PubMed Health⌕ Search

Biomedical subjects

R C Strange

Publications and source records attributed to R C Strange.

At least 19 recordsLinked to original sources
PubMed2006

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Asian People↗
PubMed2006

Asthma severity and atopy: how clear is the relationship?

BACKGROUND: The relationship between asthma severity and atopy is complex. Many studies have failed to show significant relationships between clinical severity or lung function and markers of atopic sensitisation. AIM: To determine whether increasing asthma severity is related to atopic sensitisation in a population of children with asthma. METHODS: A total of 400 children (7-18 years) with asthma were recruited as part of a multicentre study of the genetics of asthma. Detailed phenotypic data were collected on all participants. Associations between measures of asthma severity and atopic sensitisation were sought using multilevel models allowing variation at the individual and family level. RESULTS: Children recruited to the study had a range of asthma severities, with just over a third having mild persistent asthma. The logarithm of total serum IgE was associated with increased asthma severity score, decreased FEV1, increased airways obstruction, risk of hospital admission, and inhaled steroid use. Increasing skin prick test reactivity to a panel of seven aeroallergens was associated with increased risk of hospital admission, use of an inhaled steroid, and airways obstruction. The results remained highly significant after corrections for age, gender, and birth order. CONCLUSIONS: In children with asthma, increasing atopy is associated with increasing asthma severity. However, the relationships between asthma severity and skin prick tests, and asthma severity and total serum IgE values, appear subtly different.

Adolescent↗
PubMed2006

Genetics and risk factors for basal cell carcinoma.

Nonmelanoma skin cancer (NMSC) is the commonest cancer in whites and its incidence is increasing worldwide. The prevalence of this cancer is predicted to equal that of all others combined and it was estimated that there were over 2 million cases diagnosed in the U.S.A. in 2004. Patients exhibit marked differences in clinical phenotype with variations in tumour numbers, rate of tumour accrual, site and histological subtype. Furthermore, patients are at increased risk of other cutaneous and noncutaneous cancers. The factors accounting for this variation are complex and still not completely understood. Clearly, ultraviolet light (UV) exposure is a major influence but its relationship to clinical phenotype is not yet clear. In addition, immunosuppression is a significant risk factor. Our group has identified high-risk groups for the development of further basal cell carcinoma (BCC), namely patients with truncal BCC and those presenting with tumour clusters. This presentation will concentrate on these clinical subgroups as well as immunosuppressed patients. These groups represent significant management challenges and are areas where novel, nonsurgical treatment options may make a significant clinical impact in patient care. The risk factors predisposing to these clinical phenotypes will be discussed, including genetic factors and UV exposure. Potential clinical applications, including predictive indices, will be considered.

Basal Cell Carcinoma↗
PubMed2005

Glutathione S-transferase T1 polymorphisms are associated with outcome in colorectal cancer.

Colorectal cancer (CRC) remains a significant cause of mortality accounting for approximately 10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22-2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (<70 versus > or =70 years at diagnosis), in the patients diagnosed <70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31-0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12-3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.

Aged↗
PubMed2005

Regional variation of airway hyperresponsiveness in children with asthma.

Families with asthmatic children were recruited to take part in a multi-centre collaborative study into the genetics of asthma. Detailed phenotypic information was collected on all family members including: lung function, anthropomorphic measurements, response to methacholine challenge, skin prick testing, serum IgE measurements and a detailed nurse-administered questionnaire. Families were eligible for entry into the study if they had two children with a doctor-diagnosis of asthma. Bennett/Twin nebulisers were supplied to each centre from a single source and these were calibrated to determine gravimetric nebuliser output prior to use. Asthmatic probands from each centre had similar degrees of asthma severity and atopy. There was no significant difference in the sex ratios or ages of the probands or numbers of parents with a history of smoking in the families recruited at each centre. However, there was a significant difference in the number of children with airway hyperresponsiveness, with 90% of the North Staffordshire group but only 60% of the Sheffield group having a PC20 of <8 mg/ml for methacholine. This difference highlights the difficulty of using families from different centres in genetic and epidemiological studies.

Asthma↗
PubMed2005

Effects of glutathione S-transferase M1, T1 and P1 on lung function in asthmatic families.

