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Benjamin A Raby

Publications and source records attributed to Benjamin A Raby.

At least 19 recordsLinked to original sources
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

Paternal history of asthma and airway responsiveness in children with asthma.

RATIONALE: Little is known regarding the relationship between parental history of asthma and subsequent airway hyperresponsiveness (AHR) in children with asthma. OBJECTIVES: We evaluated this relationship in 1,041 children with asthma participating in a randomized trial of antiinflammatory medications (the Childhood Asthma Management Program [CAMP]). METHODS: Methacholine challenge testing was performed before treatment randomization and once per year over an average of 4.5 years postrandomization. Cross-sectional and longitudinal repeated measures analyses were performed to model the relationship between PC20 (the methacholine concentration causing a 20% fall in FEV1) with maternal, paternal, and joint parental histories of asthma. Models were adjusted for potential confounders. MEASUREMENTS AND MAIN RESULTS: At baseline, AHR was strongly associated with a paternal history of asthma. Children with a paternal history of asthma demonstrated significantly greater AHR than those without such history (median log(e)PC20, 0.84 vs. 1.13; p = 0.006). Although maternal history of asthma was not associated with AHR, children with two parents with asthma had greater AHR than those with no parents with asthma (median log(e)PC20, 0.52 vs. 1.17; p = 0.0008). Longitudinal multivariate analysis of the relation between paternal history of asthma and AHR using repeated PC20 measurements over 44 months postrandomization confirmed a significant association between paternal history of asthma and AHR among children in CAMP. CONCLUSIONS: Our findings suggest that the genetic contribution of the father is associated with AHR, an important determinant of disease severity among children with asthma.

Adolescent↗
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

TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids.

TBX21 encodes for the transcription factor T-bet (T-box expressed in T cells), which influences naive T lymphocyte development and has been implicated in asthma pathogenesis. Specifically, the T-bet knockout mouse spontaneously develops airway hyperresponsiveness and other changes consistent with asthma. Because airway responsiveness is moderated by the use of inhaled corticosteroids in asthma, it is conceivable that genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion. Here we demonstrate that the nonsynonymous variation in TBX21 coding for replacement of histidine 33 with glutamine is associated with significant improvement in the PC(20) (a measure of airway responsiveness) of asthmatic children in a large clinical trial spanning 4 years. We note that this increase occurs only in the children randomized to inhaled corticosteroids and that it dramatically enhances the overall improvement in PC(20) associated with inhaled corticosteroid usage. The average PC(20) at trial end for subjects on inhaled corticosteroids possessing a variant allele was in the normal range for nonasthmatics. In cellular models, we show that the TBX21 variant increases T helper 1 and decreases T helper 2 cytokine expression comparably with wild type. TBX21 may thus be an important determinant pharmacogenetic response to the therapy of asthma with inhaled corticosteroids.

Administration, Inhalation↗
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↗
PubMed2004

Asthma genetics 2003.

The use of positional cloning for the identification of complex trait susceptibility genes has gained momentum with the completion of the human genome project. The approach involves the collection of well-phenotyped cohorts (either family-based or case-control designs), the generation of high-density single-nucleotide polymorphism linkage disequilibrium maps, and the application of powerful statistical methods to localize narrow regions of genetic association with disease. In 2003, two novel genes relating to asthma were identified using this approach, PHF11 and DPP10, neither of which had previously been implicated in the pathobiology of either asthma or allergy. In addition, further support for ADAM33 (the first asthma susceptibility gene identified by positional cloning) as an asthma gene was presented, although with mixed results. These discoveries open new avenues for research in asthma and allergy, and highlight the power (and limitations) of positional cloning for the identification of asthma genes, and complex trait genes in general.

ADAM Proteins↗
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

Endotoxin exposure and eczema in the first year of life.

