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Biomedical subjects

R C Strange

Publications and source records attributed to R C Strange.

At least 55 records · Page 3Linked to original sources
PubMed2000

Glutathione S-transferase: genetics and role in toxicology.

The glutathione S-transferases (GST) are a supergene family of dimeric, enzymes that catalyse the conjugation of glutathione (GSH) to a variety of electrophiles including arene oxides, unsaturated carbonyls, organic halides and other substrates. Their importance is suggested by the finding that GST enzymes are expressed in probably all life forms. In humans, polymorphism in GST genes has been associated with susceptibility to various diseases though some recent data indicate that these genotypes modify disease phenotype. Thus, GST genotypes alone and in combination have been linked with clinical outcome.

Basal Cell Carcinoma↗
PubMed2000

Glutathione S-transferase polymorphisms in MS: their relationship to disability.

BACKGROUND: Oxidative stress has been implicated in inflammatory demyelination. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1/GSTT1), encode low activity variants (GSTP1), or are associated with variable inducibility (GSTM3). OBJECTIVES: To investigate the association between clinical outcome in MS and allelic variants of GSTM1, GSTM3, GSTT1, and GSTP1. METHODS: Four hundred patients with clinically definite MS were studied. Disability was measured using the Kurtzke Expanded Disability Status Scale (EDSS). Disability was graded as mild (EDSS 0-4), moderate (4.5-5.5), or severe (EDSS 6-10). PCR-based genotyping was performed using DNA extracted from lymphocytes. Significant associations between GST genotypes and clinical outcome were corrected for gender, onset age, and disease duration using logistic regression. RESULTS: We found that the GSTM3 AA genotype was associated with severe disability in patients with a disease duration of more than 10 years (p = 0.027, n = 177, OR = 2.4, 95% CI = 1.1-5.0). Homozygosity for both GSTM1*0 and GSTP1*Ile105 containing allele was associated with severe disability in patients with a disease duration greater than 10 years (p = 0.022, n = 179, OR = 5.0, 95% CI = 1.3-19.8). CONCLUSIONS: Our results suggest that long-term prognosis in MS is influenced by a genetically determined ability to remove the toxic products of oxidative stress.

Adult↗
PubMed2000

Influence of polymorphism in the manganese superoxide dismutase locus on disease outcome in rheumatoid arthritis: evidence for interaction with glutathione S-transferase genes.

OBJECTIVE: To determine whether polymorphism in the manganese superoxide dismutase (MnSOD) gene is associated with susceptibility or disease outcome in rheumatoid arthritis (RA). METHODS: We used a case-control approach with 153 RA patients and 218 control subjects to examine for any associations between MnSOD genotypes and susceptibility to RA. We also investigated the influence of genotypes on radiologic outcome, as measured using the Larsen score for radiographs of the hands and feet, and on functional outcome, as assessed by the Health Assessment Questionnaire. MnSOD typing was carried out using polymerase chain reaction-based methods. Results were analyzed using multiple regression analysis, with adjustment for age, sex, and disease duration. In separate analyses, we corrected for rheumatoid factor (RF) status and/or the presence of the HLA-DRB1 "shared epitope" (SE). We also examined whether radiologic outcome was influenced by interactions between MnSOD and glutathione S-transferase (GST) genes. RESULTS: No association between MnSOD genotype and development of RA was found. The MnSOD VV genotype was associated with a significantly higher (P = 0.04) Larsen score (104.4) than MnSOD AA (83.0), while MnSOD AV was associated with an intermediate score (91.8). Correction for RF status had no significant effect on the results of the analysis, but significance was lost (P = 0.09) after correction for the presence of the SE. There was evidence of interaction between the GSTT1 and MnSOD genotypes, with the MnSOD VV/GSTT1-null combination being associated with the highest Larsen score (142.1; P = 0.007 after correction for the SE). CONCLUSION: Polymorphism in the MnSOD gene is not associated with susceptibility to RA. Our data suggest that MnSOD VV is associated with more severe radiologic outcome, although this relationship may not be independent of the effect of the SE. However, interaction between MnSOD and GST genes appears to influence radiologic outcome independently of the SE.