RATIONALE: Previous data have suggested that glutathione-S-transferase (GST) genotypes are important in determining the rate of lung function growth in childhood. This effect was most marked in Caucasian children with asthma. OBJECTIVES: We investigated the association of lung function with GSTM1, GSTP1 and GSTT1 genotypes in Caucasian families with asthma. METHODS: Four hundred and eighteen children and 316 parents from 224 Caucasian families were recruited via a child with asthma, the proband. Associations between lung function and GST genotype were determined using multilevel models. RESULTS: There were no observed associations between lung function and GST genotype in parents. However, in the children, the GSTP1 val(105)/val(105) and GSTM1 null genotypes were associated with significantly higher forced expiratory volume in 1 s (FEV(1)) and FVC values as percentage of predicted. This effect was not statistically significant in the probands but was marked in their siblings in whom GSTP1 val(105)/val(105) was associated with 9.4% higher FEV(1) and 10.7% higher FVC (P=0.005 and 0.001, respectively). The GSTM1 null genotype was associated with a 6.7% higher FEV(1) and 4.1% higher FVC (P=0.003 and 0.063, respectively). These effects remained significant after correcting for the confounders of individual atopic status, tobacco smoke exposure and familial aggregation of lung function values. CONCLUSIONS: GSTM1 and GSTP1 genotypes are important determinants of lung function in childhood. The smaller differences seen in probands are predicted by a simple model in which more rapid decline in lung function is seen in these individuals.

Adolescent↗
PubMed2005

Basal cell carcinoma: from host response and polymorphic variants to tumour suppressor genes.

The molecular factors and events that characterize susceptibility and outcome in cutaneous basal cell carcinoma (BCC) have been the focus of much research interest. As a result, we are beginning to understand the complex relationships between exposure to ultraviolet radiation (UVR), host response and the resulting damage to key genes that characterize these tumours. In this review, we will focus on genetic factors that influence susceptibility and outcome. While the search for susceptibility genes has generally resulted in the identification of low penetrance allelic variants, studies on modifier genes influencing outcome variables such as tumour number, age of onset and tumour subtype have identified factors with higher potential impact. Here we will briefly describe some recent work on the genetic basis of the immune response to UVR, the effect of UVR on the generation of reactive oxygen species and their detoxification, and the role of onco- and tumour suppressor genes. Areas for further research are highlighted, together with a consideration of possible applications in clinical practice.

Basal Cell Carcinoma↗
PubMed2005

Maternal glutathione S-transferase GSTP1 genotype is a specific predictor of phenotype in children with asthma.

Maternal factors are known to influence the heritability and expression of asthma and atopy. We report the association of maternal, paternal and proband GSTP1 genotype with lung function in 145 Caucasian children with asthma. GSTP1 Val105/Val105 and Ala114/Val114 genotypes in the child were associated with non-significant increases in lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and the FEV1/FVC ratio). Paternal genotype had no influence on lung function in the child. In contrast, maternal GSTP1 Val105/Val105 genotype was significantly associated with offspring lung function and was strongly predictive of FEV1/FVC (Val105/Val105 105.2%, Ile105/Val105 and Ile105/Ile105 97.9% p=0.006) and maternal GSTP1 Ala114/Val114 genotype was associated with significantly higher FEV1 (Ala114/Val114 109.0%, Ala114/Ala114 99.0% p=0.008), and FEV1/FVC ratios (Ala114/Val114 104.1%, Ala114/Ala114 98.2% p=0.04). The associations between maternal GSTP1 Val105/Val105 genotype and FEV1/FVC and maternal GSTP1 Ala114/Val114 genotype and FEV1 remained significant (p=0.003 and p=0.007) after correction for child and maternal atopic status, passive smoke exposure, smoking during pregnancy, individual and paternal GSTP1 genotype and was independent of transmission to the child. These data support the hypothesis that maternal GSTP1 genotype can act as a specific risk factor which has ex utero consequences for children with asthma. As a child's genotype is not independent of maternal genotype, effects seen in candidate gene studies may be due at least in part to this phenomenon.

Adolescent↗
PubMed2004

Susceptibility and outcome in MS: associations with polymorphisms in pigmentation-related genes.

Multiple sclerosis (MS) risk is determined by environment and genes. The authors investigated in 419 cases and 422 controls if polymorphism in the vitamin D receptor (VDR), melanocortin-1 receptor (MC1R), and tyrosinase (TYR) genes is linked with MS risk and outcome. VDR ff was associated with reduced (odds ratio [OR] = 0.59) and MC1R His294-encoding alleles with increased (OR = 2.21) risk. MC1R Glu84/Glu84 was linked with disability (OR = 5.65). These preliminary data suggest a role for these genes in MS pathogenesis.

Adult↗
PubMed2004

Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population.

