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L J Palmer

Publications and source records attributed to L J Palmer.

At least 19 recordsLinked to original sources
PubMed2001

Body mass index and asthma in adults in families of subjects with asthma in Anqing, China.

We conducted a cross-sectional study of 7,109 adults from families of subjects with asthma in the province of Anhui, China. Asthma was defined either as a combination of physician-diagnosed asthma, airway responsiveness to methacholine at < or = 25 mg/ml and two or more respiratory symptoms or asthma attacks ("asthma"); or as a combination of airway responsiveness to methacholine at < or = 8 mg/ml and two or more respiratory symptoms or asthma attacks ("symptomatic airway hyperresponsiveness [AHR]"). After adjusting for intensity of cigarette smoking and other variables, both extremes of the body mass index (BMI) distribution were associated with symptomatic AHR in men and women (p < 0.01). In the multivariate analysis, both under- and overweight were associated with asthma in women, and underweight was associated with asthma in men. Among men, those with BMIs of 16 and 30 kg/m(2) had 2.5 and 2.3 times higher odds of symptomatic AHR, respectively, than those whose BMI was 21 kg/m(2) (95% CI for OR(16 vs. 21 kg/m)(2) = 1.4 to 3.8; 95% CI for OR(30) (vs.) (21) (kg/m)(2) = 1.2 to 5.0). Among women, those with BMIs of 16 and 30 kg/m(2) had 2.0 and 2.3 times higher odds of symptomatic AHR than those whose BMI was 21 kg/m(2) (95% CI for OR(16) (vs.) (21) (kg/m)(2) = 1.3 to 3.1; 95% CI(30) (vs.) (21) (kg/m)(2) = 1.2 to 4.5). Among adults in families of subjects with asthma living in rural China, both underweight and overweight are associated with an increased risk of asthma.

Adult↗
PubMed2001

Genomewide scans of complex human diseases: true linkage is hard to find.

Many "complex" human diseases, which involve multiple genetic and environmental determinants, have increased in incidence during the past 2 decades. During the same time period, considerable effort and expense have been expended in whole-genome screens aimed at detection of genetic loci contributing to the susceptibility to complex human diseases. However, the success of positional cloning attempts based on whole-genome screens has been limited, and many of the fundamental questions relating to the genetic epidemiology of complex human disease remain unanswered. Both to review the success of the positional cloning paradigm as applied to complex human disease and to investigate the characteristics of the whole-genome scans undertaken to date, we created a database of 101 studies of complex human disease, which were found by a systematic Medline search (current as of December 2000). We compared these studies, concerning 31 different human complex diseases, with regard to design, methods, and results. The "significance" categorizations proposed by Lander and Kruglyak were used as criteria for the "success" of a study. Most (66.3% [n=67]) of the studies did not show "significant" linkage when the criteria of Lander and Kruglyak (1995) were used, and the results of studies of the same disease were often inconsistent. Our analyses suggest that no single study design consistently produces more-significant results. Multivariate analysis suggests that the only factors independently associated with increased study success are (a) an increase in the number of individuals studied and (b) study of a sample drawn from only one ethnic group. Positional cloning based on whole-genome screens in complex human disease has proved more difficult than originally had been envisioned; detection of linkage and positional cloning of specific disease-susceptibility loci remains elusive.

Asthma↗
PubMed2001

Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma.

Asthma is the most common chronic childhood disease in the developed nations, and is a complex disease that has high social and economic costs. Studies of the genetic etiology of asthma offer a way of improving our understanding of its pathogenesis, with the goal of improving preventive strategies, diagnostic tools, and therapies. Considerable effort and expense have been expended in attempts to detect specific polymorphisms in genetic loci contributing to asthma susceptibility. Concomitantly, the technology for detecting single nucleotide polymorphisms (SNPs) has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a method of investigating the genetic etiology of complex human diseases. This paper reviews both current and potential future contributions of SNPs to our understanding of asthma pathophysiology.

Animals↗
PubMed2001

Pooling data and linkage analysis in the chromosome 5q candidate region for asthma.

We investigated a variety of methods for pooling data from eight data sets (n = 5,424 subjects) to validate evidence for linkage of markers in the cytokine cluster on chromosome 5q31-33 to asthma and asthma-associated phenotypes. Chromosome 5 markers were integrated into current genetic linkage and physical maps, and a consensus map was constructed to facilitate effective data pooling. To provide more informative phenotypes with better distributional properties, variance component models were fitted using Gibbs sampling methods in order to generate residual additive genetic effects, or sigma-squared-A-random-effects (SSARs), which were used as derived phenotypes in subsequent linkage analyses. Multipoint estimates of alleles shared identically by descent (IBD) were computed for all full sibling pairs. Linkage analyses were performed with a new Haseman-Elston method that uses generalized-least-squares and a weighted combination of the mean-corrected trait-sum squared and trait-difference squared as the dependent variable. Analyses were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by several meta-analytic methods. Our results provide no significant evidence that loci conferring susceptibility to asthma affection or atopy, as measured by total serum IgE levels, are present in the 5q31-33 region. This study has provided a clearer understanding of the significance, or lack of significance, of the 5q31-33 region in asthma genetics for the phenotypes studied.

