Susceptibility Genes for Rapid Decline of Lung Function in the Lung Health Study

Sandford, Andrew J.; Chagani, Tabassum; Weir, Tracey D.; Connett, John E.; Anthonisen, Nicholas R.; Paré, Peter D.

doi:10.1164/ajrccm.163.2.2006158

Cited by 239 publications

(174 citation statements)

References 22 publications

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“…A more interesting parallel can be drawn with a re- cent study indicating an effect of low-activity mEH alleles and the rapid decline of lung function in patients with emphysema. 28 Analogously to our results, in fact, differences were evidenced in the long-term outcome and the timing of disease evolution, as would be expected for the effect of a modifier trait of chronic tissue damage in diseases characterized by prolonged courses, variable clinical expression, and multiple causes. The comparison between cirrhotic patients with or without HCC indicated that mEH low-activity alleles exerted an independent effect on the risk of cancer, although this was essentially restricted to men.…”

Section: Discussionsupporting

confidence: 87%

Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease

Sonzogni

Silvestri

et al. 2002

Hepatology

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Factors influencing the progression of liver disease and the development of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infection are poorly understood. Inherited variations of drug-metabolizing enzyme (DME) activities may affect liver damage and cancer risk by modifying individual susceptibility to endogenous or exogenous toxic compounds. We investigated the association of liver disease severity with common alleles of microsomal epoxide hydrolase (mEH), an enzyme involved in the metabolism of highly reactive epoxide intermediates. Three polymorphisms (Tyr113His, His139Arg, and ؊613C/T) were analyzed by polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) in 394 patients at different stages of disease, including 92 asymptomatic carriers, 109 patients with chronic hepatitis, 100 patients with cirrhosis, and 93 patients with HCC. Reference allele frequencies were obtained from 99 healthy blood donors. Allele distributions between categories were compared using the 2 test; odds ratios (ORs) and 95% CI were calculated to express relative risks. Allele frequencies among 99 healthy controls were as follows: 15.1% for 113His/His, 4.0% for 139Arg/Arg, and 46.5% for ؊613C/T. mEH 113His/His homozygotes were overrepresented in advanced stages of disease, in particular among HCC patients (27.9%; P ‫؍‬ .03; OR, 2.2; 95% CI, 1.0-4.6). Differences were more pronounced among men and between extreme patient categories. When mEH genotypes were combined to express a metabolic phenotype, very slow metabolizers were highly prevalent among cirrhotic and HCC patients (18% vs. 3.3% in carriers; P < .001). In conclusion, mEH gene polymorphisms were significantly associated with HCV-related liver disease severity and HCC risk. Men were at higher risk than women; this might be explained by hormonal regulation of gene expression or by differential exposure to environmental toxins. (HEPATOLOGY 2002;36:195-201.) T he worldwide burden of deaths caused by liver diseases and liver cancer, which usually arises in the setting of cirrhosis and chronic viral hepatitis, is estimated to be approximately 1.3 million/yr. 1 Chronic hepatitis C virus (HCV) infections account for over 80% of cases of cirrhosis and hepatocellular carcinomas (HCC) in Italy, 2 for which over 2 million anti-HCV-positive cases are estimated. 3 HCV-related liver disease displays a multiplex phenotype in which environmental and viral factors are likely to act in concert with individual susceptibility to induce liver damage. Overall penetration of disease expression is low, because less than 20% of infected individuals will develop cirrhosis over a 20-to 30-year period. 4 Determinants of HCV pathogenesis are barely known and include age at infection, 5 disease duration, 4 sex, 6 modes of transmission, 7 immunogenetic variables, 8 and viral heterogeneity, 9 but these factors account for only a small part of the clinical variability of the disease. Dietary factors, inherited metabolic defects, such as hemochromatosis, 10 and alc...

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Section: Discussionsupporting

confidence: 87%

Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease

Sonzogni

Silvestri

et al. 2002

Hepatology

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“…(1) Even a slight decrease in AAT levels, such as that observed in individuals with the MZ genotype, can increase the risk of developing pulmonary diseases, (13) and the impaired function of AAT denatured by oxidation in smokers (even in those presenting normal AAT levels) can contribute to the development of lung injury. (5) These facts seem to indicate that AAT availability is extremely important for the protection of the lung and, probably, for the maintenance of the adequate state of many other organs and systems.…”

