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Biomedical subjects

Edwin K Silverman

Publications and source records attributed to Edwin K Silverman.

At least 55 records · Page 3Linked to original sources
PubMed2004

Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids.

Corticosteroids mediate a variety of immunological actions and are commonly utilized in the treatment of a wide range of diseases. Unfortunately, therapy with this class of medications is associated with a large proportion of non-responders and significant side effects. Inhaled corticosteroids are the most commonly used asthma controller therapy. However, asthmatic response to corticosteroids also varies widely between individuals. We investigated the genetic contribution to the variation in response to inhaled corticosteroid therapy in asthma. The association of longitudinal change in lung function and single nucleotide polymorphisms from candidate genes crucial to the biologic actions of corticosteroids were evaluated in three independent asthmatic clinical trial populations utilizing inhaled corticosteroids as the primary therapy in at least one treatment arm. Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to therapy in each of our three populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to corticosteroids compared with lack of the variants (P-values ranging from 0.006 to 0.025 for our three asthmatic populations). As the primary receptor mediating the release of adrenocorticotropic hormone, which regulates endogenous cortisol levels, CRHR1 plays a pivotal, pleiotropic role in steroid biology. These data indicate that genetic variants in CRHR1 have pharmacogenetic effects influencing asthmatic response to corticosteroids, provide a rationale for predicting therapeutic response in asthma and other corticosteroid-treated diseases, and suggests this gene pathway as a potential novel therapeutic target.

Administration, Inhalation↗
PubMed2004

Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics.

We provide a general purpose family-based testing strategy for associating disease phenotypes with haplotypes when phase may be ambiguous and parental genotype data may be missing. These tests for linkage and association can be used in candidate gene studies with tightly linked markers. Our proposed weighted conditional approach extends the method described in Rabinowitz and Laird to multiple markers. It is attractive because it provides haplotype tests for family-based studies that are efficient and robust to population admixture, phenotype distribution specification, and ascertainment based on phenotypes. It can handle missing parental genotypes and/or missing phase in both offspring and parents. It yields either haplotype-specific (univariate) tests or multi-haplotype (global) tests. This extension has been implemented in the freely available software haplotype FBAT. We used the haplotype FBAT program to test for associations between asthma phenotypes and single nucleotide polymorphisms (SNPs) in the beta-2 adrenergic receptor gene. Whereas no single SNP showed significant association with asthma diagnosis or bronchodilator responsiveness (quantitative trait), a haplotype-based global test found a highly significant association with asthma diagnosis (P value <0.00005) and the measure of bronchodilator responsiveness (P value =0.016).

Algorithms↗
PubMed2004

IL10 gene polymorphisms are associated with asthma phenotypes in children.

IL10 is an anti-inflammatory cytokine that has been found to have lower production in macrophages and mononuclear cells from asthmatics. Since reduced IL10 levels may influence the severity of asthma phenotypes, we examined IL10 single-nucleotide polymorphisms (SNPs) for association with asthma severity and allergy phenotypes as quantitative traits. Utilizing DNA samples from 518 Caucasian asthmatic children from the Childhood Asthma Management Program (CAMP) and their parents, we genotyped six IL10 SNPs: 3 in the promoter, 2 in introns, and one in the 3' UTR. Using family-based association tests, each SNP was tested for association with asthma and allergy phenotypes individually. Population-based association analysis was performed with each SNP locus, the promoter haplotypes and the 6-loci haplotypes. The 3' UTR SNP was significantly associated with FEV(1) as a percent of predicted (FEV(1)PP) (P=0.0002) in both the family and population analyses. The promoter haplotype GCC was positively associated with IgE levels and FEV(1)PP (P=0.007 and 0.012, respectively). The promoter haplotype ATA was negatively associated with lnPC(20) and FEV(1)PP (P=0.008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children.

3' Untranslated Regions↗
PubMed2004

ADAM33 polymorphisms and phenotype associations in childhood asthma.

