HLA-DPB1 E69 genotype and exposure in beryllium sensitisation and disease.

OBJECTIVES: Human leukocyte antigen-DP beta 1 (HLA-DPB1) with a glutamic acid at the 69th position of the ß chain (E69) genotype and inhalational beryllium exposure individually contribute to risk of chronic beryllium disease (CBD) and beryllium sensitisation (BeS) in exposed individuals. This retrospective nested case-control study assessed the contribution of genetics and exposure in the development of BeS and CBD. METHODS: Workers with BeS (n=444), CBD (n=449) and beryllium-exposed controls (n=890) were enrolled from studies conducted at nuclear weapons and primary beryllium manufacturing facilities. Lifetime-average beryllium exposure estimates were based on workers' job questionnaires and historical and industrial hygienist exposure estimates, blinded to genotype and case status. Genotyping was performed using sequence-specific primer-PCR. Logistic regression models were developed allowing for over-dispersion, adjusting for workforce, race, sex and ethnicity. RESULTS: Having no E69 alleles was associated with lower odds of both CBD and BeS; every additional E69 allele increased odds for CBD and BeS. Increasing exposure was associated with lower odds of BeS. CBD was not associated with exposure as compared to controls, yet the per cent of individuals with CBD versus BeS increased with increasing exposure. No evidence of a gene-by-exposure interaction was found for CBD or BeS. CONCLUSIONS: Risk of CBD increases with E69 allele frequency and increasing exposure, although no gene by environment interaction was found. A decreased risk of BeS with increasing exposure and lack of exposure response in CBD cases may be due to the limitations of reconstructed exposure estimates. Although reducing exposure may not prevent BeS, it may reduce CBD and the associated health effects, especially in those carrying E69 alleles.

Association of peritraumatic dissociation with symptoms of depression and posttraumatic stress disorder.

AIM: In this study, we evaluated whether peritraumatic dissociation (PD) was associated with symptoms of depression and posttraumatic stress disorder (PTSD), and whether this association was modified by trauma prior to police work. METHOD: Symptoms of depression, PTSD, peritraumatic dissociative experience (PDE), and trauma prior to police work were measured using the Center for Epidemiologic Studies Depression scale, PTSD Checklist-Civilian, PDE questionnaire, and the Brief Trauma questionnaire, respectively, in 328 police officers. Separate regression models were used to assess if either symptoms of depression or PTSD were associated with PD stratified by prior trauma. Means were adjusted for race, number of drinks per week, and smoking. RESULTS: PD was associated with symptoms of PTSD and depression (ß = 0.65, p < .001 and ß = 0.27, p < .001, respectively). PD was positively associated with symptoms of PTSD regardless of prior trauma (ß = 0.61, p < .001(without prior trauma), 0.75, p < .001 (with prior trauma). In contrast to PTSD, depression symptoms were significantly associated with PD scores in individuals with prior trauma (ß = 0.47, p < .001), but not in individuals without prior trauma (ß = 0.13, p = .165). LIMITATIONS: This is a cross-sectional study. Outcomes were obtained via self-report and were not clinically diagnosed. Aspects of both the trauma event as well as the symptoms and severity of PD may have introduced recall bias. CONCLUSION: These results add to the literature indicating that PD plays a role in symptoms of PTSD and depression and how prior trauma may modify this relationship. (PsycINFO Database Record

Research to Practice Implications of High-Risk Genotypes for Beryllium Sensitization and Disease.

OBJECTIVE: Beryllium workers may better understand their genetic susceptibility to chronic beryllium disease (CBD) expressed as population-based prevalence, rather than odds ratios from case-control studies. METHODS: We calculated CBD prevalences from allele-specific DNA sequences of 853 workers for Human Leukocyte Antigen (HLA)-DPB1 genotypes and groups characterized by number of E69-containing alleles and by calculated surface electronegativity of HLA-DPB1. RESULTS: Of 18 groups of at least 10 workers with specific genotypes, CBD prevalence was highest, 72.7%, for the HLA-DPB102:01:02/DPB117:01 genotype. Population-based grouped genotypes with two E69 alleles wherein one allele had -9 surface charge had a beryllium sensitization (BeS) of 52.6% and a CBD prevalence of 42.1%. CONCLUSIONS: The high CBD and BeS prevalences associated with -9-charged E69 alleles and two E69s suggest that workers may benefit from knowing their genetic susceptibility in deciding whether to avoid future beryllium exposure.

Chronic beryllium disease, HLA-DPB1, and the DP peptide binding groove.

