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Biomedical subjects

Andrew J Sandford

Publications and source records attributed to Andrew J Sandford.

At least 19 recordsLinked to original sources
PubMed2006

Transforming growth factor-beta1 polymorphisms, airway responsiveness and lung function decline in smokers.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation in the airways, parenchyma and vessels, which can cause a structural remodeling with increased fibrosis that narrows and fixes the airway lumen. Transforming growth factor-beta1 (TGF-beta1), a multifunctional growth factor, was reported to be increased in the airways of COPD patients. In this study, we hypothesized that polymorphisms in the TGF-beta1 gene would be associated with an accelerated rate of decline of forced expiratory volume in 1s (FEV(1)). Three polymorphisms, -509 (C-->T), +869 (T-->C) and +915 (G-->C), located in TGF-beta1 gene were genotyped. We determined the prevalence of these polymorphisms in 590 continuing smokers who had the fastest (n=283) and slowest (n=307) rate of decline of lung function from the NHLBI Lung Health Study. There was no association between these TGF-beta1 polymorphisms and the rate of decline of FEV(1), but in a post-hoc analysis the genotype distribution at +869 was significantly different between high and low responders to methacholine (P=0.04). These data suggest that the T-C polymorphism at position +869 in the TGF-beta1 gene contributes to airway hyperresponsiveness, but not to rapid decline of lung function.

Bronchoconstrictor Agents↗
PubMed2006

Association of Hck genetic polymorphisms with gene expression and COPD.

Polymorphonuclear leukocytes (PMNs) are major effector cells in the chronic airway inflammation in chronic obstructive pulmonary disease (COPD). PMN degranulation is associated with degradation of extracellular matrix and tissue damage. Hck is an essential molecule in the signaling pathway regulating PMN degranulation. We hypothesized that polymorphisms affect the expression level of Hck, which, in turn, modulates PMN mediator release and tissue damage and influences the development of COPD. Here we systematically investigated genetic tag polymorphisms of the Hck gene, Hck mRNA and protein expression pattern in PMNs, and PMN mediator release (myeloperoxidase) in 60 healthy white subjects, and assessed their association with the use of several genetic models. The association of genetic polymorphisms with COPD-related phenotypes was determined in the lung healthy study cohort (LHS). We identified a novel 15 bp insertion/deletion polymorphism (8,656 L/S) in intron 1 of the Hck gene, which was associated with differential expression of Hck protein and PMN myeloperoxidase release. In the LHS cohort, there was significant interaction between the 8,656 L/S polymorphism and smoking on baseline lung function and 8,656 L/S was associated with bronchodilator response. These data suggest that the insertion/deletion polymorphism could be a functional polymorphism of the Hck gene, may contribute to COPD pathogenesis and modify COPD-related phenotypes.

Adult↗
PubMed2006

Contribution of alpha- and beta-defensins to lung function decline and infection in smokers: an association study.

BACKGROUND: Alpha-defensins, which are major constituents of neutrophil azurophilic granules, and beta-defensins, which are expressed in airway epithelial cells, could contribute to the pathogenesis of chronic obstructive pulmonary disease by amplifying cigarette smoke-induced and infection-induced inflammatory reactions leading to lung injury. In Japanese and Chinese populations, two different beta-defensin-1 polymorphisms have been associated with chronic obstructive pulmonary disease phenotypes. We conducted population-based association studies to test whether alpha-defensin and beta-defensin polymorphisms influenced smokers' susceptibility to lung function decline and susceptibility to lower respiratory infection in two groups of white participants in the Lung Health Study (275 = fast decline in lung function and 304 = no decline in lung function). METHODS: Subjects were genotyped for the alpha-defensin-1/alpha-defensin-3 copy number polymorphism and four beta-defensin-1 polymorphisms (G-20A, C-44G, G-52A and Val38Ile). RESULTS: There were no associations between individual polymorphisms or imputed haplotypes and rate of decline in lung function or susceptibility to infection. CONCLUSION: These findings suggest that, in a white population, the defensin polymorphisms tested may not be of importance in determining who develops abnormally rapid lung function decline or is susceptible to developing lower respiratory infections.

