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Biomedical subjects

E K Silverman

Publications and source records attributed to E K Silverman.

At least 37 records · Page 2Linked to original sources
PubMed2000

Application of an algorithm for the diagnosis of asthma in Chinese families: limitations and alternatives for the phenotypic assessment of asthma in family-based genetic studies.

Phenotype assessment is a crucial issue in gene mapping studies of asthma. Recently, Panhuysen and coworkers proposed an algorithm to define the asthma phenotype in gene mapping family-based studies. We classified members of 2,756 Chinese families ascertained on the basis of the presence of two or more siblings and no more than one parent with asthma using a slightly modified version of the aforementioned algorithm. Among 4,097 Chinese parents, 404 (9.9%) were classified as having "definite asthma," 284 (6.9%) as "probable asthma," 1,193 (29.1%) as "unclassifiable obstructive airway disease, " 626 (15.3%) as "COPD," and 1,590 (38.8%) as "unaffected" (no obstructive airway disease). Among 6,424 Chinese offspring, 1,065 (16.6%) were classified as having "definite asthma," 820 (12.8%) as "probable asthma," 1,996 (31.1%) as "unclassifiable obstructive airway disease," 228 (3.5%) as "COPD," and 2,315 (36%) as "unaffected." The use of the algorithm proposed by Panhuysen and coworkers in a Chinese population with a high prevalence of smoking would result in the exclusion of subjects with asthma who smoke or who have severe airflow obstruction from linkage analysis, as well as in an inability to explore any potential interactions between genetic factors and cigarette smoking in the pathogenesis of asthma. In the absence of a "gold standard," definitions of asthma that incorporate a combination of respiratory symptoms, increased airway responsiveness or bronchodilator response, and a physician's diagnosis of asthma are reasonable. The choice of a particular diagnostic algorithm for family-based genetic studies of asthma should be made according to factors such as the prevalence of smoking in the study population. Genetic studies of intermediate phenotypes related to asthma, which are objectively defined and may be influenced by a smaller number of genes, continue to be of great importance.

Adolescent↗
PubMed2000

Exhaled nitric oxide in patients with asthma: association with NOS1 genotype.

An increased concentration of nitric oxide (NO) in exhaled air (FENO) is now recognized as a critical component of the asthmatic phenotype. When we identified patients with asthma on the basis of a standard case definition alone, we found that they were remarkably heterogeneous with respect to their FENO. However, when we included genotype at a prominent asthma candidate gene (i.e., NOS1) in the case definition, and determined the number of AAT repeats in intron 20, we identified a remarkably homogeneous cohort of patients with respect to FENO. Both mean FENO (p = 0.00008) and variability around the mean (p = 0.000002) were significantly lower in asthmatic individuals with a high number (> or = 12) of AAT repeats at this locus than in those with fewer repeats. These data provide a biologically tenable link between genotype at a candidate gene in a region of linkage, NOS1, and an important component of the asthmatic phenotype, FENO. We show that addition of NOS1 genotype to the case definition of asthma allows the identification of a uniform cohort of patients, with respect to FENO, that would have been indistinguishable by other physiologic criteria. Our isolation of this homogeneous cohort of patients ties together the well-established associations among asthma, increased concentrations of NO in the exhaled air of asthmatic individuals, and variations of trinucleotide repeat sequences as identified in several neurologic conditions.

Adult↗
PubMed2000

Gender-related differences in severe, early-onset chronic obstructive pulmonary disease.

