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Biomedical subjects

E K Silverman

Publications and source records attributed to E K Silverman.

At least 19 recordsLinked to original sources
PubMed2006

Genetic determinants of C-reactive protein in COPD.

Chronic obstructive pulmonary disease (COPD) is associated with a systemic inflammatory state, marked by elevations in serum inflammatory markers including C-reactive protein (CRP). The present study sought to determine epidemiological predictors of CRP levels, to estimate the genetic influence on CRP levels, and to identify genetic variants that affect CRP in a family-based study of COPD. CRP was measured by a high-sensitivity assay in participants from the Boston Early-Onset COPD Study. Predictors of CRP level were determined using multilevel linear models. Variance component analysis was used to estimate heritability and to perform genome-wide linkage analysis for CRP levels. Two variants in the surfactant protein B (SFTPB) gene were tested for association with CRP levels. Increased age, female sex, higher body mass index, greater smoking pack-yrs and reduced forced expiratory volume in one second were all associated with increased CRP levels. There was a significant genetic influence on CRP (heritability = 0.25). Genome-wide linkage analysis revealed several potentially interesting chromosomal regions, though no significant evidence for linkage was found. A short tandem repeat marker near SFTPB was significantly associated with CRP levels. There is a genetic influence on C-reactive protein levels in chronic obstructive pulmonary disease patients. Preliminary evidence suggests an association of the surfactant protein B gene with systemic inflammation in chronic obstructive pulmonary disease.

C-Reactive Protein↗
PubMed2006

Smoking related COPD and facial wrinkling: is there a common susceptibility?

BACKGROUND: Cigarette smoking causes accelerated facial wrinkling and predisposes to chronic obstructive pulmonary disease (COPD). However, it has long been recognised that there is a subgroup of susceptible smokers who are at increased risk of developing airflow obstruction. We have tested the hypothesis that there is a common susceptibility for the development of COPD and facial wrinkling in cigarette smokers. METHODS: One hundred and forty nine current and ex-smokers were recruited from a family based study of COPD genetics, 68 (45.6%) of whom fulfilled the definition of COPD. 124 (83.2%) had no or minor facial wrinkling (Daniell /=IV). Generalised estimating equations were used to adjust for familial correlations between related individuals and the potential confounding effects of age and pack years smoked. RESULTS: Forced expiratory volume in 1 second (FEV(1)) was significantly lower in those with wrinkles than in those without (mean difference in FEV(1) % predicted -13.7%, 95% CI -27.5 to 0.0, p = 0.05) and facial wrinkling was associated with a substantially increased risk of COPD (adjusted OR 5.0, 95% CI 1.3 to 18.5, p<0.02). The Daniell score correlated with the extent of emphysema on the CT scan (p<0.05) and facial wrinkling was also associated with a greater risk of more extensive emphysema (adjusted OR 3.0, 95% CI 1.0 to 9.3, p = 0.05). CONCLUSION: Facial wrinkling is associated with COPD in smokers, and both disease processes may share a common susceptibility. Facial wrinkling in smokers may therefore be a biomarker of susceptibility to COPD.

Disease Susceptibility↗
PubMed2006

Lack of association between COPD and transforming growth factor-beta1 (TGFB1) genetic polymorphisms in Koreans.

OBJECTIVE: Many genetic variations have been suggested as genetic risk factors for the development of chronic obstructive pulmonary disease (COPD), including single nucleotide polymorphisms in the transforming growth factor-beta1 (TGFB1) gene. We attempted to elucidate the association between TGFB1 genetic polymorphisms and COPD among Koreans. DESIGN: The genotypes of 102 male patients with COPD and 159 volunteers with similar distributions of age, sex and smoking intensity, as well as normal pulmonary function, were determined for three previously associated TGFB1 single nucleotide polymorphisms (SNPs), -10807G/A (rs2241712) and -509T/C (rs1800469), located in or near the promoter, and 29T/C (rs1982073), located in exon 1 of the TGFB1 gene. RESULTS: No significant associations between COPD and the three TGFB1 SNPs could be identified. In addition, the haplotypes composed of three TGFB1 SNPs were not associated with the presence of COPD. CONCLUSION: These results differ from previous reports involving Caucasians, and might reflect racial differences in the pathogenesis of COPD.

