about gene-environment interactions. We aimed to assess interactions between single nucleotide polymorphisms (SNPs) and occupational exposures on respiratory symptoms cough, dyspnea and phlegm. As identification cohort LifeLines I (n = 7976 subjects) was used. Job-specific exposure was estimated using the ALOHA + job exposure matrix. SNP-by-occupational exposure interactions on respiratory symptoms were tested using logistic regression adjusted for gender, age, and current smoking. SNP-by-exposure interactions with a p-value <10-4 were tested for replication in two independent cohorts: LifeLines II (n = 5260) and the Vlagtwedde-Vlaardingen cohort (n = 1529). The interaction estimates of the replication cohorts were meta-analyzed using PLINK. Replication was achieved when the meta-analysis p-value was <0.05 and the interaction effect had the same direction as in the identification cohort. Additionally, we assessed whether replicated SNPs associated with gene expression by analyzing if they were cis-acting expression quantitative trait loci (eQTL) in lung tissue. In the replication meta-analysis, sixteen out of 477 identified SNP-by-occupational exposure interactions had a p-value <0.05 and 9 of these interactions had the same direction as in the identification cohort. Several identified loci were plausible candidates for respiratory symptoms, such as TMPRSS9, SERPINH1, TOX3, and ARHGAP18. Three replicated SNPs were cis-eQTLs for FCER1A, CHN1, and TIMM13 in lung tissue. Taken together, this genome-wide SNP-by-occupational exposure interaction study in relation to cough, dyspnea, and phlegm identified several suggestive susceptibility genes. Further research should determine if these genes are true susceptibility loci for respiratory symptoms in relation to occupational exposures.


Assuntos
Estudo de Associação Genômica Ampla , Exposição Ocupacional , Doenças Respiratórias , Estudos de Coortes , Humanos , Exposição Ocupacional/análise , Exposição Ocupacional/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Doenças Respiratórias/epidemiologia , Doenças Respiratórias/genética
19.
Respir Res ; 19(1): 212, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390659

RESUMO

BACKGROUND: Genetic and environmental factors play a role in the development of COPD. The epigenome, and more specifically DNA methylation, is recognized as important link between these factors. We postulate that DNA methylation is one of the routes by which cigarette smoke influences the development of COPD. In this study, we aim to identify CpG-sites that are associated with cigarette smoke exposure and lung function levels in whole blood and validate these CpG-sites in lung tissue. METHODS: The association between pack years and DNA methylation was studied genome-wide in 658 current smokers with >5 pack years using robust linear regression analysis. Using mediation analysis, we subsequently selected the CpG-sites that were also associated with lung function levels. Significant CpG-sites were validated in lung tissue with pyrosequencing and expression quantitative trait methylation (eQTM) analysis was performed to investigate the association between DNA methylation and gene expression. RESULTS: 15 CpG-sites were significantly associated with pack years and 10 of these were additionally associated with lung function levels. We validated 5 CpG-sites in lung tissue and found several associations between DNA methylation and gene expression. CONCLUSION: This study is the first to validate a panel of CpG-sites that are associated with cigarette smoking and lung function levels in whole blood in the tissue of interest: lung tissue.


Assuntos
Fumar Cigarros/sangue , Fumar Cigarros/genética , Metilação de DNA/fisiologia , Estudo de Associação Genômica Ampla/métodos , Pulmão/fisiologia , Fumantes , Adulto , Idoso , Fumar Cigarros/efeitos adversos , Ilhas de CpG/fisiologia , Feminino , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
PLoS Med ; 15(8): e1002634, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30086135

RESUMO

BACKGROUND: Observational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males. METHODS AND FINDINGS: MR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12-14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10(-5)) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10(-4)), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking. CONCLUSIONS: This large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.


Assuntos
Asma/epidemiologia , Puberdade , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Menarca , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Razão de Chances , Obesidade Pediátrica/epidemiologia , Autorrelato , Reino Unido/epidemiologia
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