Loosening the cuff: important new advances in modeling antihypertensive treatment effects in genetic studies of hypertension.
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Blood Pressure↗
Biomedical subjects
Lyle J Palmer
Publications and source records attributed to Lyle J Palmer.
A whole-genome scan for obstructive sleep apnea and obesity.
Obstructive sleep apnea (OSA) is a common, chronic, complex disease associated with serious cardiovascular and neuropsychological sequelae and with substantial social and economic costs. Along with male gender, obesity is the most characteristic feature of OSA in adults. To identify susceptibility loci for OSA, we undertook a 9-cM genome scan in 66 white pedigrees (n=349 subjects) ascertained on the basis of either an affected individual with laboratory-confirmed OSA or a proband who was a neighborhood control individual. Multipoint variance-component linkage analysis was performed for the OSA-associated quantitative phenotypes apnea-hypopnea index (AHI) and body mass index (BMI). Candidate regions on chromosomes 1p (LOD score 1.39), 2p (LOD score 1.64), 12p (LOD score 1.43), and 19p (LOD score 1.40) gave the most evidence for linkage to AHI. BMI was also linked to multiple regions, most significantly to markers on chromosomes 2p (LOD score 3.08), 7p (LOD score 2.53), and 12p (LOD score 3.41). Extended modeling indicated that the evidence for linkage to AHI was effectively removed after adjustment for BMI, with the exception of the candidate regions on chromosomes 2p (adjusted LOD score 1.33) and 19p (adjusted LOD score 1.45). After adjustment for AHI, the primary linkages to BMI remained suggestive but were roughly halved. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity and that the interrelationship of OSA and obesity in white individuals may be partially explained by a common causal pathway involving one or more genes regulating both AHI and BMI levels.
Adult↗
DNA sequence variants in epithelium-specific ETS-2 and ETS-3 are not associated with asthma.
Epithelium-specific ETS-2 and ETS-3 are transcription factors that have been proposed as asthma candidate genes. To investigate the association of sequence variants in these genes with asthma, we conducted a case-control association analysis in a sample of 311 white subjects with asthma and 177 white subjects without asthma. Common polymorphisms in these genes were detected by sequencing DNA from 32 cell lines obtained from Coriel (Camden, NJ). Seven noncoding or synonymous single-nucleotide polymorphisms were detected: three in epithelium-specific ETS-2 and four in epithelium-specific ETS-3. Subjects were genotyped at all loci by mass spectroscopy. To ensure the suitability of our control subjects, we also genotyped subjects at 49 unlinked polymorphisms evenly distributed throughout the autosomes and found no evidence of population stratification. Logistic regression adjusted for age and sex suggested a weak association of one epithelium-specific ETS-2 polymorphism with asthma diagnosis (odds ratio = 1.89, 95% confidence interval = 1.13-3.18, p = 0.02). Total serum immunoglobulin E and FEV1 predicted levels were not associated with any of the polymorphisms. Extended haplotyping indicated linkage disequilibrium in these genes; however, no association or epistatic interaction was found. This study suggests that epithelium-specific ETS-2 and ETS-3 genes are unlikely to contain polymorphic loci that have a major impact on asthma susceptibility in our population.
Adolescent↗
Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes.
Toll-like receptor 4 (TLR4) is the principal receptor for bacterial endotoxin recognition, and functional variants in the gene confer endotoxin-hyporesponsiveness in humans. Furthermore, there is evidence that endotoxin exposure during early life is protective against the development of atopy and asthma, although this relationship remains poorly understood. It is therefore possible that genetic variation in the TLR4 locus contributes to asthma susceptibility. In this study we characterize the genetic diversity in the TLR4 locus and test for association between the common genetic variants and asthma-related phenotypes. In a cohort of 90 ethnically diverse subjects, we resequenced the TLR4 locus and identified a total of 29 single nucleotide polymorphisms. We assessed five common polymorphisms for evidence of association with asthma in two large family-based cohorts: a heterogeneous North American cohort (589 families), and a more homogenous population from northeastern Quebec, Canada (167 families). Using the transmission-disequilibrium test, we found no evidence of association for any of the polymorphisms tested, including two functional variants. Furthermore, we found no evidence for association between the TLR4 variants and four quantitative intermediate asthma- and atopy-related phenotypes. Based on these results, we found no evidence that genetic variation in TLR4 contributes to asthma susceptibility.
Asthma↗
Endothelial nitric oxide synthase variants in cystic fibrosis lung disease.