Chi-Square Distribution↗
PubMed2005

The protease inhibitor PI*S allele and COPD: a meta-analysis.

In many countries, the protease inhibitor (SERPINA1) PI*S allele is more common than PI*Z, the allele responsible for most cases of chronic obstructive pulmonary disease (COPD) due to severe alpha 1-antitrypsin deficiency. However, the risk of COPD due to the PI*S allele is not clear. The current authors located studies that addressed the risk of COPD or measured lung function in individuals with the PI SZ, PI MS and PI SS genotypes. A separate meta-analysis for each genotype was performed. Aggregating data from six studies, the odds ratio (OR) for COPD in PI SZ compound heterozygotes compared with PI MM (normal) individuals was significantly increased at 3.26 (95% confidence intervals (CI): 1.24-8.57). In 17 cross-sectional and case-control studies, the OR for COPD in PI MS heterozygotes was 1.19 (95%CI: 1.02-1.38). However, PI MS genotype was not associated with COPD risk after correcting for smoking. Furthermore, mean forced expiratory volume in one second, a measure of airflow obstruction and a defining feature of COPD, did not differ between PI MS and PI MM individuals. There were not enough cases to summarise the risk of COPD in PI SS homozygotes. In conclusion, the results show that the PI SZ genotype is a significant risk factor for chronic obstructive pulmonary disease. The risk of chronic obstructive pulmonary disease due to the PI MS genotype is not substantially elevated.

Alleles↗
PubMed2004

Familial aggregation of FEF(25-75) and FEF(25-75)/FVC in families with severe, early onset COPD.

BACKGROUND: The Boston Early-Onset COPD study showed that current or ex-smoking first degree relatives of severe early onset COPD probands have significantly lower forced expiratory volume in 1 second (FEV(1)) and FEV(1)/forced vital capacity (FVC) values than current or ex-smoking control subjects, which suggests the existence of genetic risk factors for the development of COPD in response to cigarette smoking. We hypothesised that first degree relatives of early onset COPD probands may also have lower values of spirometric parameters such as forced expiratory flow at the mid-portion of forced vital capacity (FEF(25-75)) and FEF(25-75)/FVC. METHODS: Using generalised estimating equations, FEF(25-75) and FEF(25-75)/FVC were analysed in 333 first degree relatives of probands with severe early onset COPD and 83 population based controls; analyses were also performed on data stratified by smoking status. Narrow sense heritability estimates were calculated using a variance component approach. RESULTS: Significantly lower FEF(25-75) and FEF(25-75)/FVC were observed in smoking (FEF(25-75): beta -0.788 l/s (95% CI -1.118 to -0.457), FEF(25-75)/FVC: beta -20.4% (95% CI -29.3 to -11.6, p<0.0001 for both phenotypes) and non-smoking (FEF(25-75): beta -0.357 l/s (95% CI -0.673 to -0.041, p = 0.0271), FEF(25-75)/FVC: beta -9.5% (95% CI -17.1 to -1.9, p = 0.0145)) first degree relatives of early onset COPD probands. Narrow sense heritability estimates for FEF(25-75) (h(2) = 0.38) and FEF(25-75)/FVC (h(2) = 0.45) were similar to those for FEV(1) and FEV(1)/FVC. CONCLUSION: Lower values of FEF(25-75) and FEF(25-75)/FVC in non-smoking first degree relatives of early onset COPD probands than in controls suggest a genetic susceptibility to develop obstructive lung disease, independent of smoking, which is magnified by exposure to deleterious environments as suggested by the further decrements in FEF(25-75) and FEF(25-75)/FVC seen in smoking first degree relatives. FEF(25-75) and FEF(25-75)/FVC have high heritability and are important intermediate phenotypes for inclusion in genetic epidemiological studies of COPD.

Adolescent↗
PubMed2004

Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis.