BACKGROUND: A disintegrin and metalloproteinase (ADAM) 33 has been implicated as an asthma susceptibility gene by using a positional cloning approach. However, genetic linkage of asthma phenotypes to chromosome 20p13 (the location of ADAM33) has not been observed in most asthma genome scans, and it is unclear whether these associations with ADAM33 are broadly generalizable. OBJECTIVE: To examine whether ADAM33 is associated with asthma in a North American population of childhood asthmatic patients. METHODS: We performed a family-based association study by using 652 nuclear families ascertained through asthmatic subjects enrolled in a large randomized clinical trial. Seventeen ADAM33 single nucleotide polymorphisms (SNPs; including 9 associated with asthma in the initial report) were genotyped by mass spectrometry. Single-SNP and haplotype association analysis was performed. RESULTS: Among white and African American subjects, no single-SNP association with asthma was observed. However, a common 16-SNP haplotype (frequency, 14.6% in white subjects) was associated with asthma (P=.006). Two SNPs in strong linkage disequilibrium (T1 and T+1) were marginally associated with asthma in the Hispanic cohort (P=.04). These data provide marginal support for an asthma locus in the ADAM33 genomic region. However, the magnitudes of the observed associations are modest at best and are inconsistent with the original report. CONCLUSIONS: We conclude that either ADAM33 has only modest effects on asthma susceptibility, and the initial reports of association were a result of analysis in a selected population, or the initial findings were a result of chance. It is also possible that the true asthma susceptibility locus in this genomic region is near, but not at, ADAM33.

ADAM Proteins↗
PubMed2004

Association between hemochromatosis genotype and lead exposure among elderly men: the normative aging study.

Because body iron burden is inversely associated with lead absorption, genes associated with hemochromatosis may modify body lead burden. Our objective was to determine whether the C282Y and/or H63D hemochromatosis gene (HFE) is associated with body lead burden. Patella and tibia lead levels were measured by K X-ray fluorescence in subjects from the Normative Aging Study. DNA samples were genotyped for C282Y and H63D using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). A series of multivariate linear regression models were constructed with bone or blood lead as dependent variables; age, smoking, and education as independent variables; and C282Y or H63D as independent risk factors and/or effect modifiers. Of 730 subjects, 94 (13%) carried the C282Y variant and 183 (25%) carried the H63D variant. In the crude analysis, mean tibia, patella, and blood lead levels were consistently lower in carriers of either HFE variant compared with levels in subjects with wild-type genotypes. In multivariate analyses that adjusted for age, smoking, and education, having an HFE variant allele was an independent predictor of significantly lower patella lead levels (p < 0.05). These data suggest that HFE variants have altered kinetics of lead accumulation after exposure. Among elderly men, subjects with HFE variants had lower patella lead levels. These effects may be mediated by alterations in lead toxicokinetics via iron metabolic pathways regulated by the HFE gene product and body iron stores.

Aged↗
PubMed2004

Beta 2-adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men.

STUDY OBJECTIVE: To investigate the relationship of common single nucleotide polymorphisms (SNPs) of the beta(2)-adrenergic receptor (AR) gene at codons 16 and 27, and the intermediate phenotype of airways hyperresponsiveness. DESIGN: A case-control study in 543 white men (152 case patients and 391 control subjects), who were nested in an ongoing longitudinal cohort. SETTING: Subjects were selected from the Normative Aging Study, an ongoing longitudinal cohort of healthy aging. PARTICIPANTS: Case patients were defined as those having a positive response to methacholine challenge testing. Control subjects were selected among those who did not have a diagnosis of asthma and who had no response to methacholine. RESULTS: There was a trend for an association of the Arg16 SNP genotype with airways hyperresponsiveness (odds ratio, 1.25; 95% confidence interval, 0.96 to 1.64 [in an additive model]). In stratified analyses, the effect of the Arg16 variant was seen mainly among nonsmokers. Smokers had increased risks for airway hyperresponsiveness regardless of genotype at either SNP. Using a program to estimate haplotype frequencies, three common haplotypes were identified. Adjusting for age, baseline FEV(1), serum IgE level, and smoking status, the Gly16/Gln27 haplotype was negatively associated with airways hyperresponsiveness in the full complement of case patients and control subjects (score statistic, - 2.43; p = 0.02). The effect of the beta(2)-AR haplotypes was much stronger among lifelong nonsmokers, among whom the Gly16/Gln27 haplotype remained negatively associated with airways hyperresponsiveness (score statistic, - 3.114; p = 0.002), whereas the Arg16/Gln27 haplotype was positively associated with airways hyperresponsiveness (score statistic, 3.142; p = 0.002). No effects were seen among ever-smokers. CONCLUSIONS: In this cohort of middle-aged to older white men, beta(2)-AR polymorphisms were associated with airways hyperresponsiveness, particularly among lifelong nonsmokers. Our results illustrate an instance in which greater power is obtained by performing haplotype analyses as opposed to single SNP analysis.

