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Biomedical subjects

Edwin K Silverman

Publications and source records attributed to Edwin K Silverman.

At least 37 records · Page 2Linked to original sources
PubMed2006

Progress in chronic obstructive pulmonary disease genetics.

Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, suggesting that genetic factors likely influence the variable development of chronic airflow obstruction in response to smoking. A variety of approaches have been used to identify novel COPD susceptibility genes, including association studies, linkage analysis, and rare variant analysis. Future directions for COPD research include genomewide association studies and animal model genetic studies.

Genetic Linkage↗
PubMed2005

The SERPINE2 gene is associated with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex human disease likely influenced by multiple genes, cigarette smoking, and gene-by-smoking interactions, but only severe alpha 1-antitrypsin deficiency is a proven genetic risk factor for COPD. Prior linkage analyses in the Boston Early-Onset COPD Study have demonstrated significant linkage to a key intermediate phenotype of COPD on chromosome 2q. We integrated results from murine lung development and human COPD gene-expression microarray studies with human COPD linkage results on chromosome 2q to prioritize candidate-gene selection, thus identifying SERPINE2 as a positional candidate susceptibility gene for COPD. Immunohistochemistry demonstrated expression of serpine2 protein in mouse and human adult lung tissue. In family-based association testing of 127 severe, early-onset COPD pedigrees from the Boston Early-Onset COPD Study, we observed significant association with COPD phenotypes and 18 single-nucleotide polymorphisms (SNPs) in the SERPINE2 gene. Association of five of these SNPs with COPD was replicated in a case-control analysis, with cases from the National Emphysema Treatment Trial and controls from the Normative Aging Study. Family-based and case-control haplotype analyses supported similar regions of association within the SERPINE2 gene. When significantly associated SNPs in these haplotypic regions were included as covariates in linkage models, LOD score attenuation was observed most markedly in a smokers-only linkage model (LOD 4.41, attenuated to 1.74). After the integration of murine and human microarray data to inform candidate-gene selection, we observed significant family-based association and independent replication of association in a case-control study, suggesting that SERPINE2 is a COPD-susceptibility gene and is likely influenced by gene-by-smoking interaction.

Amyloid beta-Protein Precursor↗
PubMed2005

T-bet polymorphisms are associated with asthma and airway hyperresponsiveness.

RATIONALE: T-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR. OBJECTIVES: To assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association. METHODS: Single nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels. MAIN RESULTS: We identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR. CONCLUSIONS: These data suggest that T-bet variation contributes to airway responsiveness in asthma.

Adolescent↗
PubMed2005

A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease.

We describe a novel variant in the terminal exon of human elastin, c.2318 G > A, resulting in an amino acid substitution of glycine 773 to aspartate (G773D) in a pedigree with severe early-onset chronic obstructive pulmonary disease (COPD). Transfection studies with elastin cDNAs demonstrate that the glycine to aspartate change compromises the ability of the mutant protein to undergo normal elastin assembly. Other functional consequences of this amino acid substitution include altered proteolytic susceptibility of the C-terminal region of elastin and reduced interaction of the exon 36 sequence with matrix receptors on cells. These results suggest that the G773D variant confers structural and functional consequences relevant to the pathogenesis of COPD.

Alternative Splicing↗
PubMed2005

Concordance of genotypes in pre- and post-lung transplantation DNA samples.

Genetic epidemiology studies of end-stage lung disease are potentially hindered by low numbers of participants due to early death of patients from the underlying disease, or due to exclusion from studies after patients have had lung transplants, because of concern about bias of genotype data due to chimerism. The number of participants enrolled in genetic studies of end-stage lung disease could be increased by including those individuals who have undergone lung transplant. We hypothesized that individuals who have had lung transplants can be included in genetic epidemiology studies that use single nucleotide polymorphism and short tandem repeat marker data, without confounding due to chimerism. Ten probands with severe, early-onset chronic obstructive pulmonary disease were included in this analysis. Pre- and post-lung transplant DNA samples were used in the investigation of concordance of genotype results for 12 short tandem repeat markers and 23 single nucleotide polymorphisms. Concordance was observed for all genotypes before and after lung transplant. We conclude that the risk of biasing genetic epidemiology studies due to donor lung-related DNA microchimerism is low, and that the inclusion of post-lung transplantation participants will allow for larger genetic epidemiology studies of individuals with end-stage lung disease.