BACKGROUND: Severe alpha(1)-antitrypsin deficiency, usually related to homozygosity for the protease inhibitor (PI) Z allele, is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The risk of COPD in PI MZ heterozygous individuals is controversial. METHODS: A search of MEDLINE from January 1966 to May 2003 identified studies that examined the risk of COPD in PI MZ individuals and studies that measured forced expiratory volume in 1 second (FEV(1)) in heterozygotes. RESULTS: In 16 studies that reported COPD as a categorical outcome, the combined odds ratio (OR) for PI MZ versus PI MM (normal genotype) was 2.31 (95% CI 1.60 to 3.35). The summary OR was higher in case-control studies (OR 2.97; 95% CI 2.08 to 4.26) than in cross sectional studies (OR 1.50; 95% CI 0.97 to 2.31) and was attenuated in studies that adjusted for cigarette smoking (OR 1.61; 95% CI 0.92 to 2.81). In seven studies that reported FEV(1) as a continuous outcome there was no difference in mean FEV(1) between PI MM and PI MZ individuals. CONCLUSIONS: Case-control studies showed increased odds of COPD in PI MZ individuals, but this finding was not confirmed in cross sectional studies. Variability in study design and quality limits the interpretation. These results are consistent with a small increase in risk of COPD in all PI MZ individuals or a larger risk in a subset. Future studies that adjust for smoking and include other COPD related phenotypes are required to conclusively determine the risk of COPD in PI MZ heterozygotes.

Forced Expiratory Volume↗
PubMed2003

Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous.

In the study of complex traits, the utility of linkage analysis and single marker association tests can be limited for researchers attempting to elucidate the complex interplay between a gene and environmental covariates. For these purposes, tests of gene-environment interactions are needed. In addition, recent studies have indicated that haplotypes, which are specific combinations of nucleotides on the same chromosome, may be more suitable as the unit of analysis for statistical tests than single genetic markers. The difficulty with this approach is that, in standard laboratory genotyping, haplotypes are often not directly observable. Instead, unphased marker phenotypes are collected. In this article, we present a method for estimating and testing haplotype-environment interactions when linkage phase is potentially ambiguous. The method builds on the work of Schaid et al. [2002] and is applicable to any trait that can be placed in the generalized linear model framework. Simulations were run to illustrate the salient features of the method. In addition, the method was used to test for haplotype-smoking exposure interaction with data from the Childhood Asthma Management Program.

Algorithms↗
PubMed2002

Univariate and multivariate family-based association analysis of the IL-13 ARG130GLN polymorphism in the Childhood Asthma Management Program.

Interleukin 13 (IL-13) has been demonstrated to have a crucial role in animal models of allergy and asthma. In human case-control genetic-association studies, the Arg130Gln polymorphism has been associated with elevated total serum IgE and an asthma diagnosis in atopic and nonatopic individuals (Graves et al. [2000] J. Allergy Clin. Immunol. 105:506-513; Heinzmann et al. [2000] Hum. Mol. Genet. 9:549-559). To apply family-based association methods, we obtained DNA samples from 685 asthmatic children from 640 sibships and their parents in the Childhood Asthma Management Program (CAMP). Six hundred and sixty-six asthmatic children had complete phenotypic information and were used for this analysis. We performed quantitative association analysis using the transmission disequilibrium test (TDT) on 22 individual phenotypes and 5 grouped phenotypes relating to allergy, airway responsiveness, pulmonary function, bronchodilator responsiveness, and asthma severity, using genotypes at the Arg130Gln polymorphism of the IL-13 gene. A positive association was obtained between Arg130Gln and a grouped phenotype of allergy (consisting of the individual phenotypes of eosinophils, IgE, and positive skin tests), using FBAT-GEE, a multivariate extension of the family-based association test (Lange et al. [2002] Biostatistics 1:1-15). The three phenotypes were then evaluated individually and revealed a significant association between total eosinophil count and the Arg130Gln locus; there was a trend for association between total IgE and the Arg130Gln polymorphism. The Arg130Gln polymorphism is associated with an elevated eosinophil count as well as with a grouped allergy phenotype, in children with mild to moderate asthma. No evidence for association was found between Arg130Gln and airway responsiveness, asthma diagnosis, or asthma severity.

Allergens↗
PubMed2002

Lack of association between a polymorphism in the interleukin-13 gene and total serum immunoglobulin E level among nuclear families in Costa Rica.