Adult↗
PubMed2004

Predictors of survival in severe, early onset COPD.

STUDY OBJECTIVES: Multiple risk factors for mortality in patients with COPD have been described, but most studies have involved older, primarily male subjects. The purpose of this study was to determine the mortality rate and predictors of survival in subjects with severe, early onset COPD. DESIGN, SETTING, AND PARTICIPANTS: The cohort of 139 probands in the Boston Early-Onset COPD Study was recruited from lung transplant and general pulmonary clinics between September 1994 and July 2002. Subjects were < 53 years old, had an FEV(1) of < 40% of predicted, did not have severe alpha(1)-antitrypsin deficiency, and had not undergone lung transplantation. The initial evaluation included a standardized respiratory questionnaire, spirometry, and a blood sample. A follow-up telephone interview was conducted between May and December 2002. MEASUREMENTS AND RESULTS: Subjects were young (mean age at enrollment, 47.9 years) and had severe airflow obstruction (mean baseline FEV(1), 19.4% predicted). A total of 72.7% of the subjects were women (p < 0.0001 [comparison to equal gender distribution]). The median estimated survival time was 7.0 years from the time of study enrollment, determined by the Kaplan-Meier method. The majority of deaths were due to cardiorespiratory illness. In a multivariable Cox proportional hazards model, adjusting for age, gender, and baseline FEV(1), lifetime cigarette consumption (hazard ratio [HR], 1.20 [per 10 pack-years]; 95% confidence interval [CI], 1.02 to 1.40) and recent smoking status (HR, 2.50; 95% CI, 1.03 to 6.05) were both significant predictors of mortality. CONCLUSION: In this cohort, recent smoking status predicted increased mortality independent of the effects of lifetime smoking intensity. Smoking cessation may confer a survival benefit even among patients with very severe COPD.

Age of Onset↗
PubMed2004

Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses.

Asthma treatment with inhaled steroids demonstrates significant between-person variability. Genetic variation could contribute to this response to inhaled glucocorticosteroids. Difficulties in performing genetic association studies are well known. We designed a test and validation strategy to assess steroid pathway candidate genes. One hundred thirty-one single nucleotide polymorphisms in 14 candidate genes in the steroid pathway were genotyped in an 8-week clinical trial of 470 adults with moderate to severe asthma. We then validated our findings in a second population of individuals with childhood asthma in a 4-year clinical trial of inhaled corticosteroids and a third population of adults with asthma. One gene, corticotrophin-releasing hormone receptor 1 (CRHR1, NM_004382), demonstrated multiple single nucleotide polymorphism associations within each of the three populations. The approach of a test and multiple replication populations is a valuable strategy in asthma pharmacogenetics, which can insure valid association findings.

Administration, Inhalation↗
PubMed2003

Lower bronchodilator responsiveness in Puerto Rican than in Mexican subjects with asthma.