Multiple epidemiologic studies demonstrate associations between chronic beryllium disease (CBD), beryllium sensitization (BeS), and HLA-DPB1 alleles with a glutamic acid residue at position 69 (E69). Results suggest that the less-frequent E69 variants (non-*0201/*0202 alleles) might be associated with greater risk of CBD. In this study, we sought to define specific E69-carrying alleles and their amino acid sequences in the DP peptide binding groove, as well as their relationship to CBD and BeS risk, using the largest case control study to date. We enrolled 502 BeS/CBD subjects and 653 beryllium-exposed controls from three beryllium industries who gave informed consent for participation. Non-Hispanic white cases and controls were frequency-matched by industry. HLA-DPB1 genotypes were determined using sequence-specific primer PCR. The E69 alleles were tested for association with disease individually and grouped by amino acid structure using logistic regression. The results show that CBD cases were more likely than controls to carry a non-*02 E69 allele than an *02 E69, with odds ratios (95% confidence interval) ranging from 3.1 (2.1-4.5) to 3.9 (2.6-5.9) (p < 0.0001). Polymorphic amino acids at positions 84 and 11 were associated with CBD: DD versus GG, 2.8 (1.8-4.6), p < 0.0001; GD versus GG, 2.1 (1.5-2.8), p < 0.0001; LL versus GG, 3.2 (1.8-5.6), p < 0.0001; GL versus GG, 2.8 (2.1-3.8), p < 0.0001. Similar results were found within the BeS group and CBD/BeS combined group. We conclude that the less frequent E69 alleles confer more risk for CBD than does *0201. Recent studies examining how the composition and structure of the binding pockets influence peptide binding in MHC genes, as well of studies showing the topology of the TCR to likely bind DPB1 preferentially, give plausible biological rationale for these findings.

C-reactive protein, interleukin-6, and posttraumatic stress disorder symptomology in urban police officers.

Our aim was to examine the relationship between the level of the inflammatory markers, C-reactive protein (CRP) and interleukin-6 (IL-6), and posttraumatic stress disorder (PTSD) symptomology in a random sample of 115 police officers. CRP was measured in citrated plasma using a particle enhanced immunonepholometric assay and IL-6 was measured in serum with a solid-phase quantitative sandwich ELISA. The presence of high PTSD symptomology was defined as having an Impact of Event Scale score (IES) of ≥ 26 compared to<26 (low PTSD symptomology). 28% of the officers had high PTSD symptomology. Mean levels of CRP and IL-6 did not differ significantly between officers with high PTSD symptomology and those with low symptomology (CRP: 0.76 mg/l vs. 0.97 mg/l; IL-6: 2.03 pg/ml vs. 1.74 pg/ml). We found no association of CRP and IL-6 levels with PTSD symptomology. This study was limited by sample size and its cross-sectional study design. A lack of association may occur if either CRP or IL-6 is elevated only at the onset of PTSD symptomology, or if inflammation is related to specific key components that define PTSD. Further research examining these relationships in a larger population may be worthwhile.

Association between IL-1A single nucleotide polymorphisms and chronic beryllium disease and beryllium sensitization.

OBJECTIVE: To determine if single nucleotide polymorphisms (SNPs) in interleukin (IL) IL-1A, IL-1B, IL-1RN, IL-2, IL-9, and IL-9R were associated with chronic beryllium disease (CBD) and beryllium sensitization (BeS). METHODS: Forty SNPs in six IL genes were evaluated in 85 individuals with CBD, 61 individuals with BeS, and 730 individuals without BeS or CBD (nonsensitized) using a 5' nuclease polymerase chain reaction assay. Logistic regression was used to evaluate the association between IL SNPs, CBD, and BeS, adjusting for plant-site and HLA-DPB1Glu69 in additive, dominant, and recessive inheritance models. RESULTS: IL-1A-1142, IL-1A-3769, and IL-1A-4697 were significantly associated with CBD in both the additive and dominant models compared to individuals with BeS or the nonsensitized. CONCLUSIONS: These results indicate that genetic variations in the IL-1A gene may play a role in the development of CBD but not BeS.

Telomere length, current perceived stress, and urinary stress hormones in women.