Twin, family and adoption studies suggest that susceptibility to multiple sclerosis is substantially mediated by genetic factors. Linkage to human chromosome 17q, homologous to a locus linked to experimental animal models of multiple sclerosis, has been widely replicated and the region likely to harbour a multiple sclerosis susceptibility gene has recently been refined to a 2.5 Mb region of 17q22-24. The candidate multiple sclerosis susceptibility gene, protein kinase C alpha (PRKCA), maps within this interval and association with 35 single-nucleotide polymorphism (SNP) markers, spanning the gene with a median spacing of 7.8 kb, was tested using a case-control approach. Single-marker genotype and estimated haplotype frequencies were compared in UK unrelated cases with multiple sclerosis (n = 184) and healthy controls (n = 340) in order to investigate association with susceptibility to disease. A haplotype of two SNPs mapping to the proximal region of the gene showed evidence for association with susceptibility (Bonferroni-corrected P value = 1.1 x 10(-5)). These findings suggest that further investigation of the PRKCA gene is warranted, particularly in cohorts with evidence of linkage to 17q22. Most of the SNPs investigated in this study were intronic and screening to identify disease-associated functional mutations is now required. Our results suggest that the promoter and proximal gene region should be not only included but prioritized in any screening strategy.

Adult↗
PubMed2004

Susceptibility to basal cell carcinoma: associations with PTCH polymorphisms.

Loss of function of the human patched gene (PTCH) is common and critical in basal cell carcinoma (BCC) development. Indirect evidence suggests polymorphism in PTCH mediates BCC risk. We studied 659 BCC cases and 300 controls to determine if exon 2(318), 3(429), 11(1552), 12(1665), 12(1686), 14(2199) and 23(3944) and intron 9(1336-135) and 15(2560+9)PTCH variants were sufficiently common for use in case-control studies, and if selected markers were associated with risk. Intron 15(2560+9) and exon 23(3944) variants were studied further. Their genotype frequencies were not significantly different in controls and cases, though frequency of the G(2560+9)-C(3944) haplotype was lower in all cases (odds ratio=0.44, p=0.009) and those stratified by BCC site and rate of development of further tumours. This association was not mediated by the extent of UVR exposure. We confirmed the robustness of these findings by showing these associations demonstrated similar odds ratios in two groups of randomly selected cases and controls, and using the false positive report probability (FPRP) approach described by Wacholder et al. (2004). The FPRP value (0.168) was in the noteworthy category. These data, showing for the first time that PTCH polymorphism mediates susceptibility, are compatible with reports showing that PTCH haploinsufficiency influences development of BCC precursor lesions.

Aged↗
PubMed2003

[First results on the influence of polymorphisms at glutathione S-transferase, cytochrome P450, and tumor necrosis factor gene loci on the development of multiple head and neck cancer].

BACKGROUND: The polymorphic gene loci of the detoxifying enzymes GST and CYP are susceptibility factors for single head and neck cancer. In patients with multiple cancer development a cumulation of genetic risk factors can be assumed. METHODS: Accordingly, we have examined genotype frequencies at GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1, CYP2E1, and TNF loci, in patients with single and multiple squamous cell carcinoma (SCC) of the head and neck, and controls. RESULTS: GSTT1 0 was increased in multiple SCC patients (36.8 %) compared with single SCC patients (21.2 %) and controls (22.2 %). GSTM3 AA was more frequent in the single SCC patients (76.6 %) and multiple SCC patients (82.1 %) compared with controls (66.5 %) but lacked significance. The TNF allele B3 was significantly increased in the single SCC group (B3-allele: 22.5 %, B3/B3 : 10.8 %) and showed a further cumulation in the multiple SCC group (B3 : 30.3 %, B3/B3 : 15.8 %). CONCLUSIONS: Patients suffering from multiple SCC development showed a cumulation of high risk genotypes at GST and TNF gene loci. Specific genetic variations could not be determined.

Adult↗
PubMed2003

Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years.

BACKGROUND: A genetic component of early-onset lung cancer has been suggested. The role of metabolic gene polymorphisms has never been studied in young lung cancer cases. Phase 1 and Phase 2 gene polymorphisms are involved in tobacco carcinogens' metabolism and therefore in lung cancer risk. METHODS: The effect of metabolic gene polymorphisms on lung cancer at young ages was studied by pooling data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database. All primary lung cancer cases of both sexes who were Caucasian and </=45 years of age at diagnosis, and the corresponding controls were selected. We obtained 261 cases and 1452 controls. RESULTS: There was a marginally significant association between lung cancer and GSTT1 null genotype (OR=1.2; 95% CI:1.0-1.6), and a significant association between lung cancer and the homozygous CYP1A1 Msp1 variant allele (CYP1A1*2A and *2B) genotype (OR=4.7 95% CI:1.2-19.0). When data were stratified by smoking status, the association between CYP1A1 genotype and lung cancer was confined to never smokers. CONCLUSIONS: These results suggest that metabolic genetic factors play a role in lung cancer developing at young ages.