Aged↗
PubMed2000

Genetic polymorphism and clinical outcome: identification of individuals at risk of a poor clinical outcome.

Susceptibility and outcome in complex disorders such as asthma and cancer appear to be determined, at least in part, by genetic polymorphism. However, while our ability to identify new allelic variants and study them in case and control populations has greatly improved, considerable difficulties remain in elucidating how many genes determine particular clinical phenotypes. This is because most studies have concentrated on study of single genes in relatively small study groups. The important issues of gene-gene interactions (epistasis) and high-risk subgroups have not yet been adequately addressed. We now describe a general approach, using patients with head and neck cancers as an example. Our purpose is to demonstrate candidate gene selection, statistical approaches, and identification of patient subgroups.

Genetic Predisposition to Disease↗
PubMed2000

Polymorphisms at the glutathione S-transferase, GSTP1 locus: a novel mechanism for susceptibility and development of atopic airway inflammation.

A common feature of environmental irritants is their ability to cause local inflammation which could alter airway function. The principal targets of such injury are the epithelial cells lining the airway passages and the lower respiratory gas-exchange areas. While host atopy is a recognized risk factor for airway inflammation, atopy alone cannot cause asthma. We hypothesize that susceptibility to persistent airway inflammation in atopic individuals is characterized by an inherited deficiency in the effectiveness of detoxification of inhaled irritants and products of oxidative stress such as reactive oxygen species (ROS). Our case-control studies show that polymorphisms at the glutathione S-transferase, GSTP1, locus on chromosome 11q13 may account for variation in host response to oxidative stress, a key component of airway inflammation. Frequency of the GSTP1 Val/Val genotype is reduced in atopic subjects compared with nonatopic subjects. Trend analysis also shows a significant decrease of GSTP1 Val/Val (with parallel increase of GSTP1 Ile/Ile) genotype frequency with increasing severity of airflow obstruction/bronchial hyperresponsiveness. The implication of specific polymorphisms at the GSTP1 locus in airway inflammation is entirely novel: however, GST are recognized as a supergene family of enzymes critical in 1) cell protection from the toxic products of ROS-mediated reactions, 2) modulation of eicosanoid synthesis.

Bronchial Hyperreactivity↗
PubMed2000

The -403 G-->A promoter polymorphism in the RANTES gene is associated with atopy and asthma.

Asthma is a complex inflammatory condition often associated with bronchial hyperreactivity and atopy. Genetic and environmental factors are implicated and several candidate genes have been implicated. Of these, the chemokine RANTES is responsible for the recruitment of inflammatory cells such as eosinophils and T-lymphocytes. We have recently identified a polymorphism within the RANTES promoter (-403 G-->A) and have examined its role, using a PCR-RFLP assay, in the development of atopy and asthma in 201 Caucasian subjects. Atopic status was determined using skin prick testing and serum IgE levels. Severity of airway dysfunction was assessed using spirometric measurement (FEV1) and methacholine challenge (PC20). The -403 A allele was associated with an increased susceptibility to both atopy and asthma. Thus, the proportion of subjects carrying this allele was higher in each of atopic non-asthmatics, non-atopic asthmatics and atopic asthmatics compared with non-atopic, non-asthmatic controls. In particular, this allele was associated with skin test positivity but not IgE level. Homozygosity for the -403 A allele conferred a 6.5-fold increased risk of moderate/severe airway obstruction (FEV1 < or = 80% predicted), a marker for established asthma. Our data, whilst preliminary, indicate that the association of RANTES genotype with both atopy and asthma reflect independent effects, suggesting different mechanisms for the role of this chemokine in atopy and development of airway obstruction.

Adenine↗
PubMed2000

Detoxifying enzyme genotypes and susceptibility to cutaneous malignancy.

While ultraviolet (UV) exposure is thought to be a major risk factor for basal cell carcinoma (BCC) and squamous cell carcinoma, more recent research has focused on genetic factors predisposing to these cancers. UV constitutes an oxidative stress with generation of free radicals, leading to lipid and DNA damage and gene mutation. It could therefore be hypothesized that individual ability to deal with these products may be important in cutaneous carcinogenesis. It is clear from recent studies that polymorphisms in detoxifying enzyme genes are important in determining susceptibility to skin cancer. The magnitude of effect in BCC is similar to that seen with many other previously described risk factors. However, uncertainties exist regarding the phenotypic consequences of some of these polymorphisms and relevant substrates. This review describes the influence of polymorphisms in detoxifying enzymes in determining susceptibility to skin cancer (in particular to BCC) and give a brief overview of the biochemistry of the detoxification process.