Men have higher prevalence rates of chronic obstructive pulmonary disease (COPD) than women, which has been attributed to the historically higher rates of cigarette smoking in males. However, the increased rates of cigarette smoking in females within the last several decades have been associated with steadily increasing rates of COPD in women. As part of a study of the genetics of severe, early-onset COPD, we assembled a group of 84 probands with severe, early-onset COPD (without severe alpha(1)-antitrypsin deficiency) and 348 of their first-degree relatives. We found a markedly elevated prevalence (71.4%) of females among the early-onset COPD probands. Among the entire group of first-degree relatives of early-onset COPD probands, univariate analysis demonstrated similar spirometric values and bronchodilator responsiveness in males and females; however, among current or ex-smokers, female first-degree relatives had significantly lower FEV(1)/ FVC (81.4 +/- 17.2% in females versus 87.0 +/- 12.9% in males, p = 0.009) and significantly greater bronchodilator responsiveness (expressed as percentage of baseline FEV(1)) (7.7 +/- 9.4% pred in females versus 4.1 +/- 6.4% pred in males, p = 0.002). Female smoking first-degree relatives were significantly more likely to demonstrate profound reductions in FEV(1) (< 40% pred) than male smoking first-degree relatives (p = 0. 03). Multivariate analysis, performed with generalized estimating equations, demonstrated that current or ex-smoking female first-degree relatives had significantly greater risk of FEV(1) < 80% pred (OR 1.91, 95% CI 1.03- 3.54), FEV(1) < 40% pred (OR 3.56, 95% CI 1.08-11.71), and bronchodilator response greater than 10% of baseline FEV(1) (OR 4.74, 95% CI 1.91-11.75). These results suggest that women may be more susceptible to the development of severe COPD.

Adult↗
PubMed2000

Heterogeneity of therapeutic responses in asthma.

Asthma is a complex clinical syndrome with multiple genetic and environmental factors contributing to its phenotypic expression. This aetiological heterogeneity adds to the complexity when addressing variation in the response to anti-asthma treatment. Currently, there are three main lines of treatment available: (i) inhaled glucocorticoids which have multiple mechanisms of action; (ii) beta 2-agonists which are very effective bronchodilators and act predominantly on airway smooth muscle; and (iii) cysteinyl-leukotriene inhibitors. Analysis of the repeatability (r) of the treatment response, defined as the fraction of the total population variance which results from among-individual differences, shows values of r between 60-80% indicating that a substantial fraction of the variance of the treatment response could be genetic in nature. Among the sources of variability that could contribute to the observed heterogeneity in the response to treatment are the degree of underlying inflammation, such as in glucocorticoid resistance, and polymorphisms in the genes encoding the drug target, such as beta 2-adrenoceptor and 5-lipoxygenase.

Adaptor Protein Complex alpha Subunits↗
PubMed1999

Association between a sequence variant in the IL-4 gene promoter and FEV(1) in asthma.

Recent family-based studies have revealed evidence for linkage of human chromosome 5q31 to the diagnosis of asthma, elevated serum IgE levels, and bronchial hyperresponsiveness. Among the candidate genes in this region is the gene encoding for human interleukin-4 (IL-4). We reasoned that this gene could also serve as a candidate gene with respect to asthma severity as indicated by the FEV(1) measured when bronchodilator treatment was withheld. To test this hypothesis, we examined a large population of patients with asthma (ascertained without respect to genetic characteristics), for associations between a genetic variant in the IL-4 promoter region (C-589T) and asthma severity, as indicated by FEV(1). We used amplification by the polymerase chain reaction followed by BsmF1 restriction digestion to assign genotypes at the IL-4 promoter C-589T locus. We compared genotypes at this locus in 772 Caucasian and African American patients with asthma of varying severity, and we used multiple regression analysis to relate genotypic findings to FEV(1). Among white individuals, the homozygous presence of the C-589T IL-4 promoter genotype (TT) was associated with a FEV(1) below 50% of predicted (p = 0.013; OR, 1.44; 95% CI: 1.09 to 1.90). Subjects with the TT genotype had mean FEV(1) (% predicted) values 4.5% lower than those of subjects with the wild-type (CC) genotype at this locus. FEV(1) values of white patients with a CC or CT genotype were broadly distributed, whereas the TT genotype was associated with a narrow distribution of low FEV(1) values. The frequency of the T allele was significantly greater (p = 1 x 10(-)(23)) among African American asthmatics (0.544) than among white asthmatics (0.183). These data provide the first evidence associating FEV(1) in patients with asthma and genetic determinants at any locus. Our data are consistent with the idea that the FEV(1) in asthma is the result of multiple factors; one of these factors is the genotype at the IL-4 C-589T locus. This locus is associated with a small but significant decrement in pulmonary function among white asthmatic subjects.