Adult↗
PubMed2001

Improved evidence for linkage on 6p and 5p with retrospective pooling of data from three asthma genome screens.

To improve our ability to identify genes for complex diseases, evaluation of new methods that retrospectively pool genotype and phenotype data collected by multiple centers is important. Availability of three whole-genome screens enabled us to compare two methods, pooling raw data and meta-analysis. Multipoint linkage analyses were performed on two outcomes, total serum IgE levels and asthma affection status, using an improved Haseman-Elston algorithm. Two regions showed stronger evidence for linkage using covariate-adjusted pooled data, compared with any individual sample. Both methods for pooling data identified strong linkage to Z-transformed logeIgE levels at a location between D6S1019 and D6S426, and to the asthma trait at D5S268. In conclusion, retrospective analysis of pooled genome scan data is a potentially powerful and useful method to examine both positive and negative evidence for linkage of quantitative and categorical phenotypes across populations.

Adult↗
PubMed2001

Segregation analysis of asthma and respiratory allergy in population-based samples of families.

Class A regressive multiple logistic segregation models with a sibling covariate were used to investigate the underlying determinants of asthma and respiratory allergy (defined from specific IgE levels to inhaled allergens) in the randomly recruited Caucasian families from the Genetic Analysis Workshop 12 asthma data sets--Perth, Busselton, and Southampton. For asthma, both a purely multifactorial model and a major gene (dominant or recessive) model with multifactorial effects fitted the data. For respiratory allergy, a dominant, dominant with multifactorial effects and a purely multifactorial model all fitted the data. However, homogeneity of the three studies was rejected for both traits indicating that the three populations are significantly different and should be analyzed separately. This finding has implications for the meta-analysis of asthma linkage studies.

Adult↗
PubMed2001

Combining multiple phenotypic traits optimally for detecting linkage with sib-pair observations.

A number of investigators have proposed regression methods for testing linkage between a phenotypic trait and a genetic marker with sib-pair observations. Xu et al. [Am J Hum Genet 67:1025-8, 2000] studied a unified method for testing linkage, which tends to be more powerful than existing procedures. Often there are multiple traits, which are linked to a common set of genetic markers. In this paper, we present a simple generalization of the unified test to combine information from multiple traits optimally. We use the simulated Genetic Analysis Workshop 12 data to illustrate this methodology and show the advantage of using the combined tests over the single-trait tests. For the four quantitative traits (Q1,...,Q4) studied, our linkage results suggest that major loci affecting Q1 and Q2 localize at or near markers D02G172, D19G032, and D09G122, while loci affecting Q3 and Q4 localize at or near markers D09G122 and D17G051.

Adult↗
PubMed2001

Genome-wide linkage analysis in a general population sample using sigma 2A random effects (SSARs) fitted by Gibbs sampling.

We used variance components analysis to investigate the underlying determinants of the quantitative phenotypes (Q1-Q5) and their interrelationships in replicate 42 of the Genetic Analysis Workshop 12 simulated general population. Variance components models were fitted using Gibbs sampling in WinBUGS v1.3. Sigma-squared-A-random-effects (SSARs) were estimated for each phenotype, and were used as derived phenotypes in subsequent linkage analyses. Whole-genome, multipoint linkage analyses were based upon a new Haseman-Elston identity-by descent sib-pair method that takes a weighted combination of the trait-sum and trait-difference. The five quantitative traits simulated were closely correlated with each other and with affection status. The whole-genome screen of quantitative traits associated with the simulated complex disease suggested that one or more major loci regulating Q1 localizes to chromosome 2p and that one or more major loci regulating Q5 may localize to chromosome 1p.

Algorithms↗
PubMed2001

Single region linkage analyses of asthma: description of data sets.

Linkage (genotypic) data from the 5q31-33 candidate region for asthma were contributed to Genetic Analysis Workshop 12 by members of the International Consortium on Asthma Genetics (COAG). Data came from five independent studies sampled from five countries. Genotypic data for a total of 26 markers were available, although the number of markers typed in each data set varied. Phenotypic and genotypic data was available from a total of 569 families and 3,175 subjects. The phenotypic data available varied among the studies; however information regarding physician-diagnosed asthma and total serum IgE levels was available in all five studies. This paper describes the ascertainment, data collection methods, phenotypic data, and genotypic data available for the single linkage region analyses undertaken for Genetic Analysis Workshop 12.