DNA-Binding Proteins↗
PubMed2005

Extended haplotype in the tumor necrosis factor gene cluster is associated with asthma and asthma-related phenotypes.

RATIONALE: Tumor necrosis factor is a proinflammatory cytokine found in increased concentrations in asthmatic airways. The TNF-alpha (TNF) and lymphotoxin-alpha (LTA) genes belong to the TNF gene superfamily located within the human major histocompatibility complex on chromosome 6p in a region repeatedly linked to asthma. The TNF position -308 and LTA NcoI polymorphisms are believed to influence TNF transcription and secretion, respectively. OBJECTIVES: This study sought to determine whether polymorphisms in TNF or LTA, or in TNF-LTA haplotypes, are associated with asthma and asthma phenotypes. METHODS: We genotyped the TNF -308 and LTA NcoI polymorphisms, and two other haplotype-tagging polymorphisms in the TNF and LTA genes, in 708 children with mild to moderate asthma enrolled in the Childhood Asthma Management Program and in their parents. Using an extension of the family-based association tests in the PBAT program, each polymorphism was tested for association with asthma, age at onset of asthma, and time series data on baseline FEV(1) % predicted, postbronchodilator FEV(1) % predicted, body mass index, and log of PC(20). MEASUREMENTS AND MAIN RESULTS: Although no associations were found for the individual single-nucleotide polymorphisms, the haplotype analysis found the LTA NcoI_G/LTA 4371T/TNF -308G/TNF 1078G haplotype to be associated with asthma and with all five phenotype groups. CONCLUSIONS: We conclude that it is unlikely that the TNF -308 or LTA NcoI polymorphisms influence asthma susceptibility individually, but that this haplotype of variants may be functional or may be in linkage disequilibrium with other functional single-nucleotide polymorphisms.

Asthma↗
PubMed2005

Genomic screening and replication using the same data set in family-based association testing.

The Human Genome Project and its spin-offs are making it increasingly feasible to determine the genetic basis of complex traits using genome-wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome-wide family-based association studies, using single SNPs or haplotypes, can identify associations that achieve genome-wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease-susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease-susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype-tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome-wide significance, as population-based designs do.

Asthma↗
PubMed2005

CD14 tobacco gene-environment interaction modifies asthma severity and immunoglobulin E levels in Latinos with asthma.

BACKGROUND: A recent family-based genomewide screen revealed linkage between the 5q31 region and the diagnosis of asthma, but only in those exposed to environmental tobacco smoke (ETS). Among the candidate genes in this region is CD14. METHODS: To determine whether polymorphisms in the CD14 gene are related to this gene-by-environment interaction in Latinos, we used both family-based and cross-sectional cohort analysis to test for interactions between CD14 genotypes/haplotypes, exposure to ETS, and asthma-related phenotypes in 659 Mexican and Puerto Rican families. RESULTS: We identified 21 single nucleotide polymorphisms (SNPs) in the CD14 gene by sequencing 72 Puerto Ricans, Mexicans, and African Americans with asthma. Three SNPs, -810, -159, and +1437, were further genotyped in families with asthma. Among all subjects with asthma exposed to ETS, without regard to ethnicity, CD14 +1437 genotypes were associated with asthma severity. SNP +1437 GG or GC genotypes were significantly associated with lower baseline FEV1 using both family-based (p = 0.0009) and cross-sectional cohort (p = 0.03) analyses. Subjects with asthma with the GG or GC genotypes who were exposed to ETS had mean baseline FEV1 (% predicted) values 8.6% lower than subjects not exposed to ETS (p = 0.03). As previously observed in whites, we found an interaction between plasma IgE levels, SNP -159 genotypes, and ETS exposure (p = 0.0002). The lowest IgE levels were in those subjects with the TT genotype and who were exposed to ETS regardless of ethnicity. CONCLUSIONS: Our data suggest a gene-by-environment interaction between CD14 genotypes and ETS, which affects pulmonary function and IgE levels among Latinos with asthma.