In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. To determine whether ethnicity-specific differences in therapeutic response, clinical response, and/or genetic factors contribute to differences in asthma outcomes, we compared asthma-related clinical characteristics among 684 Mexican and Puerto Rican individuals with asthma recruited from San Francisco, New York City, Puerto Rico, and Mexico City. Puerto Ricans with asthma had reduced lung function, greater morbidity, and longer asthma duration than did Mexicans with asthma. Bronchodilator responsiveness, measured as percentage change from baseline FEV1, was significantly lower among Puerto Ricans with asthma than among Mexicans with asthma. Puerto Ricans with asthma had on average 7.3% (95% confidence interval [CI], 4.6 to 9.9; p < 0.001) lower bronchodilator reversibility in FEV1, higher risk of an emergency department visit in the previous year (odds ratio, 2.63; 95% CI, 1.6 to 4.3; p < 0.001), and of previous hospitalization for asthma (odds ratio, 1.94; 95% CI, 1.2 to 3.2; p = 0.009) than Mexicans. Subgroup analysis corroborated that Puerto Ricans with asthma had more severe disease than did Mexicans on the basis of lung function measurements, responsiveness to beta2-adrenergic agonists, and health care use. We conclude that Puerto Ricans with asthma respond less to albuterol than do Mexicans with asthma. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and response to therapy.

Asthma↗
PubMed2003

Using the noninformative families in family-based association tests: a powerful new testing strategy.

For genetic association studies with multiple phenotypes, we propose a new strategy for multiple testing with family-based association tests (FBATs). The strategy increases the power by both using all available family data and reducing the number of hypotheses tested while being robust against population admixture and stratification. By use of conditional power calculations, the approach screens all possible null hypotheses without biasing the nominal significance level, and it identifies the subset of phenotypes that has optimal power when tested for association by either univariate or multivariate FBATs. An application of our strategy to an asthma study shows the practical relevance of the proposed methodology. In simulation studies, we compare our testing strategy with standard methodology for family studies. Furthermore, the proposed principle of using all data without biasing the nominal significance in an analysis prior to the computation of the test statistic has broad and powerful applications in many areas of family-based association studies.

Analysis of Variance↗
PubMed2003

ADAM33 is not associated with asthma in Puerto Rican or Mexican populations.

A recent study identified the ADAM33 gene as a promising candidate contributing to asthma. In Puerto Rican and Mexican populations, we have genotyped six single nucleotide polymorphisms (SNPs) that were used in the Genetics of Asthma in Latino Americans Study. We chose to study these two populations because in the United States, Puerto Ricans have the highest asthma prevalence, morbidity, and mortality and Mexicans the lowest. We used the transmission disequilibrium test to analyze associations between the ADAM33 gene variants and asthma, asthma severity, bronchodilator responsiveness, and total IgE levels using single SNPs, two to six SNP combinations, and specific haplotypes in 583 trios (proband with asthma and both biological parents). We also genotyped matched control samples to allow case-control analyses. None of the transmission disequilibrium test or case-control results showed significant association in either population. We found no evidence for association of single SNPs with asthma severity, bronchodilator response, or IgE levels in Mexicans or in the combined population. Two SNPs showed a modest association in Puerto Ricans, insignificant when the number of comparisons was taken into account. We conclude that the ADAM33 gene is not an important risk factor for asthma or for asthma-associated phenotypes in Mexicans or in Puerto Ricans.

ADAM Proteins↗
PubMed2003

Apolipoprotein E genotype predicts 24-month bayley scales infant development score.

Apolipoprotein E (APOE) regulates cholesterol and fatty acid metabolism, and may mediate synaptogenesis during neurodevelopment. To our knowledge, the effects of APOE4 isoforms on infant development have not been studied. This study was nested within a cohort of mother-infant pairs living in and around Mexico City. A multiple linear regression model was constructed using the 24-mo Mental Development Index (MDI) of the Bayley Scale as the primary outcome and infant APOE genotype as the primary risk factor of interest. Regression models stratified on APOE genotype were constructed to explore effect modification. Of 311 subjects, 53 (17%) carried at least one copy of the APOE4 allele. Mean (SD) MDI scores among carriers with at least one copy of APOE4 were 94.1 (14.3) and among E3/E2 carriers were 91.2 (14.0). After adjustment for covariates, APOE4 carrier status was associated with a 4.4 point (95% confidence interval: 0.1-8.7; p = 0.04) higher 24-mo MDI. In the stratified regression models, the negative effects for umbilical cord blood lead level on 24-mo MDI score was approximately 4-fold greater among APOE3/APOE2 carriers than among APOE4 carriers. These results suggest that subjects with the E4 isoform of APOE may have advantages over those with the E2 or E3 isoforms with respect to early life neuronal/brain development.