Adult↗
PubMed2006

Variants in the glutamate-cysteine-ligase gene are associated with cystic fibrosis lung disease.

BACKGROUND: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury. OBJECTIVES: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease. METHODS: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype. MEASUREMENTS AND MAIN RESULTS: A total of 440 subjects with CF participated in the study (51% male; mean [+/- SD] age, 26 +/- 11 yr; mean FEV(1), 62 +/- 28% predicted). In the total population, there was a trend toward an association between GCLC genotypes and CF lung disease (linear regression coefficient [SEM], 1.68 [1.0]; p = 0.097). In the stratified analysis, there was a highly significant association between GCLC genotype and CF lung function in subjects with a milder CFTR genotype (linear regression coefficient [SEM], 5.5 (1.7); p = 0.001). CONCLUSIONS: In patients with CF with a milder CFTR genotype, there is a strong association between functional polymorphisms of the GCLC gene and CF lung disease severity.

Adolescent↗
PubMed2006

Interferon gamma polymorphisms and their interaction with smoking are associated with lung function.

Interactions between genetic and environmental determinants are likely to be important in the pathogenesis of chronic obstructive pulmonary disease. We hypothesized that interferon gamma (IFNG) single nucleotide polymorphisms (SNPs) and their interaction with smoking are associated with the rate of decline or level of lung function in smokers. We studied four SNPs in IFNG in 585 non-Hispanic whites (NHW) who had the fastest (n =280) or the slowest (n=305) decline of FEV(1)% predicted selected from among continuous smokers followed for 5 years in the NHLBI Lung Health Study. We also studied 1061 NHW with the lowest (n=530) or the highest (n=531) baseline lung function at the beginning of the LHS. Two SNPs were associated with baseline levels of lung function and the p values were 0.008 for +2197T/C in a dominant model and 0.002 for +5171A/G in a recessive model. However, after adjusting for confounding factors, only +5171A/G was still significant (p=0.001 for the recessive model). In addition, there was a significant genotype and smoking interaction with p=0.006 for the +5171A/G (GG vs.GA + AA) for the baseline lung function. When comparing individuals with GG versus individuals with AG + AA for low lung function, the adjusted odds ratios decreased significantly as pack-years increased. No association was found in the rate of decline study. There was an association between IFNG genotype and baseline of lung function and this association was modified by cigarette smoking.

Case-Control Studies↗
PubMed2005

Genetic modifiers of lung disease in cystic fibrosis.

BACKGROUND: Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis. METHODS: We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the DeltaF508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease (263 patients) or mild disease (545). In the replication (second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGFbeta1 codon 10 CC genotype with low FEV1. RESULTS: In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1), particularly the -509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGFbeta1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status (P=0.0002) and FEV1 values directly (P=0.02). CONCLUSIONS: Genetic variation in the 5' end of TGFbeta1 or a nearby upstream region modifies disease severity in cystic fibrosis.

Adolescent↗
PubMed2005

Lack of association of human leukocyte antigen-B7 with COPD and rate of decline in lung function.

BACKGROUND: Although variation in the human leukocyte antigen (HLA) locus is associated with various diseases, there have been a limited number of studies that have examined the possible role of HLA in chronic obstructive pulmonary disease (COPD). Only HLA-B7 has been shown to be correlated with low forced expiratory volume in 1s (FEV1) in Caucasians; however, this finding has not been replicated. The aim of this study was to investigate the contribution of the HLA-B7 allele to COPD and to rate of decline of lung function. METHODS: We determined the prevalence of HLA-B7 in a group of COPD patients and a non-obstructed control group of smokers by using a polymerase chain reaction-based genotyping assay. We also determined the prevalence of HLA-B7 in smokers selected from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest and slowest decline of lung function. RESULTS: No significant difference was found in the frequency of HLA-B7 between the COPD and non-obstructed groups. There was also no significant association of HLA-B7 with rate of decline of lung function. CONCLUSION: These data indicate that HLA-B7 does not contribute to COPD or rate of decline of FEV1 in smokers.