Basal Cell Carcinoma↗
PubMed2000

Preliminary evidence of an association of tumour necrosis factor microsatellites with increased risk of multiple basal cell carcinomas.

Tumour necrosis factor alpha (TNF-alpha) appears important in ultraviolet-induced immunosuppression, suggesting that it is a susceptibility candidate for cutaneous basal cell carcinoma (BCC). We now describe data on the association between TNF microsatellite polymorphisms, first on susceptibility in 202 controls and 133 cases each having two to 30 BCCs, and secondly, within the cases, on BCC numbers. The data show that the proportions of individuals with TNF a1- and a7-containing genotypes were significantly different (P = 0. 0271, P = 0.0393, respectively) between cases and controls. Secondly, within the cases, TNF alleles d4 (P = 0.023) and d6 (P = 0.006) alone, and the TNF a2-b4-d5 haplotype (P = 0.007), were significantly associated with the number of BCC lesions. These preliminary data provide the first evidence that TNF microsatellite polymorphism may influence the pathogenesis of multiple BCC.

Alleles↗
PubMed2000

Multiple basal cell carcinomas and malignant melanoma following radiotherapy for ankylosing spondylitis.

We present the case of a 53-year-old Caucasian woman with seven basal cell carcinomas and one malignant melanoma in situ along her back overlying her spine, which was irradiated in 1968 for ankylosing spondylitis. These lesions developed between 1997 and 1999. She has no other known risk factors for cutaneous malignancy, in particular no history of excessive sun exposure. She has skin type 2. Molecular studies of glutathione S-transferase and cytochrome P450 status showed her genotype not to constitute an overall increased inherited susceptibility. We therefore postulate that all her skin cancers have arisen as a consequence of her radiotherapy. To our knowledge this is the first case of multiple basal cell carcinoma in addition to a malignant melanoma following radiotherapy for benign disease.

Basal Cell Carcinoma↗
PubMed2000

Glutathione S-transferase GSTP1 and cyclin D1 genotypes: association with numbers of basal cell carcinomas in a patient subgroup at high-risk of multiple tumours.

We previously described associations between basal cell carcinoma (BCC) numbers and allelic variants at loci that mediate host response to ultraviolet radiation (UV). These associations were largely exerted in cases with the multiple presentation phenotype (MPP). This phenotype describes patients who present at their first or a later presentation with a cluster of BCC (2-10 new BCC). Remaining BCC cases have the single presentation phenotype (SPP) and may develop more than one BCC but only have single new lesions at any presentation. We proposed that the MPP cases comprise a high-risk group as they suffer significantly more lesions than SPP cases. We are attempting to determine, in the total BCC case group and subgroups, how many genes influence BCC numbers and their relative importance. In this study, we assessed the influence of two further candidates, glutathione S-transferase GSTP1 and cyclin D1 (CCND1), on tumour numbers in a total group of 457 patients comprising MPP and SPP cases. The relative importance of these genes in comparison with occupational UV exposure and host response (skin type) was also considered. We found that the frequencies of GSTP1 genotypes based on the Ile105 and Val105-expressing alleles and CCND1 AA, AG, GG genotypes were similar in MPP and SPP cases and that there were no significant associations between GSTP1 or CCND1 genotypes and BCC numbers in the total or SPP groups. However, in the MPP cases, GSTP1 Val105/Val105 was associated with more tumours (P = 0.05, reference GSTP1 Ile105/Ile105). Inclusion of skin type and indoor/outdoor occupation in the negative binomial regression models did not alter the associations of these genotypes with tumour numbers. DNA from 258 cases was analysed to identify GSTP1*A (Ile105-Ala114), GSTP1*B (Val105-Ala114), GSTP1*C (Val105-Val114) and GSTP1*D (Ile105-Val114). In SPP cases, there was no association between BCC numbers and GSTP1 BB, though the association with GSTP1 BC approached significance (P = 0.09). In MPP cases, GSTP1 BC was associated with BCC numbers (P = 0.03). We also found that the interaction term, GSTP1 Val105/Val105 with CCND1 AA, was associated with BCC numbers in the total (P = 0.001) and MPP (P = 0.006) but not SPP (P = 0.68) groups. In a stepwise model including GSTP1 Val105/Val105, CCND1 AA and their interaction terms as well as GSTM1, GSTT1 and CYP2D6 genotypes, skin type 1 and gender, the combination of genotypes was the best predictor of BCC numbers. These data suggest that study of further genes involved in cell-cycle control and protection from oxidative stress will be useful, particularly in high-risk subgroups.