Apolipoprotein E2↗
PubMed2003

Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes.

Chromosome 12q13-24 is among the regions most frequently identified in genome-wide surveys for asthma susceptibility loci, with reports of two distinct clusters of positive linkage signals: one near the interferon gamma locus, the other near the nitric oxide synthase 1 locus. These results suggest that 12q harbors several asthma susceptibility loci. We evaluated this possibility in a subset of families ascertained through the Childhood Asthma Management Program (CAMP) Genetics Ancillary Study. Fifty-five nuclear families with at least two asthmatic siblings (212 individuals) were genotyped using 32 microsatellite markers. Non-parametric linkage analysis was performed for the asthma phenotype (qualitative). Multipoint variance component-based linkage analysis was performed for five quantitative asthma-related traits: (i) percent predicted forced expiratory volume in one second (FEV(1)); (ii) dose of methacholine resulting in 20% fall in FEV(1) from baseline (PC(20)); (iii) post-bronchodilator percent change in FEV(1) (BDPR); (iv) serum eosinophil levels (EOS); and (v) total serum IgE levels (IgE). Three separate and distinct loci demonstrated evidence suggestive of linkage: asthma at 68 cM (exact P-value=0.05), airways responsiveness (PC(20)) at 147 cM (P=0.01), and indices of pulmonary function (FEV1, BDPR) at 134 cM (P=0.05 and P<0.01, respectively). No linkage was observed for the atopy-related phenotypes. We provide further evidence supporting the presence of an asthma susceptibility locus at the proximal end of chromosome 12q, as well as new evidence for additional loci more distally that account for unique features of the asthma phenotype. Fine mapping efforts for these loci are warranted.

Analysis of Variance↗
PubMed2003

Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with significant and increasing morbidity and mortality. The cardinal feature of COPD is persistent airflow obstruction, measured by reductions in quantitative spirometric indices including forced expiratory volume at one second (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FEV(1)/FVC). However, many patients have substantial improvement in spirometric measures with inhaled bronchodilator medications, and bronchodilator responsiveness (BDR) has been associated with disease severity and progression. To identify susceptibility loci for BDR phenotypes, we performed a 9 cM genome scan in 72 pedigrees (n=560 members) ascertained through probands with severe, early-onset COPD. Multipoint variance component linkage analysis was performed for quantitative phenotypes including BDR measures and post-bronchodilator FEV(1) and FEV(1)/FVC. Post-bronchodilator FEV(1) was linked to multiple regions, most significantly to markers on chromosome 8p (LOD=3.30) and 1q (LOD=2.24). Post-bronchodilator FEV(1)/FVC was also linked to multiple regions, most significantly to markers on chromosome 2q (LOD=4.42) and 1q (LOD=2.52). When compared with pre-bronchodilator spirometric indices, the post-bronchodilator values demonstrated increased evidence of linkage in multiple genomic regions. In particular, the LOD score for the 8p linkage to FEV(1) roughly doubled from 1.58 to 3.30. Candidate regions on chromosomes 4p (LOD=1.28), 4q (LOD=1.56), and 3q (LOD=1.50) gave the strongest evidence for linkage to BDR measures. Our results provide evidence for significant linkage to airflow obstruction susceptibility loci on chromosomes 2q and 8p, and further suggest that post-bronchodilator spirometric measures are optimal phenotypes for COPD genetic studies. This study has also identified several genomic regions that could contain loci regulating BDR in early-onset COPD families.