BACKGROUND: IL-13 has been implicated in the pathogenesis of asthma and in the regulation of IgE synthesis in humans. Single nucleotide polymorphisms (SNPs) in the IL-13 gene have been associated with asthma and total serum IgE level in Caucasian populations. OBJECTIVE: To test for genetic association between an SNP in exon 4 of the IL-13 gene (IL-13 + 2044 or Arg130Gln) and total serum IgE level and asthma-related phenotypes in a population with high prevalence of asthma living in Costa Rica. METHODS: Family-based association study. RESULTS: Among 83 Costa Rican school children with asthma and their parents (249 individuals), there was no evidence of linkage disequilibrium between the IL-13 + 2044 SNP and any of the outcomes of interest (total serum IgE level on a logarithmic scale, number of positive skin tests to aeroallergens, and asthma). These results were not significantly changed after adjustment for age and gender. CONCLUSIONS: No significant evidence of linkage disequilibrium between an SNP in exon 4 of the IL-13 gene and total serum IgE level, sensitization to allergens or asthma was found in a family-based association study in Costa Rica.

Allergens↗
PubMed2001

The genetics of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a significant cause of global morbidity and mortality. Previous studies have shown that COPD aggregates in families, suggesting a genetic predisposition to airflow obstruction. Many candidate genes have been assessed, but the data are often conflicting. We review the genetic factors that predispose smokers to COPD and highlight the future role of genomic scans in identifying novel susceptibility genes.

Cloning, Molecular↗
PubMed2001

Linkage analysis of alpha 1-antitrypsin deficiency: lessons for complex diseases.

OBJECTIVES: Severe alpha 1-antitrypsin (A1AT) deficiency is the one proven genetic risk factor for chronic obstructive pulmonary disease (COPD). Familial aggregation has been demonstrated for COPD among individuals who do not have A1AT deficiency, but linkage analysis of COPD has not been reported. To investigate the optimal phenotype definitions and analytical methods for the linkage analysis of COPD, we examined a set of 28 A1AT- deficient families containing 155 individuals. We have used the protease inhibitor (PI) type as a genetic marker rather than a disease gene, and we have performed linkage analysis between PI type and serum A1AT level and spirometry-related phenotypes. METHODS: Linkage analysis was performed on the quantitative phenotypes forced expiratory volume at 1 s (FEV(1) as % predicted), the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC as % predicted), and serum A1AT level using the variance component approach in SOLAR, the generalized estimating equation approach in RELPAL, and the model-based classical lod score method in LINKAGE. Linkage analysis with qualitative A1AT and spirometry phenotypes was performed using a model-based method (LINKAGE) and a model-free method (GENEHUNTER). Adjustments for smoking effects were investigated under each method. RESULTS: All of the methods demonstrated linkage of PI type to serum A1AT level. Interestingly, however, the other quantitative phenotypes provided only weak evidence for linkage of PI type to lung disease. Better evidence for linkage of lung disease to PI type was found using a moderate or a mild threshold for the definition of airflow obstruction. CONCLUSIONS: For linkage analysis of spirometry phenotypes in A1AT deficiency, qualitative phenotypes provided stronger evidence for linkage than quantitative phenotypes. Possible contributors to the stronger evidence for linkage to qualitative spirometry phenotypes include the ascertainment scheme and the nonnormality of the pulmonary function data in PI Z subjects. This study provides guidelines for studies of the genetics of COPD unrelated to A1AT deficiency.

Female↗
PubMed2001

Risk factors for childhood asthma in Costa Rica.

BACKGROUND: Little is known about factors determining the pathogenesis and severity of asthma in Latin American countries. Costa Rica, one of the most prosperous Latin American nations, has a very high asthma prevalence. OBJECTIVE: To examine the relation between potential risk factors and childhood asthma in Costa Rica. METHODS: Cross-sectional study of 214 schoolchildren aged 10 to 13 years participating in phase II of the International Study of Asthma and Allergies in Childhood. RESULTS: After adjustment for age, gender, area of residence, maternal smoking during pregnancy, and airway responsiveness to hypertonic saline solution, sensitization to house dust mites was associated with asthma (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1 to 4.4; p = 0.02). In the multivariate analysis, parental education no higher than high school (OR, 3.0; 95% CI, 1.4 to 6.4; p < 0.01) and parental history of asthma (OR, 2.6; 95% CI, 1.3 to 5.2; p < 0.01) were also independent predictors of childhood asthma. CONCLUSIONS: Sensitization to house dust mites, low parental education, and parental history of asthma are associated with asthma in Costa Rica.

Adolescent↗
PubMed2001

Genetics of chronic obstructive pulmonary disease.