Variants in the genes encoding for the nitric oxide synthases may act as disease modifier loci in cystic fibrosis, affecting both an individual's nitric oxide level and pulmonary function. In this study, the 894G/T variant in exon 7 of the endothelial nitric oxide synthase gene was related to exhaled nitric oxide and pulmonary function in 70 cystic fibrosis patients who were aged 14.8 +/- 6.9 years (mean +/- SD), with a FEV1 of 69.4 +/- 24.8% predicted. Although there was no association between endothelial nitric oxide synthase genotypes and exhaled nitric oxide in males, nitric oxide levels were significantly higher in female cystic fibrosis patients with an 894T mutant allele, compared with female patients homozygous for the 894G wild-type allele (7.0 +/- 4.4 versus 3.6 +/- 1.9 parts per billion, p = 0.02). Furthermore, in female patients, colonization of airways with Pseudomonas aeruginosa was significantly (p < 0.05) less frequent when carrying an 894T mutant allele as compared with wild type. These data suggest that the 894T variant in the endothelial nitric oxide synthase gene is associated with increased airway nitric oxide formation in female cystic fibrosis patients, possibly affecting colonization of airways with P. aeruginosa.
Adolescent↗
Ascaris lumbricoides infection is associated with increased risk of childhood asthma and atopy in rural China.
There is growing international interest in the possible relationships between helminthic infection and allergic disease, although the nature of the relationships remains uncertain and controversial. The interrelationships of current and past infection with Ascaris lumbricoides and asthma and atopy were investigated in a cross-sectional sample of 2,164 children between the ages of 8 and 18 years from Anqing Province, China. The children were sampled from a larger family-based study of the genetics of asthma. The prevalence of either a history of or a positive stool examination for Ascaris was 24.5%. Asthma was defined for analytic purposes using previously validated, stringent criteria including airways responsiveness to methacholine. Independently of the other factors assessed, infection with A. lumbricoides was associated with increased risk of asthma (p < 0.001), an increased number of skin tests positive to aeroallergens (p < 0.001), and an increased dose-response slope to methacholine (p = 0.003). The association of sensitization to common aeroallergens with increased asthma risk was enhanced in those children infected with Ascaris, and such infection was associated with an increased risk of asthma independent of sensitization to aeroallergens in this selected population. These data suggest a complex relationship between ascariasis and susceptibility to childhood asthma among predisposed children that may involve an interaction with the immune response to inhaled aeroallergens.
Adolescent↗
Infants with flow limitation at 4 weeks: outcome at 6 and 11 years.
Within a longitudinal study of lung function in 243 infants, we identified a group of 23 individuals with flow limitation in tidal expiration. In infancy, flow-limited children have reduced lung function and increased airway responsiveness (AR), and at 2 years of age they are diagnosed with asthma more frequently. We hypothesized that these observations would persist throughout childhood. Data from ages 3 to 11 years were analyzed. Only at 4 years of age did the flow-limited group have increased wheeze compared with other cohort members (odds ratio, 4.25; 95% confidence interval [CI], 1.11 to 16.2; p = 0.04; n = 114). At 6 years of age, 117 cohort members were seen. The flow-limited group (n = 14) had greater AR (p = 0.009) and reduced mean FEV(1) (131 ml; 95% CI, 16 to 246; p = 0.03) and FEF(25-75) (0.28 L/second; 95% CI, 0.05 to 0.52; p = 0.02). At 11 years of age, 183 children were seen and the flow-limited group (n = 18) had greater AR (p = 0.02) and a trend toward reduced mean FEF(25-75) (0.24 L/second; 95% CI, -0.02 to 0.49; p = 0.08). Atopy and parental asthma were not increased in the flow-limited group. We suggest that the physiologic abnormality that causes flow limitation in early infancy may identify an at-risk group, different from asthma, who have reduced lung function and increased airway responsiveness in later life.
Child↗
Pharmacogenetics of asthma.
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Adrenergic beta-Agonists↗
Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV(1), FVC, and FEV(1)/FVC. In the initial genomewide scan, significant evidence for linkage to FEV(1)/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV(1)/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV(1) in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV(1) (LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV(1)/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.
Adult↗
Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes.
Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, but linkage analysis of COPD-related phenotypes has not been reported previously. An autosomal 10 cM genome-wide scan of short tandem repeat (STR) polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe alpha1-antitrypsin deficiency. Multipoint non-parametric linkage analysis (using the ALLEGRO program) was performed for qualitative phenotypes including moderate airflow obstruction [forced expiratory volume at one second (FEV(1)) < 60% predicted, FEV(1)/FVC < 90% predicted], mild airflow obstruction (FEV(1) < 80% predicted, FEV(1)/FVC < 90% predicted) and chronic bronchitis. The strongest evidence for linkage in all subjects was observed at chromosomes 12 (LOD = 1.70) and 19 (LOD = 1.54) for moderate airflow obstruction, chromosomes 8 (LOD = 1.36) and 19 (LOD = 1.09) for mild airflow obstruction and chromosomes 19 (LOD = 1.21) and 22 (LOD = 1.37) for chronic bronchitis. Restricting analysis to cigarette smokers only provided increased evidence for linkage of mild airflow obstruction and chronic bronchitis to several genomic regions; for mild airflow obstruction in smokers only, the maximum LOD was 1.64 at chromosome 19, whereas for chronic bronchitis in smokers only, the maximum LOD was 2.08 at chromosome 22. On chromosome 12p, 12 additional STR markers were genotyped, which provided additional support for an airflow obstruction locus in that region with a non-parametric multipoint approach for moderate airflow obstruction (LOD = 2.13) and mild airflow obstruction (LOD = 1.43). Using a dominant model with the STR markers on 12p, two point parametric linkage analysis of all subjects demonstrated a maximum LOD score of 2.09 for moderate airflow obstruction and 2.61 for mild airflow obstruction. In smokers only, the maximum two point LOD score for mild airflow obstruction was 3.14. These observations provide suggestive evidence that there is a locus on chromosome 12p which contributes to susceptibility to early-onset COPD.
Adult↗
Single-nucleotide polymorphisms in the interleukin-10 gene: differences in frequencies, linkage disequilibrium patterns, and haplotypes in three United States ethnic groups.
Interleukin-10 (IL-10) is a cytokine that seems to function as a downregulator of the innate (nonadaptive) immune system. Approximately three-quarters of interindividual variability in human IL-10 levels has been attributed to genetic variation, and there is evidence suggesting a potential role for IL-10 in a range of human diseases. To provide a basis for haplotype analysis and future disease association studies, we characterized genetic variation in IL10 by sequencing all exons, and 2.5 kb of the 5'- and the 3'-flanking region in a panel of DNA samples from 24 African Americans, 23 European Americans, and 24 Hispanic Americans. The region sequenced was found to contain 28 single-nucleotide polymorphisms (SNPs), 16 with frequency >2% and 14 with frequency >5%. All SNPs with frequency >5% were present in subjects from all three populations. No SNP caused amino acid changes. Differences in pairwise linkage-disequilibrium (LD) patterns and in SNP and haplotype frequency distributions among the three populations may be of potential importance for disease association studies.
Bayes Theorem↗
Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease.
Under selective pressure from infectious microorganisms, multicellular organisms have evolved immunological defense mechanisms, broadly categorized as innate or adaptive. Recent insights into the complex mechanisms of human innate immunity suggest that genetic variability in genes encoding its components may play a role in the development of asthma and related diseases. As part of a systematic assessment of genetic variability in innate immunity genes, we have thus far have examined 16 genes by resequencing 93 unrelated subjects from three ethnic samples (European American, African American and Hispanic American) and a sample of European American asthmatics. Approaches to discovering and understanding variation and the subsequent implementation of disease association studies are described and illustrated. Although highly conserved across a wide range of species, the innate immune genes we have sequenced demonstrate substantial interindividual variability predominantly in the form of single nucleotide polymorphisms (SNPs). Genetic variation in these genes may play a role in determining susceptibility to a range of common, chronic human diseases which have an inflammatory component. Differences in population history have produced distinctive patterns of SNP allele frequencies, linkage disequilibrium and haplotypes when ethnic groups are compared. These and other factors must be taken into account in the design and analysis of disease association studies.
Animals↗
Relation between tumour necrosis factor polymorphism TNFalpha-308 and risk of asthma.