Aged↗
PubMed2005

Selection of reference genes for gene expression studies in human neutrophils by real-time PCR.

BACKGROUND: Reference genes, which are often referred to housekeeping genes, are frequently used to normalize mRNA levels between different samples. However the expression level of these genes may vary among tissues or cells, and may change under certain circumstances. Thus the selection of reference gene(s) is critical for gene expression studies. For this purpose, 10 commonly used housekeeping genes were investigated in isolated human neutrophils. RESULTS: Initial screening of the expression pattern demonstrated that 3 of the 10 genes were expressed at very low levels in neutrophils and were excluded from further analysis. The range of expression stability of the other 7 genes was (from most stable to least stable): GNB2L1 (Guanine nucleotide binding protein, beta polypeptide 2-like 1), HPRT1 (Hypoxanthine phosphoribosyl transferase 1), RPL32 (ribosomal protein L32), ACTB (beta-actin), B2M (beta-2-microglobulin), GAPD (glyceraldehyde-3-phosphate dehydrogenase) and TBP (TATA-binding protein). Relative expression levels of the genes (from high to low) were: B2M, ACTB, GAPD, RPL32, GNB2L1, TBP, and HPRT1. CONCLUSION: Our data suggest that GNB2L1, HPRT1, RPL32, ACTB, and B2M may be suitable reference genes in gene expression studies of neutrophils.

Actins↗
PubMed2004

Glutathione S-transferase variants and their interaction with smoking on lung function.

We studied glutathione S-transferase (GST) polymorphisms in 1,098 whites with the lowest (n = 544, FEV(1) % predicted mean +/- SEM = 62.6 +/- 0.1) and the highest (n = 554, FEV(1) % predicted mean +/- SEM = 91.8 +/- 0.1) lung function at the beginning of the Lung Health Study. Homozygosity for GSTP1 105Val was significantly more frequent in the low- than in the high-function group (13.2 vs. 9.3%) (odds ratio = 1.69, 95% confidence interval [CI] = 1.11-2.61, p = 0.016), after adjustment for confounding variables. Subjects with 105Val homozygotes had higher rates of lung function decline in the high-function group (p = 0.017). The frequencies of GSTM1, GSTT1 null genotypes were similar between the high- and low-function groups, but subjects with the GSTT1 null genotype had a faster decline of lung function in the low-function group (p = 0.032). In addition, there was a significant interaction of GSTT1 genotype and pack-years on lung function. When comparing individuals with GSTT1 null genotype with wild type, the adjusted odds ratio was 3.49 (95% CI, 1.48-8.39, p = 0.005) in mild smokers (< or = 25 pack years). We conclude that GST genotypes are risk factors for rapid decline or low lung function in smokers with mild to moderate airflow obstruction.

Acyltransferases↗
PubMed2004

Reconcilable differences: a cross-sectional study of the relationship between socioeconomic status and the magnitude of short-acting beta-agonist use in asthma.

