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4.
Epigenetics ; 7(7): 720-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22617718

RESUMO

Alpha-1 antitrypsin (AAT) deficiency and tobacco smoking are confirmed risk factors for Chronic Obstructive Pulmonary Disease. We hypothesized that variable DNA methylation would be associated with smoking and inflammation, as reflected by the level of C-Reactive Protein (CRP) in AAT-deficient subjects. Methylation levels of 1,411 autosomal CpG sites from the Illumina GoldenGate Methylation Cancer Panel I were analyzed in 316 subjects. Associations of five smoking behaviors and CRP levels with individual CpG sites and average methylation levels were assessed using non-parametric testing, linear regression and linear mixed effect models, with and without adjustment for age and gender. Univariate linear regression analysis revealed that methylation levels of 16 CpG sites significantly associated with ever-smoking status. A CpG site in the TGFBI gene was the only site associated with ever-smoking after adjustment for age and gender. No highly significant associations existed between age at smoking initiation, pack-years smoked, duration of smoking, and time since quitting smoking as predictors of individual CpG site methylation levels. However, ever-smoking and younger age at smoking initiation associated with lower methylation level averaged across all sites. DNA methylation at CpG sites in the RUNX3, JAK3 and KRT1 genes associated with CRP levels. The most significantly associated CpG sites with gender and age mapped to the CASP6 and FZD9 genes, respectively. In summary, this study identified multiple potential candidate CpG sites associated with ever-smoking and CRP level in AAT-deficient subjects. Phenotypic variability in Mendelian diseases may be due to epigenetic factors.


Assuntos
Proteína C-Reativa/análise , Metilação de DNA , Fumar/efeitos adversos , Deficiência de alfa 1-Antitripsina/genética , Adulto , Caspase 6/genética , Ilhas de CpG , Feminino , Receptores Frizzled/genética , Loci Gênicos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etiologia , Deficiência de alfa 1-Antitripsina/sangue
5.
Respir Res ; 13: 16, 2012 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-22356581

RESUMO

BACKGROUND: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. METHODS: The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. RESULTS: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. CONCLUSIONS: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.


Assuntos
Proteína 2 Reguladora do Ferro/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Receptores Nicotínicos/genética , Deficiência de alfa 1-Antitripsina/genética , Adulto , Cromossomos Humanos Par 15/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Enfisema Pulmonar/genética , Enfisema Pulmonar/fisiopatologia , Testes de Função Respiratória , Índice de Gravidade de Doença , Fatores Sexuais , Deficiência de alfa 1-Antitripsina/fisiopatologia
6.
Chest ; 138(5): 1125-32, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20595457

RESUMO

BACKGROUND: Severe α1-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α1-antitrypsin, but whether they have an increased risk of COPD is uncertain. METHODS: We compared PI MZ and PI MM individuals in two large populations: a case-control study from Norway (n = 1,669) and a multicenter family-based study from Europe and North America (n = 2,707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT scan measurements of emphysema and airway disease. RESULTS: PI MZ was associated with a 3.5% lower FEV1/FVC ratio in the case-control study (P = .035) and 3.9% lower FEV1/vital capacity (VC) ratio in the family study (P = .009). In the case-control study, PI MZ also was associated with 3.7% more emphysema on quantitative analysis of chest CT scans (P = .003). The emphysema result was not replicated in the family study. PI MZ was not associated with airway wall thickness or COPD status in either population. Among subjects with low smoking exposure (< 20 pack-years), PI MZ individuals had more severe emphysema on chest CT scan than PI MM individuals in both studies. CONCLUSIONS: Compared with PI MM individuals, PI MZ heterozygotes had lower FEV1/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to the development of airflow obstruction than PI MM individuals.