Basal Cell Carcinoma↗
PubMed2000

Glutathione S-transferase polymorphisms and their biological consequences.

Two supergene families encode proteins with glutathione S-transferase (GST) activity: the family of soluble enzymes comprises at least 16 genes; the separate family of microsomal enzymes comprises at least 6 genes. These two GST families are believed to exert a critical role in cellular protection against oxidative stress and toxic foreign chemicals. They detoxify a variety of electrophilic compounds, including oxidized lipid, DNA and catechol products generated by reactive oxygen species-induced damage to intracellular molecules. An increasing number of GST genes are being recognized as polymorphic. Certain alleles, particularly those that confer impaired catalytic activity (e.g. GSTM1(*)0, GSTT1(*)0), may be associated with increased sensitivity to toxic compounds. GST polymorphisms may be disease modifying; for example, in subgroups of patients with basal cell carcinoma or bronchial hyper-responsiveness, certain GST appear to exert a statistically significant and biologically relevant impact on disease susceptibility.

Animals↗
PubMed2000

Polymorphism at the glutathione S-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma.

Most genetic studies of asthma have concentrated on genes on chromosomes 11q and 5q and their association with the key asthma-related phenotypes of bronchial hyperresponsiveness (BHR) and atopy. Although asthma is characterized by airway inflammation, a critical component of which is oxidative stress, few data exist on genes involved in protecting against this insult. We describe an association study designed to examine whether allelic variation at the glutathione-S-transferase GSTP1 locus influences expression of the BHR and atopy phenotypes in asthma. The enzyme encoded by GSTP1 utilizes a variety of lipid and DNA products of oxidative stress, and polymorphic variants of this gene are associated with altered catalytic function of this enzyme. We found that the frequency of GSTP1 Val(105)/Val(105) was significantly lower in asthmatic than in control subjects. Indeed, the presence of this genotype conferred a sixfold lower risk of asthma than did GSTP1 Ile(105)/Ile(105). Remarkably, asthma risk in Val(105) homozygotes was further reduced (by ninefold) after correction for atopic indices, age, and gender. Trend analysis after stratification according to the degree of bronchial reactivity/obstruction showed that the frequency of GSTP1 Val(105)/Val(105) correlates with decreasing severity of airway dysfunction. Furthermore, subjects with GSTP1 Val(105)/Val(105) have four- and 10-fold lower risks, respectively, of exhibiting atopy defined by skin test positivity and IgE level. These data show that GSTP1 polymorphism is strongly associated with asthma and related phenotypes, and provide an alternative explanation for the linkage of chromosome 11q13 with BHR and atopy.

Adult↗
PubMed2000

Polymorphisms of apolipoprotein E; outcome and susceptibility in multiple sclerosis.

Allelic variants of the apolipoprotein E (APOE) gene influence the course of several neurological diseases. In multiple sclerosis the concentration of APOE in cerebrospinal fluid and its intrathecal synthesis is reduced. Specific isoforms of APOE may also be important and it has been suggested that possession of the epsilon4 allele may be associated with a more aggressive disease process. These data prompted us to re-examine, in a large group of patients with multiple sclerosis, the proposal that allelism in the apolipoprotein gene influences disease course. Genotypes were determined in a well-defined group of 370 unrelated Caucasians with clinically definite multiple sclerosis and in 159 healthy controls. Age at onset, sex, disease duration, disease subtype were recorded. Disability was measured using the Kurtzke expanded disability status score in patients with a disease duration of 10 years or greater. There was no significant difference in APOE allele or genotype frequencies between patients and controls, between disease subtypes or between genders. APOE genotype did not significantly influence age of onset, and no significant relationship between genotype, allele frequency and disease severity was found. This study suggests that individual APOE alleles or genotypes do not determine disease susceptibility or the clinical course of multiple sclerosis.