Adolescent↗
PubMed2005

Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations.

Case-control studies have successfully identified many significant genetic associations for complex diseases, but lack of replication has been a criticism of case-control genetic association studies in general. We selected 12 candidate genes with reported associations to chronic obstructive pulmonary disease (COPD) and genotyped 29 polymorphisms in a family-based study and in a case-control study. In the Boston Early-Onset COPD Study families, significant associations with quantitative and/or qualitative COPD-related phenotypes were found for the tumor necrosis factor (TNF)-alpha -308G>A promoter polymorphism (P < 0.02), a coding variant in surfactant protein B (SFTPB Thr131Ile) (P = 0.03), and the (GT)(31) allele of the heme oxygenase (HMOX1) promoter short tandem repeat (P = 0.02). In the case-control study, the SFTPB Thr131Ile polymorphism was associated with COPD, but only in the presence of a gene-by-environment interaction term (P = 0.01 for both main effect and interaction). The 30-repeat, but not the 31-repeat, allele of HMOX1 was associated (P = 0.04). The TNF -308G>A polymorphism was not significant. In addition, the microsomal epoxide hydrolase "fast" allele (EPHX1 His139Arg) was significantly associated in the case-control study (P = 0.03). Although some evidence for replication was found for SFTPB and HMOX1, none of the previously published COPD genetic associations was convincingly replicated across both study designs.

Adult↗
PubMed2005

Association of defensin beta-1 gene polymorphisms with asthma.

BACKGROUND: Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness. OBJECTIVE: We characterized the genetic diversity in the defensin beta-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis. METHODS: To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses' Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program. RESULTS: Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5' genomic SNP (g.-1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma ( P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.-1816 T>C and IVS+692 G>A demonstrated significant transmission distortion ( P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (-1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted ( P = .04) and was more prominent in female subjects ( P = .007). CONCLUSION: Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.

Asthma↗
PubMed2004

Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma.

BACKGROUND: In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. Ethnic-specific differences in the response to drug treatment may contribute to differences in disease outcomes. Genetic variants at the beta(2)-adrenergic receptor (beta(2)AR) may modify asthma severity and albuterol responsiveness. We tested the association of beta(2)AR genotypes with asthma severity and bronchodilator response to albuterol in Puerto Ricans and Mexicans with asthma. METHODS: We used both family-based and cross-sectional tests of association with 8 beta(2)AR single nucleotide polymorphisms in 684 Puerto Rican and Mexican families. Regression analyses were used to determine the interaction between genotype, asthma severity, and bronchodilator drug responsiveness. RESULTS: Among Puerto Ricans with asthma, the arginine (Arg) 16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.00001-0.01). We found a strong interaction of baseline FEV(1) with the Arg16Glycine (Gly) polymorphism in predicting bronchodilator response. Among Puerto Ricans with asthma with baseline FEV(1) < 80% of predicted, but not in those with FEV(1) > 80%, there was a very strong association between the Arg16 genotype and greater bronchodilator responsiveness. No association was observed between Arg16Gly genotypes and drug responsiveness among Mexicans with asthma. CONCLUSIONS: Ethnic-specific pharmacogenetic differences exist between Arg16Gly genotypes, asthma severity, and bronchodilator response in Puerto Ricans and Mexicans with asthma. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and drug responsiveness.

Adolescent↗
PubMed2004

Genome-wide linkage of forced mid-expiratory flow in chronic obstructive pulmonary disease.