Assuntos
Obstrução das Vias Respiratórias/genética , Predisposição Genética para Doença , Doença Pulmonar Obstrutiva Crônica/complicações , Deficiência de alfa 1-Antitripsina/complicações , alfa 1-Antitripsina/genética , Idoso , Obstrução das Vias Respiratórias/enzimologia , Obstrução das Vias Respiratórias/etiologia , Europa (Continente) , Feminino , Volume Expiratório Forçado , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Noruega , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/fisiopatologia
7.
Am J Respir Crit Care Med ; 178(5): 500-5, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18565956

RESUMO

RATIONALE: It is unclear whether airway wall thickening and emphysema make independent contributions to airflow limitation in chronic obstructive pulmonary disease (COPD) and whether these phenotypes cluster within families. OBJECTIVES: To determine whether airway wall thickening and emphysema (1) make independent contributions to the severity of COPD and (2) show independent aggregation in families of individuals with COPD. METHODS: Index cases with COPD and their smoking siblings underwent spirometry and were offered high-resolution computed tomography scans of the thorax to assess the severity of airway wall thickening and emphysema. MEASUREMENTS AND MAIN RESULTS: A total of 3,096 individuals were recruited to the study, of whom 1,159 (519 probands and 640 siblings) had technically adequate high-resolution computed tomography scans without significant non-COPD-related thoracic disease. Airway wall thickness correlated with pack-years smoked (P < or = 0.001) and symptoms of chronic bronchitis (P < 0.001). FEV(1) (expressed as % predicted) was independently associated with airway wall thickness at a lumen perimeter of 10 mm (P = 0.0001) and 20 mm (P = 0.0013) and emphysema at -950 Hounsfield units (P < 0.0001). There was independent familial aggregation of both the emphysema (adjusted odds ratio, 2.1; 95% confidence interval, 1.1-4.0; P < or = 0.02) and airway disease phenotypes (P < 0.0001) of COPD. CONCLUSIONS: Airway wall thickening and emphysema make independent contributions to airflow obstruction in COPD. These phenotypes show independent aggregation within families of individuals with COPD, suggesting that different genetic factors influence these disease processes.


Assuntos
Saúde da Família , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Bronquiectasia/epidemiologia , Bronquiectasia/genética , Bronquiectasia/patologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Enfisema Pulmonar/epidemiologia , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologia , Irmãos , Fumar/efeitos adversos , Tomografia Computadorizada por Raios X
8.
Am J Respir Cell Mol Biol ; 38(1): 114-20, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17690329

RESUMO

Severe alpha(1)-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV(1)) and the ratio of FEV(1)/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV(1)

Assuntos
Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Doença Pulmonar Obstrutiva Crônica/genética , Deficiência de alfa 1-Antitripsina/genética , Adulto , Criança , Estudos de Coortes , Volume Expiratório Forçado/genética , Haplótipos , Homozigoto , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Fumar/genética , Espirometria , Fator de Necrose Tumoral alfa/genética , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/fisiopatologia
9.
Thorax ; 62(9): 806-13, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17389752

RESUMO

BACKGROUND: Severe alpha(1)-antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency. METHODS: The AAT Genetic Modifier Study is a multicentre family-based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33-80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV(1)) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV(1) <50% predicted). RESULTS: In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV(1 )percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV(1) values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non-index cases (p<0.01). Men had lower pre- and post-bronchodilator FEV(1) percentage predicted than women (p<0.0001); the lowest FEV(1) values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non-index groups were examined separately, with men representing the majority of non-index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician's report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non-index men but not women. CONCLUSION: In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.


Assuntos
Doença Pulmonar Obstrutiva Crônica/etiologia , Deficiência de alfa 1-Antitripsina/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/complicações , Bronquite/complicações , Broncodilatadores/farmacologia , Estudos de Coortes , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Análise de Regressão , Fatores Sexuais , Capacidade Vital/fisiologia
10.
J Biol Chem ; 282(19): 14645-54, 2007 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-17384412

RESUMO

Human leukocyte elastase (HLE) and cathepsin G (CG) are expressed at high levels on the surface of activated human neutrophils (PMN) in catalytically active but inhibitor-resistant forms having the potential to contribute to tissue injury. Herein we have investigated the mechanisms by which HLE and CG bind to PMN plasma membranes. (125)I-Labeled HLE and CG bind to PMN at 0 degrees C in a saturable and reversible manner (K(D) = 5.38 and 4.36 x 10(-7) m and 11.5 and 8.1 x 10(6) binding sites/cell, respectively). Incubation of PMN with radiolabeled HLE and CG in the presence of a 200-fold molar excess of unlabeled HLE, CG, myeloperoxidase, lactoferrin, proteinase 3, phenylmethylsulfonyl fluoride (PMSF)-inactivated HLE, or PMSF-inactivated CG inhibited binding of radiolabeled ligands. This indicates that these PMN granule proteins share binding sites on PMN and that functional active sites of HLE and CG are not required for their binding to PMN. The sulfate groups of heparan sulfate- and chondroitin sulfate-containing proteoglycans are the PMN binding sites for HLE and CG since binding of HLE and CG to PMN was inhibited by incubating PMN with 1) trypsin, chondroitinase ABC, and heparitinases, but not other glycanases, and 2) purified chondroitin sulfates, heparan sulfate, and other sulfated molecules, but not with non-sulfated glycans. Thus, heparan sulfate- and chondroitin sulfate-containing proteoglycans are low affinity, high volume PMN surface binding sites for HLE and CG, which are well suited to bind high concentrations of active serine proteinases released from degranulating PMN.