Adolescent↗
PubMed2001

Gibbs sampling-based segregation analysis of asthma-associated quantitative traits in a population-based sample of nuclear families.

Asthma is a common, complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, and increased airway responsiveness are physiological traits that are characteristic of asthma. Few studies have investigated major gene effects for these traits in a population-based sample. Further, it is not known if any putative major genes may be common to two or more of these traits. We investigated the existence and nature of major genes modulating asthma-associated quantitative traits in an Australian population-based sample of 210 Caucasian nuclear families. The sharing of these major genes was also investigated. Segregation analysis was based upon a Markov Chain Monte Carlo (Gibbs sampling) approach as implemented in the program BUGS v0.6. All models included adjustment for age, height, tobacco smoke exposure, and gender. The segregation of total IgE levels, blood eosinophil counts, and dose-response slope (DRS) of methacholine challenge were all consistent with major loci at which a recessive allele acted to increase or decrease the phenotype. The respective estimated frequencies of the recessive alleles were 68% (total IgE), 10% (blood eosinophil count), and 27% (DRS). Extensive modelling suggested that the major loci controlling total serum IgE levels, blood eosinophil counts, and airway responsiveness represent different genes. These data provide evidence, for the first time, of the existence of at least 3 distinct genetic pathways involving major gene effects on physiological traits closely associated with asthma. These results have implications for gene discovery programs.

Adolescent↗
PubMed2001

Polymorphisms in the angiotensinogen gene are associated with carotid intimal-medial thickening in females from a community-based population.

BACKGROUND: Polymorphisms within genes of the renin-angiotensin system have been associated with an increased risk of cardiovascular disease. We investigated the association of polymorphisms in the angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1) genes with increased intima-media thickness (IMT) and the presence of plaques in carotid arteries. METHODS: Subjects (1111) from the Perth Carotid Ultrasound Disease Assessment Study (CUDAS) were genotyped for three polymorphisms: two in the promoter of the AGT gene, G-6A and A-20C; and one in the AGTR1 gene, A1166C. RESULTS: Using multivariate generalised linear models, the AGT-6A allele (P<0.001) and the AGT-20C allele (P<0.03) were significantly associated with increased mean carotid IMT in females but not in males when adjusted for conventional risk factors. The AGTR1 A1166C polymorphism did not show any significant relationship to mean IMT. Results suggest that the I allele of the angiotensin converting enzyme insertion/deletion polymorphism may interact with the AGT-6G allele to increase mean carotid IMT in the population as a whole. None of the polymorphisms investigated were significantly associated with the presence of carotid plaques. CONCLUSION: This study shows that polymorphisms in the angiotensinogen gene are associated with an increased risk of carotid intimal-medial wall thickening in females.

Adult↗
PubMed2001

The immune anti-tumor effects of GM-CSF and B7-1 gene transfection are enhanced by surgical debulking of tumor.

Malignant mesothelioma (MM) is a solid tumor largely unresponsive to conventional therapies. Immunological gene therapy shows promise in murine models and human clinical trials; however, the role of surgery in combination with gene therapy has not been widely studied. The aim of this study was to determine if debulking surgery improved the effectiveness of gene therapy in a murine MM model. Mice were subcutaneously inoculated with the MM cell line, AC29, at two different sites, 4 days apart, to allow a surgical and distal site tumor to develop. Once tumors were established, the surgical site tumor was debulked and vaccination of syngeneic tumor transfectants encoding genes for IL-4, IL-2, GM-CSF, B7-1 or allogeneic MHC molecules commenced at a site away from both tumors, and tumor growth was measured. Neither debulking surgery nor gene therapy alone delayed tumor growth. However, there was a clear delay of tumor growth when debulking surgery was combined with vaccination of tumor transfectants expressing B7-1 or high levels of GM-CSF. Combinations of these two transfectants did not lead to a synergistic effect. This study demonstrates that debulking surgery can augment the immunostimulatory effects of immunological gene therapy and can delay tumor growth. This has implications for the future design of human gene therapy trials for solid tumors such as MM.

Animals↗
PubMed2001

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

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

Female↗
PubMed2001

Airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age.