Adult↗
PubMed1999

Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD.

Bronchodilator responsiveness has been associated with a subsequent accelerated decline in forced expiratory volume in one second (FEV1). Therefore, bronchodilator responsiveness and total serum immunoglobulin E(IgE) levels were assessed in 184 adult first-degree relatives of probands with severe early-onset chronic obstructive pulmonary disease (COPD) and a control group. Greater bronchodilator responsiveness was found among current smokers or exsmokers who were first-degree relatives of early-onset COPD probands than in currently or exsmoking controls, expressed as increase in FEV1 as a percentage of baseline (5.8+/-8.1 versus 2.9+/-5.1%, p<0.01), absolute increase in FEV1 from baseline (120+/-130 versus 60+/-110 mL, p<0.05), and increase in FEV1 as a percentage of the predicted value (3.6:4.1 versus 2.2+/-3.9%, p<0.05). However, elevated total serum IgE levels were not found in first-degree relatives of early-onset COPD probands compared with control subjects. The increased bronchodilator responsiveness among currently smoking/exsmoking first-degree relatives of early-onset COPD probands suggests that these individuals may have enhanced susceptibility to the detrimental effects of cigarette smoking.

Adult↗
PubMed1998

Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease. Risk to relatives for airflow obstruction and chronic bronchitis.

Severe alpha-1-antitrypsin deficiency is the only proven genetic risk factor for chronic obstructive pulmonary disease (COPD). We have assembled a cohort of 44 probands with severe, early-onset COPD, who do not have severe alpha-1-antitrypsin deficiency. A surprisingly high prevalence of females (79.6%) was found. Assessment of the risk to relatives of these early-onset COPD probands for airflow obstruction and chronic bronchitis was performed to determine whether significant familial aggregation for COPD, independent of alpha-1-antitrypsin deficiency, could be demonstrated. First- degree relatives of early-onset COPD probands had significantly lower FEV1 and FEV1/FVC values than control subjects (p < 0.01), despite similar pack-years of smoking. Reduced spirometric values in first-degree relatives of early-onset COPD probands were found only in current or ex-cigarette smokers. The mean FEV1 in current or ex-smoking first-degree relatives was 76.1 +/- 20.9% predicted compared to 89.2 +/- 14.4% predicted in current or ex-smoking control subjects (p < 0.01); in lifelong nonsmokers, the mean FEV1 was 93.4% predicted for both control subjects and first-degree relatives of early-onset COPD probands. Generalized estimating equations, adjusting for age and pack-years of smoking, demonstrated increased odds of reduced FEV1 and chronic bronchitis in current or ex-smoking first-degree relatives of early-onset COPD probands. Using a new method to estimate relative risk from relative odds, we estimate that the relative risks for FEV1 below 60%, FEV1 below 80%, and chronic bronchitis are each approximately three in current or ex-smoking first-degree relatives of early-onset COPD probands. The increased risk to relatives of early-onset COPD probands for reduced FEV1 and chronic bronchitis, limited to current or ex-smokers, suggests genetic risk factor(s) for COPD that are expressed in response to cigarette smoking.

Bronchitis↗
PubMed1997

Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription.

Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.

Alleles↗
PubMed1996

Risk factors for the development of chronic obstructive pulmonary disease.

Cigarette smoking clearly has been shown to be the major environmental risk factor predisposing to the development of COPD. Occupational exposures to dust and fumes, air pollution, passive smoke exposure, childhood respiratory infections, and diet may also contribute. Airway hyperresponsiveness is a risk factor for the development of decline in FEV1, but its role in the development of COPD remains uncertain. Alpha1-antitrypsin deficiency is an important genetic risk factor for COPD in the small minority of COPD patients who inherit this deficiency. Other genetic factors are likely involved but have not yet been identified. Elucidation of additional genetic risk factors may provide useful insights into the pathogenesis of COPD. Potential interactions between the various environmental and genetic risk factors may be extremely important in determining the variable development of COPD.