Adult↗
PubMed2000

Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma.

Calcitriol [1,25(OH)2D3], the hormonal derivative of vitamin D3, is an antiproliferative and prodifferentiation factor for several cell types, including cultured melanocytes and malignant melanoma (MM) cells. Several polymorphisms of the vitamin D receptor (VDR) gene have been described including a FokI RFLP in exon 2, BsmI, and ApaI polymorphisms in intron 8 and an adjacent TaqI RFLP in exon 9. Alterations in vitamin D/1,25(OH)2D3 levels and polymorphisms of the VDR have been shown to be associated with several systemic malignancies. We hypothesize that polymorphism in this gene may be associated with altered susceptibility and outcome in patients with MM. A hospital-based case-control study, using 316 MM cases and 108 controls, was used to assess associations with MM susceptibility. Breslow thickness, the most important single prognostic factor in MM, was used as the outcome measure. Polymorphisms at the FokI and TaqI restriction sites were determined using PCR-based methods. Polymorphism at the FokI, but not TaqI, RFLP was associated with an altered risk of MM (P = 0.014). More importantly, variant alleles were associated with increased Breslow thickness. Thus, homozygosity for variant alleles at both RFLP (ttff genotype combination) was significantly associated with thicker tumors. (> or = 3.5 mm; P = 0.001; odds ratio = 31.5). Thus, polymorphisms of the VDR gene, which would be expected to result in impaired function, are associated with susceptibility and prognosis in MM. These data suggest that 1,25(OH)2D3, the ligand of the VDR, may have a protective influence in MM, as has been proposed for other malignancies.

Case-Control Studies↗
PubMed1999

Interleukin-10 (IL10) promoter polymorphisms and multiple sclerosis.

Interleukin-10 (IL10) is an anti-inflammatory cytokine which may modulate disease expression in multiple sclerosis (MS). Three dimorphic polymorphisms within the IL10 promoter region at positions - 1082, -819 and -519 have previously been identified. The - 1082*A allele has been associated with low and the - 1082*G allele with high in vitro IL10 production. We have genotyped 185 Caucasian MS patients and 211 ethnically matched controls for each of these three dimorphisms. MS patients were stratified for severity of disease outcome. No associations were found for any IL10 promoter polymorphisms when the MS cases were compared with controls or with disease outcome with regards to disability. IL10 polymorphism does not appear to be associated with MS or to influence disease progression.

Adult↗
PubMed1999

Phenol sulphotransferase SULT1A1 polymorphism: molecular diagnosis and allele frequencies in Caucasian and African populations.

Sulphation, catalysed by members of the sulphotransferase (SULT) enzyme family, is an important component of the body's chemical defence mechanism, but also acts to bioactivate mutagens such as hydroxylated aryl and heterocyclic amines. A major human sulphotransferase, SULT1A1 (P-PST), metabolizes and/or bioactivates many drugs, iodothyronines and hydroxylated aromatic amines. The enzyme activity varies widely within the population and is under genetic control. We have developed an assay detecting a G-->A transition in SULT1A1 that causes an Arg213-->His substitution associated with low SULT activity and altered enzyme properties, and have used it to assess the SULT1A1 genotype in Caucasian (n=293) and African (Nigerian, n=52) populations. We show that the mutant SULT1A1*2 allele is present at frequencies of 0.321 and 0.269 in the Caucasian and African populations respectively. We also demonstrate a significant age-related difference in SULT1A1 genotype within our Caucasian population, with increasing incidence of SULT1A1*1 homozygosity and decreasing incidence of SULT1A1*2 homozygosity with increasing age, indicating a potential association of SULT1A1*1 allozyme(s) with protection against cell and/or tissue damage during aging.

Adolescent↗