It has been suggested that interleukin (IL)-18 plays a role in the development of inflammatory and fibrosing lung diseases. Associations of polymorphisms in the genes coding for IL-18 (IL18 /G-656T, C-607A, G-137C, T113G, C127T) and its receptor (IL18R1 /C-69T) with coal workers' pneumoconiosis (CWP) were studied in 200 miners who were examined in 1990, 1994 and 1999. Coal-dust exposure was assessed according to job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-yr change in CT score and CWP incidence and prevalence. CT score in 1990 was a good predictor of radiographic grade in 1999 and, therefore, an appropriate subclinical quantitative trait. The IL18 -137C allele was associated with lower CT score in 1990 and 1994 (1.24 versus 1.69 and 1.57 versus 2.46, respectively), slower progression of CT score between 1990 and 1994 and lower pneumoconiosis prevalence in 1999 relative to the G allele (0.33 versus 0.77 and 8.2 versus 19.6%, respectively). Smoking- or dust-adjustment, and stratification on IL18R1 genotype and adjustment for haplotype effects did not change the conclusions. In conclusion, the results of the present study suggest a role for IL18 in reducing the development of this fibrosing lung disease.

Chemokines and their receptors are key regulators of inflammation and may participate in the lung fibrotic process. Associations of polymorphisms in CCL5 (G-403A) and its receptor CCR5 (Delta32), CCL2 (A-2578G) and CCR2 (V64I), and CX3CR1 V249I and T280M with coal worker's pneumoconiosis (CWP) were investigated in 209 miners examined in 1990, 1994 and 1999. Coal dust exposure was assessed by job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-year change in CT score, and CWP prevalence in 1999. CCR5 Delta32 carriers had significantly higher CT score in 1990 and 1994 (2.15 vs. 1.28, p=0.01; 3.04 vs. 1.80, p=0.04). The CX3CR1 I249 allele was significantly associated with lower 1990 CT score and lower progression in 4-year change in CT score in CCR5 Delta32 carriers only (p for interaction=0.03 and 0.02). CX3CR1 V249I was associated with lower 1999 CWP prevalence (16.7%, 13.2%, 0.0% for VV, VI and II); the effect was most evident in miners with high dust exposure (31.6%, 21.7%, 0.0%). Our findings indicate that chemokine receptors CCR5 and CX3CR1 may be involved in the development of pneumoconiosis.

Anopheles gambiae transcript responses to experimental challenge with heat inactivated Salmonella typhimurium, Staphylococcus aureus and Beauveria bassiana have been analyzed with an Affymetrix GeneChip comprising the entire predicted mosquito transcriptome. Significant up- or down-regulation (greater than 2-fold) can be assayed for approximately 2% of the mosquito transcriptome and affected genes represent a variety of functional classes that include immunity, apoptosis, stress response, detoxification, metabolism, blood digestion, olfaction and others. Transcript responses to the 3 microbial elicitors exhibit an exceptionally high degree of specificity and only a few genes are significantly regulated by more than 1 of the tested elicitors. This study identifies several transcripts that have not been linked directly to immune response in A. gambiae previously; their infection responsiveness and sequence features do however suggest implication in defence reactions; examples are genes encoding leucine-rich repeat domain proteins, cuticle domain proteins and proteins containing immunoglobulin and fibronectin domains.

OBJECTIVES:To assess the relations between homocysteine levels and neurobehavioral test scores representing a broad range of cognitive domains in a population-based study of older adults.DESIGN:Cross-sectional analysis of first-visit data of subjects in the Baltimore Memory Study, a longitudinal study.SETTING:Specific neighborhoods in Baltimore.PARTICIPANTS:Participants were 1,140 randomly selected residents aged 50 to 70 with a mean age+/-standard deviation of 59.3+/-5.9; 65.9% were female, and 54.2% were white and 41.1% African-American.MEASUREMENTS:Twenty neurobehavioral test scores in eight cognitive domains.RESULTS:Linear regression models revealed that homocysteine was consistently and strongly associated with worse neurobehavioral test performance, in crude analysis and after control for a large set of important covariates. Associations were observed in all eight cognitive domains assessed but were strongest and most consistent in the domains of simple motor and psychomotor speed, eye-hand coordination/manual dexterity, and verbal memory and learning. On average, an increase in homocysteine levels from the 25th to the 75th percentile, all in the generally accepted normal range, was equivalent in its association with neurobehavioral test scores to an increase of 4.2 years of age. Logistic regression models revealed that, on average, for the neurobehavioral tests associated with homocysteine, subjects in the highest quartile of homocysteine levels were more than two times as likely to be in the lowest quartile of neurobehavioral test scores as those in the lowest quartile.CONCLUSION:Higher homocysteine levels were associated with worse function across a broad range of cognitive domains, and the magnitude of the associations was large. The data suggest that homocysteine may be a potentially important modifiable cause of cognitive dysfunction.