OBJECTIVE: Exposure to endotoxin in early life has been proposed as a factor that may protect against the development of allergic diseases such as eczema. The objective of this study was to examine the relation between endotoxin exposure in early life and eczema in the first year of life in children with parental history of asthma or allergies. METHODS: This study used a prospective birth cohort study of 498 children who had a history of allergy or asthma in at least 1 parent and lived in metropolitan Boston. A subset of 401 living rooms had house dust samples adequate for analysis of endotoxin. RESULTS: In multivariate analyses adjusting for gender, income, and season of birth, endotoxin levels in the living room at 2 to 3 months of age was inversely associated with physician- or nurse-diagnosed eczema in the first year of life (odds ratio [OR] for each quartile increment: 0.76; 95% confidence interval [CI]: 0.61-0.96). Exposure to a dog in the home at age 2 to 3 months was also inversely associated with eczema in the first year of life, but the CI widened when endotoxin was included in the multivariate model (OR: 0.54; 95% CI: 0.27-1.09). Other variables associated with eczema in the first year of life included paternal history of eczema (OR: 1.91; 95% CI: 1.03-3.55) and maternal specific immunoglobulin E positivity to > or =1 allergen (OR: 1.61; 95% CI: 1.01-2.56). CONCLUSIONS: Among children with parental history of asthma or allergies, exposure to high levels of endotoxin in early life may be protective against eczema in the first year of life. In these children, paternal history of eczema and maternal sensitization to at least 1 allergen are associated with an increased risk of eczema in the first year of life.

Analysis of Variance↗
PubMed2004

Low-normal gestational age as a predictor of asthma at 6 years of age.

BACKGROUND: Perinatal factors, including gestational age and birth weight, influence the development of atopy in early life. However, the role of these factors in the development of asthma in later life among children who do not develop perinatal respiratory disease remains unclear. METHODS: Four hundred fifty-four infants who had a history of allergy or asthma in at least 1 parent, were born in the 36th week of gestation or later, and did not develop perinatal respiratory distress were monitored for at least 6 years. Associations between predictor variables and asthma and wheeze were assessed with multivariate logistic regression and repeated-event analyses. RESULTS: Although we previously observed a relationship between low birth weight and persistent wheeze in the first 1 year of life, we did not observe similar associations between low birth weight and asthma at 6 years of age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 0.40-2.73). However, a strong relationship was found between low-normal gestational age and asthma at 6 years of age (OR: 4.7; 95% CI: 2.1-10.5). The effects of low-normal gestational age were significantly greater among boys than among girls (boys: OR: 8.15; 95% CI: 2.98-22.3; girls: OR: 1.90; 95% CI: 0.38-13.83). Longitudinal analysis of the relationship between gestational age and wheeze during the 6 years of observation confirmed these gender differences. CONCLUSIONS: Among children at high risk of developing atopic disease, late prematurity might be an important additional determinant of asthma later in life, and these effects are gender specific.

Analysis of Variance↗
PubMed2003

Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma.

Transforming growth factor-beta1 (TGF-beta1) is increased in the lungs of individuals with asthma and may modulate airway inflammation and remodeling. Some genetic studies have found that a C-to-T single-nucleotide polymorphism (C-509T) in the TGF-beta1 gene promoter may be associated with altered gene expression and asthma phenotype. To build on these data, we performed a case-control association study at this locus involving 527 subjects with asthma and 170 control subjects without asthma. All individuals were white. Genotyping at 49 unlinked polymorphisms indicated that a subset of case subjects and all control subjects were well matched and without evidence of population stratification. Logistic regression was used to model the effects of age, sex, and genotype on case-control status. The diagnosis of asthma was positively associated with the T allele and TT genotype under a codominant model (odds ratio, 2.98; 95% confidence interval, 1.45 to 6.25; p = 0.003). Total serum IgE, eosinophil count, and FEV1% predicted levels were not associated with this polymorphism. Furthermore, we show that the C-509T polymorphism alters TGF-beta1 promoter-reporter activity and promoter interactions with the transcription factor Yin Yang 1. We conclude that the T allele of C-509T is associated with the diagnosis of asthma and may enhance TGF-beta1 gene transcription.

Adult↗
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

The molecular basis of glutamate formiminotransferase deficiency.

Glutamate formiminotransferase deficiency, an autosomal recessive disorder and the second most common inborn error of folate metabolism, is presumed to be due to defects in the bifunctional enzyme glutamate formiminotransferase-cyclodeaminase (FTCD). Features of a severe phenotype, first identified in patients of Japanese descent, include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematological abnormalities. We found mutations in the human FTCD gene in three patients with putative glutamate formiminotransferase deficiency. Two siblings were heterozygous for missense mutations, c.457C>T (R135C) and c.940G>C (R299P). Mutagenesis of porcine FTCD and expression in E. coli showed that the R135C mutation reduced formiminotransferase activity to 61% of wild-type, whereas the R299P mutation reduced this activity to 57% of wild-type. The third patient was hemizygous for c.1033insG, with quantitative PCR indicating that the other allele contained a deletion. These mutations are the first identified in glutamate formiminotransferase deficiency and demonstrate that mutations in FTCD represent the molecular basis for the mild phenotype of this disease.

Ammonia-Lyases↗
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↗