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Biomedical subjects

Ian A Yang

Publications and source records attributed to Ian A Yang.

10 recordsLinked to original sources
PubMed2007

Gene-environmental interaction in asthma.

PURPOSE OF REVIEW: Asthma is likely to result from the effects of environmental stimuli in genetically susceptible individuals. This review summarizes recent studies of gene-environmental interaction in the pathogenesis of asthma, focusing on study designs. RECENT FINDINGS: Studies using genetic epidemiology, in-vitro and ex-vivo models and in-vivo model organisms demonstrate that gene-environmental interaction in involved in the development of asthma. Genetic association studies show a reduced risk of asthma and atopy with early life exposure to farming environments and house dust endotoxin, and increased risk with environmental tobacco smoke. These associations are modified by CD14 genotype. In people with a specific genotype, high environmental exposure may have the opposite effect of low exposure, possibly explaining some of the inconsistencies in previous studies. In-vitro and ex-vivo cell culture experiments show gene-environmental interactions with Toll-like receptor agonists, viruses and tobacco smoke. Interactions between innate immunity genes and exposure to endotoxin and air pollution have been observed in in-vivo mouse models. SUMMARY: The expanding evidence for gene-environmental interaction in asthma indicates the importance of measuring environmental factors in genetic studies of asthma. Understanding gene-environmental interaction would facilitate risk prognostication, improve preventive strategies and develop targeted interventions in people with asthma.

Animals↗
PubMed2006

Association of asthma with a functional promoter polymorphism in the IL16 gene.

BACKGROUND: IL-16, a multifunctional cytokine with increased expression in the airways of asthmatic subjects, inhibits allergic airway inflammation in animal models. A T-->C single nucleotide polymorphism (SNP) at the -295 position in the promoter region of the IL16 gene has been described. OBJECTIVE: We sought to examine the functional significance of this promoter SNP and its relationship to asthma. METHODS: We examined the effect of the -295 SNP on promoter activity in cell-line (HBE4-E6/E7) transfection experiments. We investigated the association of the IL16 -295 genotype with asthma among 341 affected sib-pair white families and 184 unrelated nonasthmatic control subjects. We analyzed the association between the IL16 genotype and asthma using family-based association test and case-control analyses. RESULTS: In in vitro transfection experiments the T allele in the -295 position was associated with substantially reduced promoter activity compared with the C allele. In the family study the more common T allele at the -295 position was significantly associated with all asthma phenotypes (P = .002 to P = .015). In the case-control analysis asthmatic subjects were more likely than unrelated nonasthmatic control subjects to have the -295 TT genotype, but this did not reach statistical significance (odds ratio, 1.36; 95% CI, 0.92-2.02). CONCLUSIONS: The T allele at the -295 position in the IL16 promoter region is associated with reduced promoter activity relative to the C allele and with asthma in this white population. Further investigation is needed to delineate the mechanisms underlying these findings and the relationship of the IL16 -295 genotype to asthma in other populations.

Adolescent↗
PubMed2006

The role of Toll-like receptors and related receptors of the innate immune system in asthma.

PURPOSE OF REVIEW: The biology of the innate immunity receptors is of central importance in the host response to the environment. Identifying genetic variants that alter the innate immune response is highly relevant to understanding asthma pathogenesis. This review summarizes recent studies of the role of innate immunity receptors, including Toll-like receptors and CD14, in the pathogenesis of asthma. RECENT FINDINGS: The majority of studies published since 2004 have been genetic association studies in various clinical settings, which have found positive associations of single nucleotide polymorphisms in TLR2, TLR4, TLR6 and TLR10 with asthma or atopy, although the number of studies is small and the results not yet replicated. The designs for CD14 genetic studies have been more sophisticated and have included gene-environment interaction. The results of CD14 gene associations with asthma and atopy are suggestive but have not been fully replicated. Potential reasons for non-replication of TLR and CD14 association studies include insufficient power, type I error, population heterogeneity and different phenotypes studied. In addition, there may be differences in CD14 genetic effects between childhood and adulthood, and between levels of endotoxin exposure. SUMMARY: The evidence is still being accumulated for the role of Toll-like receptor polymorphisms in the pathogenesis of asthma. There is emerging evidence for the role of CD14 polymorphisms in the development of asthma and atopy. Further studies of innate immunity in asthma and allergy are required, using rigorous study design, measurement of environmental exposure and intermediate phenotypes to demonstrate single nucleotide polymorphism functionality.

Asthma↗
PubMed2006

Epigenetics of lung cancer.

Epigenetics is the study of heritable changes in gene expression that occur without changes in DNA sequence. It has a role in determining when and where a gene is expressed during development. Perhaps the most well known epigenetic mechanism is DNA methylation whereby cytosines at position 5 in CpG dinucleotides are methylated. Histone modification is another form of epigenetic control, which is quite complex and diverse. Histones and DNA make up the nucleosome which is the structural unit of chromatin which are involved in packaging DNA. Apart from the crucial role epigenetics plays in embryonic development, transcription, chromatin structure, X chromosome inactivation and genomic imprinting, its role in an increasing number of human diseases is more and more recognized. These diseases include cancer, and lung cancer in particular has been increasingly studied for the potential biological role of epigenetic changes with the promise of better and novel diagnostic and therapeutic tools.

DNA Methylation↗
PubMed2005

Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction.