Familial aggregation of forced expiratory flow during the middle half of the FVC (FEF(25-75%)) and FEF(25-75%)/FVC has been observed in the Boston Early-Onset Chronic Obstructive Pulmonary Disease Study, but linkage results have not been reported for these phenotypes. An autosomal whole genome-wide linkage scan was performed in 72 pedigrees ascertained through a proband with severe, early-onset chronic obstructive pulmonary disease, and linkage analyses of FEF(25-75%) and FEF(25-75%)/FVC were performed using Sequential Oligogenic Linkage Analysis Routines. There was suggestive evidence for linkage of FEF(25-75%)/FVC with chromosome 2 (LOD 2.60 at 216 cM). In a smokers-only analysis, evidence for linkage was observed for postbronchodilator FEF(25-75%) with chromosome 12 (LOD 5.03 at 35 cM) and chromosomes 2 and 12 for FEF(25-75%)/FVC (LOD 4.12 at 221 cM and LOD 3.46 at 35 cM, respectively); in the smokers-only model, evidence for linkage also was robust for FEV(1)/FVC on chromosome 2 (LOD 4.13 at 229 cM) and FEV(1) on chromosome 12 (LOD 3.26 at 36 cM). Our analyses provide evidence for linkage of FEF(25-75%) and FEF(25-75%)/FVC on chromosomes 2q and 12p. LOD scores of greater than two were also observed for chromosomes 16, 20, and 22 with the smokers-only analysis, which may suggest gene-by-smoking interactions in these regions.

Adult↗
PubMed2004

The IL12B gene is associated with asthma.

The IL12B gene on chromosome 5q31-33 encodes the p40 subunit of interleukin 12, an immunomodulatory cytokine. To test the hypothesis that the IL12B gene contains polymorphisms associated with asthma, we genotyped six haplotype-tagging polymorphisms in the IL12B gene, both in 708 children enrolled in the Childhood Asthma Management Program (CAMP) and in their parents. Using the family-based association test (FBAT) program and its haplotype (HBAT) and phenotype (PBAT) options, we tested each polymorphism and haplotype for association with asthma and asthma-related phenotypes. We tested positive associations for replication in a case-control study comparing 177 adult moderate-to-severe asthmatics with 177 nonasthmatic controls. In whites in the CAMP cohort, the A allele of the IL12B G4237A polymorphism was undertransmitted to asthmatic children (P=.0008, recessive model), the global test for haplotypes for affection status was positive (P=.009, multiallelic chi (2)), and two polymorphisms were associated with different atopy phenotypes. In addition, we found a strong association between the IL12B_4237 and IL12B_6402 polymorphisms and an asthma-severity phenotype in whites, which we also found in the independent population of white adult asthmatics. IL12B may be an important asthma gene.

Adult↗
PubMed2004

A family-based association test for repeatedly measured quantitative traits adjusting for unknown environmental and/or polygenic effects.

We propose a family-based association test, FBAT-PC, for studies with quantitative traits that are measured repeatedly. The traits may be influenced by partially or completely unknown factors that may vary for each measurement. Using generalized principal component analysis, FBAT-PC amplifies the genetic effects of each measurement by constructing an overall phenotype with maximal heritability. Analytically, and in the simulation studies, we compare FBAT-PC with standard methodology and assess both the heritability of the overall phenotype and the power of FBAT-PC. Compared to univariate analysis, FBAT-PC achieves power gains of up to 200%. Applications of FBAT-PC to an osteoporosis study and to an asthma study show the practical relevance of FBAT-PC. FBAT-PC has been implemented in the software package PBAT and is freely available at http://www.biostat.harvard.edu/~clange/default.htm.

Journal Article↗
PubMed2004

Association of vitamin D receptor gene polymorphisms with childhood and adult asthma.