Adult↗
PubMed2003

Sunshine is good medicine. The health benefits of ultraviolet-B induced vitamin D production.

Most public health statements regarding exposure to solar ultraviolet radiation (UVR) recommend avoiding it, especially at midday, and using sunscreen. Excess UVR is a primary risk factor for skin cancers, premature photoageing and the development of cataracts. In addition, some people are especially sensitive to UVR, sometimes due to concomitant illness or drug therapy. However, if applied uncritically, these guidelines may actually cause more harm than good. Humans derive most of their serum 25-hydroxycholecalciferol (25(OH)D3) from solar UVB radiation (280-315 nm). Serum 25(OH)D3 metabolite levels are often inadequate for optimal health in many populations, especially those with darker skin pigmentation, those living at high latitudes, those living largely indoors and in urban areas, and during winter in all but the sunniest climates. In the absence of adequate solar UVB exposure or artificial UVB, vitamin D can be obtained from dietary sources or supplements. There is compelling evidence that low vitamin D levels lead to increased risk of developing rickets, osteoporosis and osteomaloma, 16 cancers (including cancers of breast, ovary, prostate and non-Hodgkin's lymphoma), and other chronic diseases such as psoriasis, diabetes mellitus, hypertension, heart disease, myopathy, multiple sclerosis, schizophrenia, hyperparathyroidism and susceptibility to tuberculosis. The health benefits of UVB seem to outweigh the adverse effects. The risks can be minimized by avoiding sunburn, excess UVR exposure and by attention to dietary factors, such as antioxidants and limiting energy and fat consumption. It is anticipated that increasing attention will be paid to the benefits of UVB radiation and vitamin D and that health guidelines will be revised in the near future.

Journal Article↗
PubMed2002

Interleukin 1 genotypes in multiple sclerosis and relationship to disease severity.

We studied the association between clinical outcome in MS and allelic variants single nucleotide polymorphisms (SNPs) of interleukin-1alpha (IL-1alpha), IL-1beta and a variable number tandem repeat (VNTR) in IL-1 receptor antagonist (IL-1RN). A total of 377 patients with MS were studied. Significant associations between IL-1 genotypes and clinical outcome were found using logistic regression after correction for gender, onset age and disease duration. The same trends were subsequently demonstrated in a second independent group of 67 primary progressive patients. Our results suggest that genetically determined immunomodulation mediated by IL-1 influences long-term prognosis in multiple sclerosis (MS).

Adjuvants, Immunologic↗
PubMed2002

An association study between the Clara cell secretory protein CC16 A38G polymorphism and asthma phenotypes.

BACKGROUND: Previously, an association has been reported between an increased risk of asthma and a polymorphism in the Clara cell secretory protein (CC16) gene [namely, an adenine to guanine substitution in the CC16 gene at position 38 (A38G) downstream from the transcription initiation site within the noncoding region of exon 1]. Homozygous individuals for the polymorphic sequence (AA genotype) were reported to have a significant (6.9 fold) increased risk of developing asthma. This finding has not been confirmed independently. OBJECTIVE: To validate the association of CC16 A38G polymorphism to asthma in a separate well-characterized population through a case-control study. METHODS: We conducted an association study using a sample of 217 unrelated Northern European Caucasians. Individuals were clinically characterized by a validated respiratory questionnaire, spirometry and bronchial reactivity measurement, and genotyped for the A38G polymorphism using PCR and restriction digestion. Association analysis was performed using the nonparametric Chi-squared tests. RESULTS: In the unselected population, 43.3% participants were homozygous for the CC16*G allele and 45.4% were heterozygous (AG). We observed no significant difference in the distribution of positive bronchial reactivity to methacholine (at FEV1 PC20 of </= 8 mg/mL) across the three genotypes. Homozygous individuals for the CC16*A allele did not demonstrate an increased risk of asthma when compared to heterozygous or GG homozygotes. In addition, no significant difference was observed in the distribution of the CC16*A or *G alleles in the asthmatics vs. non-asthmatics. CONCLUSION: CC16 polymorphism A38G does not influence the predisposition to asthma in this sample.

Adolescent↗