STUDY OBJECTIVE: To assess the association between socioeconomic status (SES) and short-acting (SA) beta-agonist use, controlling for asthma severity. DESIGN: Cross-sectional study. SETTING: Vancouver, BC, Canada. PARTICIPANTS: Two hundred two asthmatics between 19 years and 50 years of age and residing in the greater Vancouver regional district. MEASUREMENTS: The quantity of SA beta-agonist used in the previous year was collected by self-report; pulmonary function and beta-receptor genotype were measured on each participant. SES was measured at both the individual and population levels. Five methods of adjustment for asthma severity were used, as follows: the Canadian Asthma Consensus Guidelines, three previously developed asthma-severity scores, and forward stepwise multiple regression modeling. Polychotomous logistic regression was used to assess all relationships. RESULTS: Independent of the method used to measure SES or adjust for asthma severity, lower SES was consistently and significantly associated with the use of greater amounts of SA beta-agonist. Adjusting for severity using the multivariate model explained the most variance of SA beta-agonist use (R(2) adjusted, 0.35 to 0.37). In this model, social assistance recipients were more likely to use greater amounts of SA beta-agonist (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.7 to 6.5). An inverse relationship between SA beta-agonist use and both annual household income (> $50,000; OR, 0.28; 95% CI, 0.13 to 0.60; and $20,000 to $50,000; OR, 0.44; 95% CI, 0.21 to 0.96; relative to <$20,000) and education (completing a bachelor's degree vs no formal education; OR, 0.25; 95% CI, 0.14 to 0.71). Participants living in a neighborhood with higher median household income (OR, 0.91; 95% CI, 0.84 to 0.98 per $1,000 increase) or a higher prevalence of having attained a bachelor's degree (OR, 0.96; 95% CI, 0.84 to 0.98 per 1% increase) were also less likely use greater amounts of SA beta-agonist. Results were consistent for neighborhood unemployment rate. CONCLUSIONS: The social gradient in asthma-related outcomes may be at least partially attributable to poorer asthma control in lower-SES asthmatics.

Adrenergic beta-Agonists↗
PubMed2004

Therapeutic response to asthma medications: genotype predictors.

Asthma is a major social and economic burden. Studies have shown that genetic polymorphisms can influence drug efficacy and/or toxicity. The understanding of the pharmacogenetics of asthma will allow therapeutic regimens to be tailored on an individual basis. It is hoped that linkage and association studies will define new therapeutic targets for asthma but until then, studies have focused on improving response to beta(2)-adrenoceptor agonist and leukotriene modifier therapy. Genetic polymorphism may account for interindividual differences in toxicity and efficacy of asthma medications. To date, single nucleotide polymorphism and limited haplotype analysis have provided inconclusive evidence as to how genotype predictors can be used to optimize current asthma therapies based on each patient's genetic profile.

Adrenergic beta-Agonists↗
PubMed2003

Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease.

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) genotype does not explain the heterogeneity observed in CF pulmonary disease severity. Modifier genes are implicated for this heterogeneity. alpha1-antitrypsin (alpha1-AT) is one of the few antiproteases capable of inactivating neutrophil elastase. We investigated whether alpha1-AT alleles (Z, S deficiency alleles and the 3' G1237-->A mutation) were associated with increased disease severity and the alpha1-AT acute phase response during pulmonary exacerbations. This was a multicenter Canadian study. Seven hundred sixteen patients with CF (age range, 5.0-63.6 yr) were genotyped for the Z, S, and G1237-->A polymorphisms of the alpha1-AT gene. Stable and acute levels of alpha1-AT were measured on 31 adult patients with CF and were correlated to clinical parameters. There were 69, 13, and 18 patients with CF who were MS, SS, and MZ, respectively. There were 95 and 7 patients with CF heterozygous or homozygous for the A1237 allele, respectively. alpha1-AT genotype did not predict pulmonary disease severity, and was not associated with more severe clinical outcome (death or lung transplantation) or age of onset of Pseudomonas aeruginosa infection. Body mass index was a significant predictor of alpha1-AT levels during exacerbations. alpha1-AT genotype is not a major contributor to the variability of pulmonary disease severity in CF.

Acute-Phase Reaction↗
PubMed2003

Polymorphisms in the IL13, IL13RA1, and IL4RA genes and rate of decline in lung function in smokers.