Vitamin D receptor (VDR) polymorphisms have been associated with several immune-related diseases, and VDR and vitamin D itself modulate T cell differentiation. VDR maps to chromosome 12q, near a region commonly linked to asthma. We evaluated VDR as part of a 12q positional candidate survey, and in response to observations of VDR polymorphism associations with asthma and atopy in a founder population of Quebec. Twenty-eight loci in 7 positional candidates (7 in VDR) were genotyped in 582 families. Whereas other candidates demonstrated no association, the VDR ApaI polymorphism demonstrated significant transmission distortion, with undertransmission of the C allele in a ratio of 4:5 (p = 0.01). This association was most prominent in girls, in whom distortion was more marked (p = 0.009). Sex-specific associations between multiple VDR polymorphisms and immunoglobulin E levels were also observed (p = 0.006-0.01). Asthma associations were replicated in a second cohort (517 females with asthma and 519 matched control subjects): 4 of 6 VDR variants demonstrated significant association (p = 0.02-0.04). The direction of association in this second cohort was opposite to the effects seen in the trios, but similar to findings in the Quebec study. These results suggest that VDR influences asthma and allergy susceptibility in a complex manner.

Asthma↗
PubMed2004

TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples.

TOLL-like receptor 10 (TLR10) is the most recently identified human homolog of the Drosophila TOLL protein. In humans, the TOLL-like receptors recognize pathogen-associated molecular patterns (PAMPs) as part of innate immune host defenses. Localized to chromosome 4p14, the specific ligands and functions of TLR10 are currently unknown, although it is expressed in lung and in B-lymphocytes. TLR10 is a potential asthma candidate gene because early life innate immune responses to ubiquitous inhaled allergens and PAMPs may influence asthma susceptibility. Resequencing in 47 subjects revealed a total of 78 single nucleotide polymorphisms (SNPS) (1 SNP per 106 bp) of which only 11 had been previously published. A significant association (p < or = 0.02) between two SNPs (c.+1031G>A, c.+2322A>G) and physician-diagnosed asthma was observed in a case control study (517 cases, 519 control subjects) of European American subjects nested within the Nurses' Health Study cohort. The association for these same two SNPs (p < or = 0.015) replicated in an independent family based cohort, where a measure of airway hyperresponsiveness (PC20) was also associated (p = 0.026 for c.+1031G>A). Consistent association in two independent samples and association with an intermediate phenotype provides strong support for TLR10 genetic variation contributing to asthma risk.

Black or African American↗
PubMed2004

The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD).

Although cigarette smoking is the primary environmental risk factor, genetic risk factors likely influence the development of chronic obstructive pulmonary disease (COPD). Linkage analysis between short-tandem repeat markers on chromosome 19 and COPD phenotypes was followed by association analysis of single nucleotide polymorphisms in a gene on chromosome 19q [transforming growth factor-beta1 (TGFB1)] and COPD phenotypes in a family-based sample and a case-control study (cases with severe COPD and control subjects with significant history of smoking but no COPD). Stratification by smoking status substantially improved the evidence of linkage to chromosome 19q for COPD phenotypes. Among former and current smokers in the Boston Early-Onset COPD Study, there was significant evidence of linkage between chromosome 19q and pre-bronchodilator (pre-BD) FEV(1) (LOD=3.30) and suggestive evidence of linkage between chromosome 19q and other COPD phenotypes. In these families, a SNP in the promoter region of TGFB1 (rs2241712) and two SNPs in the 3' genomic region of TGFB1 (rs2241718 and rs6957) were significantly associated with pre- and post-BD FEV(1) (P<0.05). Among smokers in the COPD cases and control subjects, two SNPs in the promoter region of TGFB1 (rs2241712 and rs1800469) and one SNP in exon 1 of TGFB1 (rs1982073) were significantly associated with COPD (P</=0.02 in all cases). Chromosome 19q likely contains a genetic locus (or loci) that influences COPD through an interaction with cigarette smoking. We hypothesize that genetic variants in or near the TGFB1 gene influence the pathogenesis of COPD among cigarette smokers.

Case-Control Studies↗