Variation in the gene encoding toll-like receptor 4 (TLR4), a transmembrane receptor that mediates inflammatory responses to bacterial endotoxin, has been associated with susceptibility to atherosclerosis and its complications, such as myocardial infarction (MI), the pathogenesis of which involves inflammation. A recent study has also indicated that TLR4 gene variation influences the effect of statin treatment on reducing atherosclerosis complications. We studied the TLR4 gene Asp299Gly polymorphism in relation to susceptibility to myocardial infarction in a cohort of patients with angiographically documented coronary artery disease, and performed a meta-analysis using data sets from three independent studies. The meta-analysis showed that overall, odds ratio (OR) for MI was 0.73 [95% confidence interval (CI) 0.55-0.96, P=0.024] in 299Gly carriers compared to non-carriers, and there was no evidence of heterogeneity among the sample sets (P=0.679). In our patient cohort, a significant association of 299Gly bearing genotypes with lower susceptibility to myocardial infarction was observed only in patients receiving statin treatment, with 299Gly carriers having an OR of 0.49 (95% CI 0.27-0.78, P=0.015) for MI compared to non-carriers. These results are consistent with the notion that variation in the TLR4 gene contributes to inter-individual variability in susceptibility to coronary ischaemic events, and that TLR4 genotype and statin treatment may have a synergistic effect.

Aged↗
PubMed2005

Mucociliary clearance in patients with chronic asthma: effects of beta agonists.

OBJECTIVE: Chronic asthma is characterized by airway inflammation, mucus hypersecretion and impaired mucociliary clearance (MCC). We investigated baseline MCC and the acute effect of terbutaline in chronic asthmatics with sputum production while on long-term treatment with salmeterol in combination with inhaled corticosteroids (ICS). METHODOLOGY: MCC was measured at baseline and in response to 1 mg terbutaline (or placebo) on three visits over 80 min in 16 asthmatics (52+/-13 years of age). Subjects who had greater than 10% absolute increase in MCC above baseline and placebo, after terbutaline, were categorized in group A and subjects who had less than 10% in group B. RESULTS: In group A subjects (n=6), MCC increased from 23.7+/-4.0% at baseline to 43.7+/-4.9% with terbutaline (P<0.0001) and to 34.4+/-5.7% with placebo (P<0.01). In group B subjects (n=10), MCC remained similar: 11.3+/-3.2% at initial baseline, 12.0+/-3.2% with terbutaline and 7.3+/-3.0% with placebo (P>0.05). Group B subjects withdrew from all beta(2) agonists for a week and MCC was remeasured. After withdrawal, baseline MCC (7.0+/-1.8%) was similar to the initial baseline value (P>0.1) and MCC with terbutaline (15.8+/-4.9%) was greater than baseline (P<0.005) but remained abnormal in most subjects. Baseline percentage predicted FEV(1) and FEF(25--75%) were 77.3+/-7.2 and 41.7+/-5.6 in group A and 59.9+/-8.1 and 29.5+/-8.4 in group B subjects, respectively. CONCLUSION: MCC was impaired in most of these asthmatics with persistent airway obstruction and sputum production, despite regular treatment with ICS and salmeterol. In addition, there was little or no stimulation of MCC acutely after terbutaline in most of these asthmatics.

Administration, Inhalation↗
PubMed2005

Effectiveness of hospital-based smoking cessation.

STUDY OBJECTIVES: Smoking cessation for current smokers is a health-care imperative. It is not clear which approaches to smoking cessation are the most effective in the hospital setting and which factors predict long-term abstinence. We hypothesized that a hospital-based smoking cessation program involving behavioral modification and support would provide an effective intervention for smoking cessation. DESIGN: Prospective cohort study. SETTING: Smoking cessation clinics in a tertiary referral, cardiothoracic hospital. PATIENTS OR PARTICIPANTS: Two hundred forty-three smokers and 187 never-smoker control subjects. INTERVENTIONS: Smokers underwent specific sessions of individual counseling on behavioral modification, including written information, advice about quit aids, and support during the quit attempt. Abstinence was confirmed by exhaled carbon monoxide measurements. MEASUREMENTS AND RESULTS: Compared to never-smoker control subjects, smokers were more likely to have grown up with a smoking father or siblings, and to currently live or socialize with other smokers. Two hundred sixteen smokers attended at least two sessions of the smoking cessation program. Of these, 25% were unavailable for follow-up at 12 months and were assumed to be smoking. The point prevalence abstinence rate at 12 months was 32%. Independent factors associated with abstinence at 12 months were self-belief in quitting ability, having a heart condition, growing up without siblings who smoked, and increasing number of pack-years. CONCLUSIONS: This prospective study has demonstrated that this hospital-based smoking cessation program was as effective as programs in other settings. Social and psychological factors were associated with a greater chance of abstinence.

Adolescent↗
PubMed2004

Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function.

Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.

Adult↗
PubMed2003

TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis.

UNLABELLED: Inflammation and innate immunity may play a role in the pathogenesis of atherosclerosis. The Asp299Gly polymorphism in the toll-like receptor 4 (TLR4) gene reduces responsiveness to lipopolysaccharide and has been associated with reduced incidence and slower progression of carotid atherosclerosis. We analyzed this polymorphism in relation to susceptibility to and severity of coronary artery disease. METHODS: 1400 participants (mean age: 63 years, 31% female) in the Southampton Atherosclerosis Study were genotyped for the TLR4 Asp299Gly polymorphism using the tetra-primer PCR method. RESULTS: There was no significant difference between the frequencies of the Asp/Gly or Gly/Gly genotypes combined, compared to the Asp/Asp genotype, in patients with 0, 1, 2 or 3 coronary arteries with >50% stenosis (chi2(3 d.f.)2=0.4, P=0.94). No associations were observed between genotype groups and cardiac risk factors (P>0.05). CONCLUSION: The findings of this study do not support the hypothesis that the TLR4 Asp299Gly polymorphism influences predisposition to and progression of coronary artery disease.

Coronary Stenosis↗