Asthma is the most common chronic childhood disease in developed nations. Little is known about the relationship between airway responsiveness in infancy and the development of asthma later in life. The relationship of airway responsiveness at 1 mo with asthma, atopy, lower respiratory symptoms, and lung function at 6 yr of age was investigated prospectively in 95 white children from a randomly ascertained birth cohort. Baseline spirometry, airway responsiveness to histamine, and skin reactivity to common allergens were assessed at the age of 1 mo and 6 yr. Total serum immunoglobulin E (IgE) was measured from cord blood and at 6 yr. Blood eosinophil counts were measured at 6 yr only. Family, symptom, and exposure histories at both time points were derived from questionnaire data. Independently of the other factors assessed, increased airway responsiveness at 1 mo was significantly associated with the following parameters measured at six yr: decreased FEV(1) (p < 0.001); decreased FVC (p < 0.001); physician-diagnosed asthma (p < 0.001); and lower respiratory tract symptoms (p < 0.05). None of the other physiologic factors measured in infancy showed such consistent associations with important clinical and physiologic outcomes at age 6. These data suggest that airway responsiveness in early life defines a functional state that is associated with abnormal airway function, lower respiratory symptoms, and the emergence of asthma by 6 yr of age.

Age Factors↗
PubMed2001

Asthma, rhinitis, and skin test reactivity to aeroallergens in families of asthmatic subjects in Anqing, China.

In industrialized countries with a Western lifestyle, sensitization to perennial aeroallergens is strongly associated with asthma, whereas sensitization to seasonal aeroallergens is closely related to allergic rhinitis. Little is known, however, about the relation between skin test reactivity to aeroallergens and either asthma or rhinitis in mainland China. We studied 10,009 members of 2,544 families in Anqing (China) that were selected on the basis of physician-diagnosed asthma in at least two siblings. Generalized estimating equations were employed to study the association between skin test reactivity to aeroallergens and either asthma or rhinitis. After adjustment for age, sex, intensity of smoking, skin test reactivity to other aeroallergens, and household correlations, sensitization to dust mite was an independent predictor of both asthma (OR = 1.3, 95% CI = 1.1 to 1.5, p = 0.008) and rhinitis (OR = 1.3, 95% CI = 1.0 to 1.8, p = 0.04). Sensitization to mold was significantly associated with asthma (OR = 1.6, 95% CI = 1.1 to 2.3, p = 0.008), and sensitization to silk was an independent predictor of rhinitis (OR = 1.5, 95% CI = 1.1 to 2.2, p = 0.02). Although 46.9% of the study participants were sensitized to at least one allergen, only 3.5% of study subjects reported nasal symptoms consistent with rhinitis. Among asthmatic subjects, 6.2% reported nasal symptoms. Whereas sensitization to perennial aeroallergens was associated with asthma among families of asthmatic subjects in rural China, sensitization to silk was the strongest predictor of rhinitis in this population. Our findings also suggest that allergic rhinitis is far less common among asthmatic subjects in rural China than in asthmatic subjects in industrialized countries with a Western lifestyle.

Adolescent↗
PubMed2001

Familial aggregation and heritability of adult lung function: results from the Busselton Health Study.

Decreased spirometric indices are characteristic of asthma and other respiratory diseases. The aim of this study was to investigate the genetic and environmental components of variance of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured in adulthood in an Australian population-based sample of 468 Caucasian nuclear families. The inter-relationships of the genetic determinants of these traits with asthma and atopic rhinitis were also investigated. Serial cross-sectional studies were conducted in the town of Busselton in Western Australia between 1966 and 1981 and follow-up of previous attendees was undertaken in 1995. Data from each subject included in this study were from a single survey in adulthood (25-60 yrs of age) when the subject was as close to age 45 yrs as possible. Multivariate analysis suggested that FEV1 and FVC levels were associated with age, sex, height, tobacco smoke exposure, asthma and atopic rhinitis. After adjustment for relevant covariates, FEV1 levels had a narrow-sense heritability (h2N) of 38.9% (SE 9.1%). FVC levels had an h2N of 40.6% (SE 8.9%). Extended modelling demonstrated little overlap in the genetic determinants of asthma or atopic rhinitis and either FEV1 or FVC levels. The results of this study were consistent with the existence of important genetic determinants of adult lung function that are independent of asthma or other atopic disease, cigarette smoking, height, age or sex.

Adult↗
PubMed2001

Sensitization to silk and childhood asthma in rural China.

OBJECTIVE: Sensitization to perennial aeroallergens is associated with asthma in industrialized countries with a Western lifestyle. Because silk products are commonly used in Chinese society, we were interested in examining the relation between sensitization to silk and asthma. DESIGN: Cross-sectional study of 871 children in 503 families living in Anqing, a predominantly rural province of China. RESULTS: After adjustment for age, gender, familial correlations, and sensitization to other aeroallergens, skin test reactivity to silk was an independent predictor of asthma (odds ratio = 2.6; 95% confidence interval = 1.2-5.7). This association became stronger after inclusion of the eosinophil count and history of parasitic diseases of the participants in the multivariate model (odds ratio = 3.6; 95% confidence interval = 1.4-8.9). CONCLUSION: Because sericulture is an important activity in China and other countries throughout the world, sensitization to silk may influence the pathogenesis and severity of asthma in people living in these nations.

Allergens↗