Bronchodilator Agents↗
PubMed2003

Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management program.

BACKGROUND: Beta2-adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies. OBJECTIVE: We sought to apply family-based association methods to individual single nucleotide polymorphisms (SNPs) and haplotypes of SNPs in B2AR to define the relationship of these genetic variants to asthma-related phenotypes. METHODS: DNA samples were obtained from 707 Childhood Asthma Management Program participants, representing 650 sibships, as well as their parents. Genotyping was performed at 8 B2AR SNPs. Qualitative asthma-related phenotypes were analyzed with single SNPs and haplotypes by using TRANSMIT; quantitative asthma-related phenotypes were analyzed with the Family-Based Association Test. RESULTS: Several SNPs, including SNP -654 and SNP +46, demonstrated significant associations (P <.05) to postbronchodilator FEV1 as both a qualitative (<80% of predicted value) and quantitative phenotype. Quantitative phenotypic association analysis demonstrated significant evidence for association of SNP +523 with bronchodilator responsiveness expressed as a percentage of baseline FEV1 (P =.012) or a percentage of predicted FEV1 (P =.008). Similar evidence for association between the +523 SNP and qualitative bronchodilator responsiveness phenotypes was also found. Analysis of haplotypes supported an association of B2AR variants with spirometric values and bronchodilator responsiveness. CONCLUSION: B2AR variants are associated with spirometric values and bronchodilator responsiveness, but different regions of the gene provide evidence for association with these phenotypes.

Alleles↗
PubMed2003

Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies.

TLR9 is a mammalian Toll-like receptor homologue that appears to function as an innate immune pattern recognition protein for motifs that are far more common in bacterial than in mammalian DNA. The gene was sequenced in 71 subjects from three self-identified U.S. ethnic groups to identify single-nucleotide polymorphisms (SNPs). A total of 20 SNPs were found of which only 20% were in the public dbSNP database. Four SNPs were relatively common in all three ethnic samples. Using these four SNPs, seven distinct haplotypes were statistically inferred, of which four accounted for 75% or more chromosomes. These four haplotypes could be distinguished from each other by the alleles of two SNPs (-1237 and 2848). Five exploratory nested case-control disease-association studies (asthma, DVT, MI, and COPD in European Americans and asthma in African Americans) were performed by genotyping DNA collected from four ongoing cohort studies. There was evidence suggesting increased risk for asthma with a C allele at -1237 (odds ratio 1.85, 95%CI 1.05 to 3.25) among European Americans (genotypes available from 67 cases and 152 controls). No other significant disease associations were detected. Replication of this finding in other, larger samples is needed. This study suggests that there is substantial diversity in human TLR9, possibly associated with asthma in Europeans but not African Americans. No association was detected with three other diseases potentially related to innate immunity.

Black People↗
PubMed2003

Genetics of chronic obstructive pulmonary disease.

Variability in the susceptibility to develop chronic obstructive pulmonary disease (COPD) is related to both genetic and environmental factors. COPD is likely a genetically complex disease, but severe alpha 1-antitrypsin (AAT) deficiency [e.g., protease inhibitor (PI) Z] remains the only proven genetic risk factor for COPD. Even among PI Z individuals, substantial variability in lung function is observed, suggesting that genetic modifiers may influence the expression of lung disease in severe AAT deficiency. The variable development of COPD in smokers without alpha 1-antitrypsin deficiency and the familial aggregation of lung function measurements also suggest the presence of genetic influences on lung function growth and decline leading to COPD. Many candidate gene loci have been investigated as potential COPD genetic determinants by case-control genetic association studies. However, inconsistent results of these association studies have been frequent. Genetic heterogeneity and population stratification are two potential reasons for the conflicting findings between association studies. Linkage analysis studies have recently been published that may identify regions of the genome that contain COPD susceptibility genes. Future investigations of genetic influences in COPD should consider the use of family-based designs for association studies and the study of positional candidate genes within regions of linkage.

Journal Article↗