We tested the hypotheses that catalase activity is modified by CAT single nucleotide polymorphisms (SNPs) (-262;-844), and by their interactions with oxidant exposures (coal dusts, smoking), lymphotoxin alpha (LTA, NcoI) and tumor necrosis factor (TNF, -308) in 196 miners. Erythrocyte catalase, superoxide dismutase, and glutathione peroxidase activities were measured. The CAT -262 SNP was related to lower catalase activity (104, 87 and 72 k/g hemoglobin for CC, CT and TT, respectively, p < 0.0001). Regardless of CAT SNPs, the LTA NcoI but not the TNF-308 SNP was associated with catalase activity (p = 0.04 and p = 0.8). CAT -262 T carriers were less frequent in highly exposed miners (OR = 0.39 [0.20-0.78], p = 0.007). In CAT -262 T carriers only, catalase activity decreased with high dust exposure (p = 0.01). Haplotype analyses (combined CAT SNPs) confirm these results. Results show that CAT -262 and LTA NcoI SNPs, and interaction with coal dust exposure, influenced catalase activity.

Background: Occupational exposure of healthcare workers to natural rubber latex has led to sensitization and potentially life-threatening anaphylaxis. Although environmental exposure to natural rubber latex products is necessary for sensitization, it is not sufficient. A number of genetic factors also seem to contribute to the latex sensitization; however, the multigenic nature of the allergic phenotype has made the identification of susceptibility genes difficult. The current study tests the hypothesis that known functional polymorphisms in genes encoding interleukin 4, interleukin 13, and interleukin 18 occur in a higher frequency in healthcare workers with natural rubber latex allergy. Methods: Four hundred thirty-two healthcare workers with occupational exposure to natural rubber latex were screened using a clinical history questionnaire and latex-specific immunoglobulin E serology. Genomic DNA was extracted from peripheral blood lymphocytes and analyzed for single-nucleotide polymorphisms in candidate genes of interest. Data from cases and controls were analyzed by nominal logistic regression, with P < 0.05 considered significant. Results: The latex allergy phenotype was significantly associated with promoter polymorphisms in IL13 1055 (P 0.02), IL18 607 (P 0.02), and IL18 656 (P 0.02) compared with nonatopic controls. Conclusions: The significant association of IL13 and IL18 promoter polymorphisms with latex allergy suggests a potential location for genetic control in the induction of latex allergy in individuals and extends the understanding of the genetic basis for the induction of immediate-type hypersensitivity in healthcare workers occupationally exposed to natural rubber latex.

Introduction: Interaction between genetic background and oxidative environmental stimuli in the pathogenesis of human lung disease has been largely unexplored. Methods: A prospective epidemiological study was undertaken in 253 coal miners. Intermediate quantitative phenotypes of response to oxidant exposure, including erythrocyte glutathione peroxidase (GSH-Px) and catalase activities, were studied. Oxidant exposures studied were smoking habits and cumulative dust exposure assessed by job history and ambient measures. Disease phenotypes included subclinical computed tomography score at the first survey and x ray profusion grades twice, five years apart, to assess established coal workers’ pneumoconiosis (CWP). Miners were genotyped for common functional polymorphisms in the gene for tumour necrosis factor α (TNF) and lymphotoxin α (LTA), two proinflammatory cytokines that have been implicated in the pathogenesis of chronic lung diseases. Results: Regarding gene-environment interaction on intermediate phenotypes, results showed interaction of a promoter polymorphism at the –308 position in TNF with occupational exposure on erythrocyte GSH-Px activity with a significant association in those with high exposure (p=0.003), whereas no association was observed among those with low exposure (interaction p=0.06). Regarding gene intermediate phenotype interaction on clinical outcome, results showed an association of CWP prevalence with an NcoI polymorphism in LTA in those with low catalase activity (p=0.05), whereas no association was observed in those with high activity (interaction p=0.03). No other significant association was observed. Conclusion: The results suggest that interactions of genetic background with environmental exposure and intermediate response phenotypes are important components in the pathogenesis of CWP.

RATIONALE: Occupational exposure to natural rubber latex can lead to type I, IgE-mediated immediate hypersensitivity.The objective of our study was to identify potential genetic markers (polymorphisms in candidate susceptibility genes) for latex allergy.METHODS: We studied 129 anesthesiologists (44% male, 56% female, age 39.6 _+ 9.4 yrs) who were occupationally exposed to contact and airborne natural rubber latex proteins from medical gloves and supplies.Whole blood (20ml) was collected with consent and analyzed for latexspecific IgE (Pharmacia CAP System) from volunteers at the 1999/2000 American Society of Anesthesiologists meetings.Genomic DNA from each subject was genotyped for functional polymorphisms in heat shock protein 70 (HSPAIB), interleukin (IL) 4 (IL4), ILl3, ILl8, lymphotoxin alpha (LTA), toll-like receptor 4 (TLR4), and tumor necrosis factor alpha (TNF).Association of polymorphism frequencies with allergic status was evaluated by Chi-square analyses.RESULTS: Twenty-four individuals were IgE anti-latex positive.Seronegative controls (n=105) were all non-atopic by history and asymptomatic following latex exposures.Statistically significant positive associations were found in this cohort for latex allergy with promoter polymorphisms at the -1055 position (C to T) in ILl3 (p=0.05) and the -607 position (C to A) in ILl8 (p=0.05).CONCLUSIONS: Among individuals with similar occupational exposures to latex, inter-individual variation in allergic status has been identified which suggests that genetic background has an important role in disease pathogenesis.Significant association of polymorphisms in the immunomodulatory cytokine genes ILl3 and ILl8 with allergic status suggests these polymorphisms may predispose to the development of latex allergy.