Tumour necrosis factor (TNF) alpha affects immune response and airway inflammation, which are characteristics of asthma. Genetic factors may impact TNFalpha levels, and several polymorphisms in the TNF gene cluster on chromosome 6p21 have been associated with TNFalpha production and potential increased risk of asthma. The present paper evaluates the relation between two single nucleotide polymorphisms (SNPs) in the TNF gene cluster and asthma risk. The SNPs investigated here are guanine (G) to adenosine (A) substitutions in the TNFalpha and lymphotoxin alpha (LTalpha) genes. The TNFalpha SNP is at position -308 in the promoter region (TNFalpha-308), while the LTalpha SNP is in the first intron NcoI recognition sequence (LTalpha-NcoI). (For both SNPs the G allele is denoted as 1, and the A allele 2.) We determined TNFalpha-308 and LTalpha-NcoI genotypes in 511 individuals: 236 asthma cases and 275 non-asthmatic controls. Data were analysed by logistic regression of asthma status on the genotypes and potential confounders. TNFalpha-308*2 was positively associated with asthma, and this relation was strengthened when restricting cases to individuals reporting acute asthma: the adjusted odds ratio (OR) comparing carriers of one or two TNFalpha-308*2 alleles versus none was 1.86 (95% confidence interval (CI)=1.03-3.34, P=0.04). Further restricting the subjects to those with a family history of asthma, and those of European-American ancestry strengthened the association even more: adjusted OR=3.16 (95% CI=1.04-9.66; P=0.04). LTalpha-NcoI*1 was weakly associated with asthma, and analysis of both genes suggests that only the TNFalpha-308*2 allele increases risk of asthma.
Adult↗
Postdisaster emotional distress, depression and event-related variables: findings across child and adolescent developmental stages.
OBJECTIVE: Developmental approaches have not been widely used in child and adolescent posttraumatic stress disorder research, and little is known about developmental differences in response to postdisaster trauma. Our objective was to investigate postdisaster depression and emotional distress psychopathology across a broad child and adolescent developmental range. METHOD: Six months following a bushfire disaster, 2379 grade 4-12 school students -completed an extensive self-report battery, which included the Impact of Event Scale and the Birleson Depression Inventory. Generalized linear models were constructed to model the effects of multiple covariates on continuous outcome measures of depression and emotional distress. RESULTS: Significant independent predictors of persisting depressive symptoms were increased symptoms of emotional distress; increased symptoms of anxiety; evacuation experience; and school grade. Significant independent predictors of emotional distress were persisting depressive symptoms; perception of threat to self or to parents; evacuation experience; and school grade. Gender was not a significant predictor in either the depression or emotional distress multivariate models. Complex, non-linear relationships between depression, emotional distress and school grade were found. CONCLUSION: This study suggests that important developmental differences in postdisaster psychological responses exist across a broad spectrum of developmental stages in children.
Adolescent↗
1-hydroxypyrene as a biomarker of occupational exposure to polycyclic aromatic hydrocarbons (PAH) in boilermakers.
A repeated measures short-term prospective study was performed in boilermakers to determine occupational polycyclic aromatic hydrocarbon (PAH) exposure using the biomarker, 1-hydroxypyrene (1-OHP). Two work sites were studied; an apprentice school (metal fume exposure) and a boiler overhaul (residual oil fly ash [ROFA] and metal fume exposure). Pre- and postshift urine samples (n = 241; 41 male subjects) were analyzed for cotinine and 1-OHP. Descriptive statistics and generalized estimating equations were calculated. At the apprentice school cross-shift 1-OHP levels did not significantly differ. At the overhaul 1-OHP levels increased during the week in smokers and nonsmokers; in nonsmokers the 1-OHP level increased significantly postshift compared to preshift. In conclusion this study suggests that boilermakers exposed to occupational particulates are exposed to PAH. The urinary 1-OHP level may be a useful biomarker of PAH exposure in boilermakers exposed to ROFA, particularly in nonsmokers.
Adult↗
Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung.
Family studies of asthma suggest that the genes ESE-2 and ESE-3 contain polymorphisms that contribute to disease susceptibility. Each gene codes for an ETS transcription factor that is characterized by epithelium-restricted constitutive expression and may function as a context-dependent activator or repressor of transcription; however, nothing is known about the role of these genes in lung homeostasis or the pathogenesis of airway disease. In this study, we show that ESE-3 mRNA and protein are constitutively expressed in bronchial and mucous gland epithelial cells. Consistent with these findings, ESE-3 mRNA is constitutively expressed in human bronchial epithelial cells grown in tissue culture. In contrast, ESE-2 mRNA could not be detected in the lung or cultured human bronchial epithelial cells. Human bronchial smooth muscle cells and fibroblasts do not constitutively express ESE-3; however, after stimulation with interleukin-1beta or tumor necrosis factor-alpha, levels of ESE-3 mRNA and protein increase dramatically by 24 h. This cytokine induction is dose-dependent and abrogated by specific inhibitors of the MEK1/2 (U0126) and p38 (SB03580) signal transduction pathways. Overexpression of ESE-3 protein in 3T3 cells and human bronchial smooth muscle cells inhibits MMP-1 promoter activity, suggesting that ESE-3 may function as a transcriptional repressor.
3T3 Cells↗
Parametric linkage analysis.
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ABO Blood-Group System↗