Air Pollution↗
PubMed1992

Family study of alpha 1-antitrypsin deficiency: effects of cigarette smoking, measured genotype, and their interaction on pulmonary function and biochemical traits.

To gain insight into the variable expression of lung disease in alpha 1-antitrypsin (alpha 1AT) deficiency, five quantitative variables including forced expiratory volume at 1 sec (FEV1), forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF25-75), total serum alpha 1AT, oxidized serum alpha 1AT, and total serum immunoglobulin E (IgE) were measured in alpha 1AT deficient individuals and their families. The effect of a known, measured genotype (the Pi type) was estimated for each quantitative trait; the influence of mode of case ascertainment on the measured genotype effect was also assessed. These analyses showed that total alpha 1AT levels are strongly influenced by Pi type; IgE levels are unaffected by Pi type; and FEV1, FEF25-75, and oxidized alpha 1AT are moderately influenced by Pi type. The effect of genotype-by-environment interaction between Pi type and pack-years of cigarette smoking on the five quantitative phenotypes was studied using an analysis of covariance. Significant Pi x pack-years interaction was evident for FEV1, but this effect is confounded in this data set with the Pi x age interaction. Probands who were ascertained because they had chronic obstructive pulmonary disease (COPD) do not demonstrate the significant Pi x pack-years interaction effect of the Pi x pack-years subjects ascertained for other reasons demonstrate. The effect of the Pi x pack-years interaction on FEV1 was no longer significant on a transformed scale, (FEVf12,) thus providing an additive scale for future data analysis. The increased sensitivity of Pi MZ individuals in our sample to cigarette smoking reduced the Pi x packs-years interaction effect on FEF25-75 to borderline significance. This investigation has provided an opportunity to incorporate both measured genotype and genotype-by-environment interaction analyses into the study of the variable expression of lung disease in Pi Z individuals.

Family↗
PubMed1992

Plasma levels of elastase-specific fibrinopeptides correlate with proteinase inhibitor phenotype. Evidence for increased elastase activity in subjects with homozygous and heterozygous deficiency of alpha 1-proteinase inhibitor.

There is indirect evidence that unopposed human neutrophil elastase (HNE) is responsible for emphysema in patients with alpha 1-proteinase inhibitor (Pi) deficiency. To directly explore this possibility, we developed an assay for fibrinopeptide A alpha 1-21 and its degradation products and used it to measure HNE activity in 128 subjects of known Pi phenotype. The mean elastase-specific fibrinopeptide (ESF) level in 49 deficient PiZ individuals is significantly higher than that in 56 PiMZ heterozygotes (4.5 and 1.5 nM, respectively; P less than 0.01), while the mean ESF value in heterozygotes is significantly elevated over that in 23 normal PiM subjects (1.5 and 0.6 nM, respectively; P less than 0.01), consistent with increased HNE activity in those deficient in the major regulator of the enzyme. These results are not due to differences in smoking history because after correction for pack-years of smoking, ESF values in PiZ subjects are fourfold higher than those in PiMZ individuals (P = 0.005), while the ESF levels in heterozygotes are threefold higher than those in PiM subjects (P = 0.02). In addition, this analysis suggests that cigarette smoking and alpha 1-proteinase inhibitor deficiency have additive effects on ESF levels thereby explaining why PiZ and some PiMZ individuals are at especially high risk for the development of lung disease if they smoke. Finally, the observation that ESF levels in nonsmoking PiZ subjects are inversely related to the percent of predicted forced expiratory volume in 1 s (FEV 1%) provides direct support for the concept that unregulated HNE activity causes alveolar septal destruction in patients with alpha 1-proteinase inhibitor deficiency.