Targeted expression of interleukin (IL)-13 in the adult murine lung has been shown to cause emphysema. We hypothesized that variants in the IL13, IL13RA1, and IL4RA genes would be associated with an accelerated rate of decline of lung function among smokers. We determined the allele frequencies of five polymorphisms in the IL13, IL13RA1, and IL4RA genes in 588 continuing smokers chosen from the NHLBI Lung Health Study for having the fastest (n = 282) and slowest (n = 306) 5-yr rate of decline of lung function (mean change in FEV(1) %predicted/yr = -4.1 and +1.1, respectively). The IL4RA 551RR genotype was associated with rapid decline of lung function (odds ratio, 2.24; P = 0.043). However, none of the other four polymorphisms was associated with rate of decline in lung function. The association of 551RR with rapid decline of lung function became more significant in subjects who also had either the IL13 130RR or -1112TT genotypes. However, because multiple comparisons were made and only a few individuals had the 551RR genotype, these associations may represent type 1 error. Haplotypes consisting of alleles from the IL13 polymorphisms or from the IL4RA polymorphisms were not associated with rate of decline in lung function in smokers.

Adult↗
PubMed2002

Antioxidant gene polymorphisms and susceptibility to a rapid decline in lung function in smokers.

Oxidative stress is believed to play an important role in the pathogenesis of smoking-induced chronic obstructive pulmonary disease. We hypothesized that polymorphisms of antioxidant genes glutathione S-transferase M1 (GSTM1), GSTT1, GSTP1, and heme oxygenase-1 (HMOX1) would be associated with susceptibility to accelerated decline of lung function in smokers. We genotyped 621 subjects (299 rapid decliners [change in forced expiratory volume in 1 second (DeltaFEV(1)) = -152 +/- 2.5 ml/year] and 322 nondecliners [DeltaFEV(1) = +15 +/- 1.5 ml/year]) selected from among smokers followed for 5 years in the National Heart, Lung, and Blood Institute Lung Health Study. Because genotype frequencies were different between ethnic groups, we limited the association study to 594 whites (286 rapid decliners and 308 nondecliners). None of the genotypes studied had a statistically significant effect on decline of lung function when analyzed separately. There was an association between rapid decline of lung function and presence of all three GST polymorphisms (odds ratio [OR] = 2.83; p = 0.03). A combination of a family history of chronic obstructive pulmonary disease with GSTP1 105Ile/Ile genotype was also associated with rapid decline of lung function (OR = 2.20; p = 0.01). However, due to the multiple comparisons that were made, these associations may represent type 1 error. There was no association between HMOX1 (GT)n alleles and the rate of decline in lung function in smokers.

Adult↗
PubMed2002

The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function.

The matrix metalloproteinases (MMPs) comprise a family of at least 20 proteolytic enzymes that play an essential role in tissue remodeling. MMP1 (interstitial collagenase), MMP9 (gelatinase B) and MMP12 (macrophage elastase) are thought to be important in the development of emphysema. A number of naturally occurring polymorphisms of human MMP gene promoters have been identified and found to alter transcriptional activity. Additionally, we detected a novel polymorphism in the MMP12 coding region (Asn357Ser). The aim of this study was to investigate the role of MMP polymorphisms in the development of chronic obstructive lung disease. We determined the prevalence of these polymorphisms in 590 continuing smokers chosen from the National Heart Lung and Blood Institute, Lung Health Study for having the fastest (n = 284) and slowest (n = 306) 5 year rate of decline of lung function. Of the five polymorphisms, only G-1607GG was associated with a rate of decline in lung function. The -1607GG allele was associated with a fast rate of decline (P = 0.02) [corrected]. However, haplotypes consisting of alleles from the MMP1 G-1607GG and MMP12 Asn357Ser polymorphisms were associated with rate of decline of lung function (P = 0.0007). These data suggest that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms.

Base Sequence↗
PubMed2002

Genetic risk factors of chronic obstructive pulmonary disease.

Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, only a minority of cigarette smokers develop symptomatic disease. Family and twin studies suggest that genetic factors also contribute to the development of COPD. We present a detailed literature review of the genes which have been investigated as potential risk factors for this disease.

Cystic Fibrosis Transmembrane Conductance Regulato↗