In humans, glutathione-dependent conjugation of halomethanes is polymorphic, with 60% of the population classed as conjugators and 40% as non-conjugators. We report the characterization of the genetic polymorphism causing the phenotypic difference. We have isolated a cDNA that encodes a human class Theta GST (GSTT1) and which shares 82% sequence identity with rat class Theta GST5-5. From PCR and Southern blot analyses, it is shown that the GSTT1 gene is absent from 38% of the population. The presence or absence of the GSTT1 gene is coincident with the conjugator (GSST1+) and non-conjugator (GSTT1-) phenotypes respectively. The GSTT1+ phenotype can catalyse the glutathione conjugation of dichloromethane, a metabolic pathway which has been shown to be mutagenic in Salmonella typhimurium mutagenicity tester strains and is believed to be responsible for carcinogenicity of dichloromethane in the mouse. In humans, the enzyme is found in the erythrocyte and this may act as a detoxification sink. Characterization of the GSTT1 polymorphism will thus enable a more accurate assessment of human health risk from synthetic halomethanes and other industrial chemicals.
Environmental and genetic factors are thought to interact in the manifestation of psoriasis, but knowledge about the involved genes and antigens is incomplete. This study has focused on the association between psoriasis and inherited variations in xenobiotic metabolism and cytokine production as two components that may influence cutaneous immune responses to foreign substances. Polymorphisms of N-acetyltransferase 2, glutathione S-transferases T1 and M1, and promoter polymorphisms of the genes encoding for tumor necrosis factor-alpha and interleukin-10 were investigated in 151 Caucasian patients with psoriasis (100 with type I and 51 with type II psoriasis) and in 123 healthy controls. Polymorphisms were detected by polymerase chain reaction-based methods, restriction enzyme analysis, and direct sequencing. There were no significant differences in the distribution of enzyme polymorphisms or point mutations at position -1082 of the interleukin-10 promoter between the psoriasis groups and the control group. The G-->A polymorphism at position -238 of the tumor necrosis factor-alpha promoter (TNF alpha-238*A allele) was more common in type I psoriasis (27%) than in the controls [9.8%; odds ratio 3.4 (95% confidence interval 1.6-7.2); p = 0.0012; pcorr = 0.018]. Surprisingly, this overrepresentation of the tumor necrosis factor alpha-238*A allele was observed in male patients [4.1 (1.5-11.0); p = 0.0046; pcorr = 0.064] but not in female patients [1.8 (0.5-6.5); p = 0.5]. The G-->A polymorphism at position -308 of the tumor necrosis factor-alpha promoter was less frequent in type I psoriasis (23%) compared with controls (35.7%), although the negative association was weak [0.54 (0.3-0.97); p = 0.041; pcorr = not significant]. The distribution of the TNF alpha-238*A and TNF alpha-238*A alleles was similar in type II patients and controls. Our results suggest that male carriers of the G-->A polymorphism at position -238 of the tumor necrosis factor-alpha promoter are at an increased risk to develop early-onset psoriasis.
The exposure to organic dust at workplaces of composting facilities is associated with adverse acute and chronic respiratory health effects, including MMI, chronic bronchitis, and an accelerated decline of FVC%. The pattern of health effects differs from those at other workplaces with exposures to organic dust possibly due to high concentrations of thermo-tolerant/thermophilic actinomycetes and filamentous fungi at composting plants.
Objectives-In a cross sectional study, work related health complaints and diseases of 58 compost workers and 53 biowaste collectors were investigated and compared with 40 control subjects. Levels of specific IgG antibodies to moulds and bacteria were measured as immunological markers of exposure to bioaerosols. Methods-With a standardised protocol, the participants of the study were interviewed for work related symptoms, conditions of exposure to bioaerosols at their workplaces, exposure to bioaerosols from other sources, atopic diseases, and smoking habits. They were clinically examined by physicians specialised in occupational medicine. Also, concentrations of specific IgG antibodies against antigens of moulds and actinomycetes occurring regularly at these workplaces were measured and compared with the health complaints of the workers. Results-Compost workers had significantly more symptoms and diseases of the airways (p=0.003) and the skin (p=0.02) than the control subjects. Health complaints of biowaste collectors did not diVer significantly from those of the control group. Subjects with atopic diseases were underrepresented in the compost workers (p=0.003). Significantly increased antibody concentrations against fungi and actinomycetes were measured in workers at composting plants. The concentrations in biowaste collectors did not diVer significantly from those in the control subjects. A significant association between the diseases and increased antibody concentrations were found in the compost workers. Conclusion-The high exposure to bioaerosols of compost workers is significantly associated with a higher frequency of health complaints and diseases as well as higher concentrations of specific antibodies against moulds and actinomycetes. A healthy worker eVect is indicated by the underrepresentation of atopic diseases among the compost workers compared with biowaste collectors and the control group.
Susceptibility to contact allergy may be influenced by genetically determined alterations in the production of pro- and anti-inflammatory cytokines. This report focuses on functional polymorphisms in the genes encoding for several cytokines involved in the pathogenesis of contact allergic responses, including tumour necrosis factor (TNF)-alpha (G-238 A, G-308 A), interleukin (IL)-1beta (C-511G, T+ 3953C), its natural antagonist, the IL-1 receptor antagonist (VNTR intron 2), and IL-6 (G-174C). Polymorphisms were investigated by PCR techniques among polysensitized individuals, defined as individuals with confirmed contact sensitization to para-substituted aryl compounds and at least one other structurally unrelated allergen (n = 86), and healthy control individuals without a history of eczema (n = 310). The distribution of TNFA-308 genotypes was significantly different in these groups (Padjusted= 0.0378). Compared with carriers of 2 wild-type alleles (TNFA-308*1/1 (*G/G)), carriers of the TNFA-308*1/2 (*G/A) and TNFA-308*2/2 (*A/A) genotypes tended to be more common among polysensitized individuals [OR = 1.54, 95% CI (0.92-2.55) and OR = 2.36 (0.84-6.51), respectively]. No significantly different distribution of genotypes was detected at any other polymorphic loci among control individuals without eczema and polysensitized subjects. These findings suggest a possible relationship between the TNFA-308 polymorphism and contact allergy. The results need to be confirmed in future studies.
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