The marked variability in the development of chronic obstructive pulmonary disease (COPD) in response to cigarette smoking has been known for decades, but severe alpha 1-antitrypsin deficiency (PI Z) remains the only proven genetic risk factor for COPD. With cigarette smoking, PI Z subjects tend to develop more severe pulmonary impairment at an earlier age than non-smoking PI Z individuals. However, PI Z individuals exhibit wide variability in pulmonary function impairment, even among individuals with similar smoking histories. Therefore, other genes and environmental exposures are also likely involved. The role of heterozygosity for the Z allele as a risk factor for COPD remains controversial, but accumulating evidence suggests that at least some PI MZ individuals are at increased risk of developing airflow obstruction. In individuals without alpha 1-antitrypsin deficiency, familial aggregation of COPD has been reported in several studies. To study novel genetic determinants of COPD, our research group enrolled 44 severe, early-onset COPD probands (FEV1 < 40%, age < 53 yrs, non-PI Z) and 266 of their relatives. A marked female predominance was noted among the early-onset COPD probands. In addition, increased risk to current or ex-smoking first-degree relatives of early-onset COPD probands for reduced FEV1, chronic bronchitis and spirometric bronchodilator responsiveness has been demonstrated. These data strongly support the genetic basis for the development of COPD and the potential for gene-by-environment interaction. A variety of studies have examined candidate gene loci with association studies, comparing the distribution of variants in genes hypothesized to be involved in the development of COPD in COPD patients and control subjects. For most genetic loci which have been tested, there have been inconsistent results. Genetic heterogeneity could contribute to difficulty in replicating associations between studies. In addition, case-control association studies are susceptible to supporting associations based purely on population stratification, which can result from incomplete matching between cases and controls--including differences in ethnicity. No association studies in COPD have been reported which used family-based controls, a study design which is immune to such population stratification effects. More importantly, no linkage studies have been published in COPD to identify regions of the genome which are likely to contain COPD susceptibility genes--regions in which association studies are likely to be more productive.

Humans↗
PubMed2000

A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma.

Recent family-based studies have revealed evidence for linkage of chromosomal region 12q to both asthma and high total serum immunoglobulin E (IgE) levels. Among the candidate genes in this region for asthma is neuronal nitric oxide synthase (NOS1). We sought a genetic association between a polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1 gene were significantly different between 490 asthmatic and 350 control subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49 [95% CI 1.17-1.90], P = 0.013) while allele 18 was less common in the asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34-0. 69], P = 0.0004). To confirm these results we genotyped an additional 1131 control subjects and found the frequencies of alleles 17 and 18 to be virtually identical to those ascertained in our original control subjects. Total serum IgE was not associated with any allele of the polymorphism. These findings provide support, from case-control association analysis, for NOS1 as a candidate gene for asthma.

Adult↗
PubMed2000

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma.

Inhaled beta-adrenergic agonists are the most commonly used medications for the treatment of asthma although there is evidence that regular use may produce adverse effects in some patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect regulation of the receptor. Smaller studies examining the effects of such polymorphisms on the response to beta-agonist therapy have produced inconsistent results. We examined whether polymorphisms at codon 16 (beta(2)-AR-16) and codon 27 (beta(2)-AR-27) of the beta(2)-AR might affect the response to regular versus as-needed use of albuterol by genotyping the 190 asthmatics who had participated in a trial examining the effects of regular versus as needed albuterol use. During the 16-wk treatment period there was a small decline in morning peak expiratory flow in patients homozygous for arginine at B(2)-AR-16 (Arg/Arg) who used albuterol regularly. This effect was magnified during a 4-wk run out period, during which all patients returned to using as-needed albuterol, so that by the end of the study Arg Arg patients who had regularly used albuterol had a morning peak expiratory flow 30. 5 +/- 12.1 L/min lower (p = 0.012) than Arg/Arg patients who had used albuterol on an as needed basis. There was no decline in peak flow with regular use of albuterol in patients who were homozygous for glycine at beta(2)-AR-16. Evening peak expiratory flow also declined in the Arg/Arg patients who used albuterol regularly but not in those who used albuterol on an as-needed basis. No significant differences in outcomes between regular and as-needed treatment were associated with polymorphisms at position 27 of the beta(2)-AR. No other differences in asthma outcomes that we investigated occurred in relation to these beta(2)-AR polymorphisms. Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.

Adolescent↗