Carboxypeptidases↗
PubMed1990

Biochemical intermediates in alpha 1-antitrypsin deficiency: residual family resemblance for total alpha 1-antitrypsin, oxidized alpha 1-antitrypsin, and immunoglobulin E after adjustment for the effect of the Pi locus.

alpha 1-antitrypsin (alpha 1 AT) deficiency is variably associated with the development of pulmonary emphysema. To gain insight into the process which begins the Z point mutation at the Protease Inhibitor (Pi) locus and results in the variable development of emphysema, three quantitative phenotypes, including total alpha 1 AT, oxidized alpha 1 AT, and total immunoglobulin E (IgE), were measured in sera from alpha 1-antitrypsin-deficient individuals and their families. The mean and variance effects of the Pi locus on these biochemical phenotypes were removed, and path analysis of the residual phenotypes was performed by using a TAU model to investigate whether there was any additional multifactorial transmission. Significant transmission was demonstrated for total serum IgE and serum-oxidized alpha 1 AT, which could be due to major genes other than the Pi locus, polygenes, or familial environment. Segregation analysis of the residual phenotypes was performed to determine whether additional major gene effects, other than the Pi effect, influence these quantitative phenotypes. Convincing evidence for an additional major gene was not found for oxidized alpha 1 AT, total alpha 1 AT, or IgE.

Data Interpretation, Statistical↗
PubMed1990

Variability of pulmonary function in alpha-1-antitrypsin deficiency: residual family resemblance beyond the effect of the Pi locus.

To gain insight into the variable expression of lung disease in alpha 1-antitrypsin deficiency, two pulmonary function tests, FEV1 and FEF25-75, were examined in alpha 1-antitrypsin-deficient individuals and their families. The mean and variance effects of Pi type, age, and sex on the pulmonary function variables were removed by stepwise multiple regression, and the residual phenotypes were analyzed. Path analysis of the residual phenotypes with environmental indices in 46 nuclear families demonstrated highly significant cultural inheritance. Significant polygenic inheritance was not demonstrated for FEV1 but was shown for FEF25-75. For FEV1, adjustment for the significant interaction between Pi type and pack-years of smoking tended to increase the estimated contribution of polygenic inheritance and to decrease the estimated contribution of cultural inheritance. Segregation analysis of the residual phenotypes in 44 nuclear families was carried out to determine whether another major gene, other than the Pi locus, may be influencing pulmonary function in this population. Statistical evidence was found for an additional major gene influencing FEV1; however, the evidence diminished after adjusting for the effects of pack-years and the interaction between Pi type and pack-years. This apparent drop in the importance of genetic factors would not be surprising if the effect of the putative major gene is to enhance susceptibility to effects of cigarette smoking. Finally, our investigation demonstrates the feasibility of dissecting residual familial effects on complex multifactorial traits.

Factor Analysis, Statistical↗
PubMed1990

A family study of the variability of pulmonary function in alpha 1-antitrypsin deficiency. Quantitative phenotypes.

A group of 52 alpha 1-antitrypsin-deficient individuals of phenotype Pi Z and 117 of their relatives underwent a protocol including pulmonary function testing, completion of a questionnaire, and blood donation. Our population permitted a minimum frequency estimate (7 x 10(-4)) for Pi null alleles. Five quantitative phenotypes were measured, including FEV1, FEF25-75, total serum alpha 1AT, oxidized serum alpha 1AT, and total serum IgE. We found that (1) total alpha 1AT levels were higher in Pi Z subjects with lung function impairment (FEV1 less than or equal to 65% of predicted) than in Pi Z subjects who were not impaired; (2) Pi Z subjects with lung function impairment had elevated serum levels of oxidized alpha 1AT; and (3) IgE levels were relatively elevated in first-degree Pi MZ relatives of impaired Pi Z subjects. Moreover, FEV1 tended to be relatively reduced in heterozygous parents of impaired Pi Z subjects, suggesting that a subset of Pi MZ individuals are at risk for development of lung disease because of familial factors. These results represent an initial step toward the development of intermediate phenotypes that will be predictive of a severe course in alpha 1AT deficiency; they suggest that, in addition to cigarette smoking, atopic predisposition and undetermined familial factors may be important codeterminants of lung disease progression.