Section: Resultsmentioning

confidence: 99%

Avaliação da concentração de alfa 1-antitripsina e da presença dos alelos S e Z em uma população de indivíduos sintomáticos respiratórios crônicos

et al. 2008

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Objective: To determine the levels of alpha-1 antitrypsin (AAT) and the presence of S and Z alleles in patients with chronic respiratory symptoms. Methods: Patients with chronic cough and dyspnea were submitted to clinical evaluation, pulmonary function tests, high-resolution computed tomography, nephelometric determination of AAT and determination of S and Z alleles by polymerase chain reaction. Smoking and AAT levels were considered the dependent variables. Results: Of the 89 patients included in the study, 44 were female. The mean age was 51.3 ± 18.2 years. The S and Z alleles were detected in 33.3% and 5.7%, respectively, and the gene frequency was 0.16 and 0.028, respectively. Two patients were SZ heterozygotes (AAT levels ≤ 89 mg/dL). The patients were divided into groups based on AAT level: ≤ 89 mg/ dL (deficiency, no group); 90-140 mg/dL (intermediate, Group 1, n = 30); and ≥ 141 mg/dL (normal, Group 2, n = 57). The frequency of smokers was the same in both groups, although tobacco intake was greater in Group 2. The S allele was present in 13 and 14 patients in Groups 1 and 2, respectively, whereas the Z allele was present in 2 and 1 patient in the same groups. There was no difference in the results of pulmonary function tests or in the frequency of bronchiectasis or emphysema between the two groups. Spirometric values and AAT levels were similar in smokers and nonsmokers. Bronchiectasis was more common in nonsmokers, and emphysema was more common in smokers. Conclusions: Thirty patients presented AAT levels lower than the mean values found in patients with the MM or MS genotype, and this fact could not be explained by an increased frequency of S and Z alleles.Keywords: Alpha 1-antitrypsin; Emphysema: Lung diseases; Alleles. ResumoObjetivo: Determinar a concentração de alfa 1-antitripsina (AAT) e a prevalência dos alelos S e Z em indivíduos sintomáticos respiratórios crônicos. Métodos: Pacientes com tosse crônica e dispnéia foram submetidos à avaliação clínica, espirometria, tomografia computadorizada de tórax, dosagem de AAT por nefelometria e pesquisa das mutações S e Z por reação em cadeia da polimerase. Foram consideradas como variáveis dependentes a concentração de AAT e o tabagismo. Resultados: Dos 89 pacientes incluídos no estudo (44 mulheres; idade média, 51,3 ± 18,2 anos), os alelos S e Z foram detectados em 33,3% e 5,7%, respectivamente, com freqüência gênica dos alelos S e Z de 0,16 e 0,028. Dois pacientes tinham genótipo SZ (AAT ≤ 89 mg/dL). Os pacientes foram divididos em grupos segundo a concentração de AAT: ≤ 89 mg/dL (deficiência, nenhum grupo); 90-140 mg/dL (faixa intermediária, Grupo 1, n = 30); e ≥ 141 mg/dL (normal, Grupo 2, n = 57). A freqüência de fumantes foi igual nos dois grupos, com carga tabágica maior no Grupo 2. O alelo S estava presente em 13 e 14 pacientes dos Grupos 1 e 2, respectivamente, enquanto que o alelo Z estava presente em 2 e 1 paciente dos mesmos grupos. Não houve diferença nos testes de função pulmonar, nem na freqüência de bronquiectasias ou enfisema en...

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“…Sandford and his colleagues have taken advantage of the well-characterized Lung Health Study cohort study to examine gene variants associated with rapid decline in lung function (1). They selected the phenotypic extremes from among the approximately 6,000 individuals in that study; the approximately 300 continued smokers who had the most rapid and the approximately 300 who had the least rapid decline in FEV 1 over the first 5 years of the study.…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

Genetics and Genomics of Chronic Obstructive Pulmonary Disease

Silverman

Spira²,

Paré³

2009

Proceedings of the American Thoracic Society

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Chronic obstructive pulmonary disease (COPD) fulfills criteria for a complex genetic disease in which environmental factors interact with multiple polymorphic genes to influence susceptibility. Finding the genes that influence susceptibility can be approached in hypothesis testing or unbiased study designs. In candidate gene association studies, genetic variation in, and/or levels of, expression of genes known or suspected to be involved in the pathogenesis of COPD are compared in affected and unaffected individuals. Although this approach is useful it is limited by our present knowledge of disease pathophysiology. Genomewide studies of gene expression and of genetic variation are now possible and are not constrained by our limited knowledge. Although both of these unbiased approaches are in their infancy, they have already provided exciting new avenues for future investigation and potentially now approaches to risk prediction and therapy.

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Susceptibility Genes for Rapid Decline of Lung Function in the Lung Health Study

Cited by 239 publications

References 22 publications

Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease

Polymorphisms of microsomal epoxide hydrolase gene and severity of HCV-related liver disease

Avaliação da concentração de alfa 1-antitripsina e da presença dos alelos S e Z em uma população de indivíduos sintomáticos respiratórios crônicos

Genetics and Genomics of Chronic Obstructive Pulmonary Disease

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