Assuntos
Catepsinas/metabolismo , Membrana Celular/metabolismo , Sulfatos de Condroitina/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Elastase de Leucócito/metabolismo , Neutrófilos/metabolismo , Proteoglicanas/metabolismo , Serina Endopeptidases/metabolismo , Sítios de Ligação , Catepsina G , Células Cultivadas , Sulfatos de Condroitina/química , Proteoglicanas de Heparan Sulfato/química , Humanos , Lactoferrina/metabolismo , Mieloblastina/metabolismo , Proteoglicanas/química , Sulfatos/química
11.
Hum Mol Genet ; 11(6): 623-32, 2002 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-11912177

RESUMO

Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, but linkage analysis of COPD-related phenotypes has not been reported previously. An autosomal 10 cM genome-wide scan of short tandem repeat (STR) polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe alpha1-antitrypsin deficiency. Multipoint non-parametric linkage analysis (using the ALLEGRO program) was performed for qualitative phenotypes including moderate airflow obstruction [forced expiratory volume at one second (FEV(1)) < 60% predicted, FEV(1)/FVC < 90% predicted], mild airflow obstruction (FEV(1) < 80% predicted, FEV(1)/FVC < 90% predicted) and chronic bronchitis. The strongest evidence for linkage in all subjects was observed at chromosomes 12 (LOD = 1.70) and 19 (LOD = 1.54) for moderate airflow obstruction, chromosomes 8 (LOD = 1.36) and 19 (LOD = 1.09) for mild airflow obstruction and chromosomes 19 (LOD = 1.21) and 22 (LOD = 1.37) for chronic bronchitis. Restricting analysis to cigarette smokers only provided increased evidence for linkage of mild airflow obstruction and chronic bronchitis to several genomic regions; for mild airflow obstruction in smokers only, the maximum LOD was 1.64 at chromosome 19, whereas for chronic bronchitis in smokers only, the maximum LOD was 2.08 at chromosome 22. On chromosome 12p, 12 additional STR markers were genotyped, which provided additional support for an airflow obstruction locus in that region with a non-parametric multipoint approach for moderate airflow obstruction (LOD = 2.13) and mild airflow obstruction (LOD = 1.43). Using a dominant model with the STR markers on 12p, two point parametric linkage analysis of all subjects demonstrated a maximum LOD score of 2.09 for moderate airflow obstruction and 2.61 for mild airflow obstruction. In smokers only, the maximum two point LOD score for mild airflow obstruction was 3.14. These observations provide suggestive evidence that there is a locus on chromosome 12p which contributes to susceptibility to early-onset COPD.


Assuntos
Cromossomos Humanos Par 12/genética , Ligação Genética/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idade de Início , Idoso , Mapeamento Cromossômico , Feminino , Volume Expiratório Forçado/fisiologia , Predisposição Genética para Doença/genética , Genoma Humano , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Polimorfismo Genético/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Sequências de Repetição em Tandem/genética
12.
Am J Hum Genet ; 70(5): 1229-39, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11914989

RESUMO

Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV(1), FVC, and FEV(1)/FVC. In the initial genomewide scan, significant evidence for linkage to FEV(1)/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV(1)/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV(1) in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV(1) (LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV(1)/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos/genética , Genoma Humano , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Adulto , Idade de Início , Idoso , Cromossomos Humanos Par 12/genética , Feminino , Volume Expiratório Forçado/fisiologia , Predisposição Genética para Doença/genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Polimorfismo Genético/genética , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Testes de Função Respiratória , Espirometria , Sequências de Repetição em Tandem/genética
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