Adult↗
PubMed1989

Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates.

STUDY OBJECTIVE: To determine the range of pulmonary function variability in alpha-1-antitrypsin-deficient persons and to identify epidemiologic factors and pulmonary symptoms and conditions associated with this variability. DESIGN: Case series ascertained through investigation of extant obstructive lung disease (index cases, 22 subjects) or by other means (non-index cases, 30 subjects). SETTING: Referral-based pulmonary division at a tertiary care medical center. PARTICIPANTS: Fifty-two alpha-1-antitrypsin-deficient persons of type Pi Z ascertained by: extant chronic obstructive pulmonary disease (22 cases), family studies (20 cases), liver disease (4 cases), population screening (4 cases), and other pulmonary problems (2 cases). MEASUREMENTS AND MAIN RESULTS: Pulmonary function tests and a version of the American Thoracic Society 1978 standard respiratory epidemiology questionnaire were used. Persons of type Pi Z who were not specifically ascertained with chronic obstructive pulmonary disease had values of forced expiratory volume in 1 second over 65% of predicted in 20 out of 30 cases and frequently had normal lung function. Univariate and multivariate analyses of possible causes of lung disease showed that the following factors were significant (P less than 0.05): pulmonary symptoms (effects associated with chronic obstructive pulmonary disease), including dyspnea and chronic cough; age and pack-years of smoking (epidemiologic correlates); and other pulmonary conditions (potential causes or effects) including asthma, pneumonia, and episodes of increased cough and phlegm. Finally, we found a striking excess of questionnaire-reported parental emphysema in families of type Pi Z persons with chronic obstructive pulmonary disease compared with families of type Pi Z persons without disease. CONCLUSIONS: Many persons with alpha-1-antitrypsin deficiency do not have clinically significant lung function impairment: the perceived natural history of antitrypsin deficiency has been distorted by ascertainment bias. In addition to cigarette smoking, it appears that asthma, lower respiratory infections, and possibly some familial factors contribute to a severe clinical course. Follow-up of our cohort with widely varying lung function will provide insights into the natural history of the emphysema associated with alpha-1-antitrypsin deficiency.

Adolescent↗
PubMed1989

Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.

Human peripheral blood monocytes contain human leukocyte elastase (HLE) and cathepsin G (CG), serine proteinases originally described in azurophil granules of polymorphonuclear neutrophils (PMN). Immunoreactive HLE and CG of freshly harvested monocytes have been quantified in this study; to begin to elucidate potential roles for these enzymes in extracellular events, release in response to stimuli has been measured, along with proteolytic activity of monocytes toward surface-bound proteins. Our results indicate that whole-cell extracts of monocytes contain approximately 6% of the amount of HLE as do extracts of comparable numbers of PMN. In response to PMA in vitro, monocytes released 39 to 53% of their content of HLE and CG within 60 min, a fractional release greater than that of PMN. Furthermore, when phorbol-stimulated monocytes were adherent to a fibronectin-coated surface, extensive HLE-mediated proteolysis of the surface-bound protein was observed. Proteolysis by such cells in the presence of proteinase inhibitors was of considerable interest, since a subpopulation (15 to 20% of the total) expressed marked but localized proteolytic activity, possibly escaping inhibition through contact-mediated mechanisms. These data indicate that a subpopulation of freshly harvested monocytes is rich in HLE and CG (serine proteinases traditionally associated with PMN), can promptly release HLE and CG in response to stimuli, and can utilize HLE for extracellular proteolysis. Monocyte-derived serine proteinases may participate in extracellular events formerly associated with PMN-derived HLE and CG.

Cathepsin G↗