Telomeres are repetitive DNA sequences that cap and protect the ends of chromosomes; critically short telomeres may lead to cellular senescence or carcinogenic transformation. Previous findings suggest a link between psychosocial stress, shorter telomeres, and chronic disease risk. This cross-sectional study examined relative telomere length in relation to perceived stress and urinary stress hormones in a sample of participants (n = 647) in the National Institute of Environmental Health Sciences Sister Study, a cohort of women ages 35 to 74 years who have a sister with breast cancer. Average leukocyte telomere length was determined by quantitative PCR. Current stress was assessed using the Perceived Stress Scale and creatinine-adjusted neuroendocrine hormones in first morning urines. Linear regression models estimated differences in telomere length base pairs (bp) associated with stress measures adjusted for age, race, smoking, and obesity. Women with higher perceived stress had somewhat shorter telomeres [adjusted difference of -129bp for being at or above moderate stress levels; 95% confidence interval (CI), -292 to 33], but telomere length did not decrease monotonically with higher stress levels. Shorter telomeres were independently associated with increasing age (-27bp/year), obesity, and current smoking. Significant stress-related differences in telomere length were seen in women ages 55 years and older (-289bp; 95% CI, -519 to -59), those with recent major losses (-420bp; 95% CI, -814 to -27), and those with above-average urinary catecholamines (e.g., epinephrine: -484bp; 95% CI, -709 to -259). Although current perceived stress was only modestly associated with shorter telomeres in this broad sample of women, our findings suggest the effect of stress on telomere length may vary depending on neuroendocrine responsiveness, external stressors, and age.

Impact of negatively charged patches on the surface of MHC class II antigen-presenting proteins on risk of chronic beryllium disease.

Chronic beryllium disease (CBD) is a granulomatous lung disease that occurs primarily in workers who are exposed to beryllium dust or fumes. Although exposure to beryllium is a necessary factor in the pathobiology of CBD, alleles that code for a glutamic acid residue at the 69th position of the HLA-DPbeta1 gene have previously been found to be associated with CBD. To date, 43 HLA-DPbeta1 alleles that code for glutamic acid 69 (E69) have been described. Whether all of these E69 coding alleles convey equal risk of CBD is unknown. The present study demonstrates that, on the one hand, E69 alleloforms of major histocompatibility complex class II antigen-presenting proteins with the greatest negative surface charge convey the highest risk of CBD, and on the other hand, irrespective of allele, they convey equal risk of beryllium sensitization (BeS). In addition, the data suggest that the same alleles that cause the greatest risk of CBD are also important for the progression from BeS to CBD. Alleles convey the highest risk code for E26 in a constant region and for E69, aspartic acid 55 (D55), E56, D84 and E85 in hypervariable regions of the HLA-DPbeta1 chain. Together with the calculated high binding affinities for beryllium, these results suggest that an adverse immune response, leading to CBD, is triggered by chemically specific metal-protein interactions.

TNF-alpha polymorphisms in chronic beryllium disease and beryllium sensitization.

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine involved in normal immune functions. The aim of this study was to investigate if there is an association between chronic beryllium disease or beryllium sensitization and two variants of the TNF-alpha gene located at -308 and -238 called TNF-alpha-308*02 and TNF-alpha-238*02. METHODS: TNF-alpha-308 and TNF-alpha-238 genotyping was conducted in a large, population-based cohort consisting of 886 beryllium workers (92 individuals with chronic beryllium disease, 64 who were beryllium sensitized, and 730 individuals without sensitization or disease). RESULTS: The odds of chronic beryllium disease in the presence of at least one TNF-alpha-308*02 or TNF-alpha-238*02 allele was not significant (OR=1.0; 95% CI=0.7, 1.7 and OR=0.8; 95% CI=0.4, 1.6). This was true regardless of whether a worker was homozygous or heterozygous for TNF-alpha-308*02 or TNF-alpha-238*02. Similarly, neither allele was associated with sensitization (P>0.05). CONCLUSIONS: Unlike an earlier report, there was no association between these specific TNF-alpha alleles and either chronic beryllium disease or sensitization to beryllium.

Immunogenetic factors in beryllium sensitization and chronic beryllium disease.

Exposure to beryllium in the workplace can cause beryllium sensitization and chronic beryllium disease. Sensitization to beryllium can be detected in the laboratory using the beryllium lymphocyte proliferation test. It was shown that anti-HLA antibodies could block the beryllium-specific response in the beryllium lymphocyte proliferation test, thereby implicating HLA genes in chronic beryllium disease. A supratypic genetic marker, HLA-DPB1*E69, was found to be strongly associated with immunologic sensitization to beryllium and chronic beryllium disease in beryllium workers. However, there are 40 HLA-DPB1 gene variants that have E69 but that also have other DNA sequence variations. The purpose of the study was to evaluate the evidence for potential differential susceptibility that may be associated with the physical characteristics of HLA protein molecules for which different HLA-DPB1*E69 variants code; that is, do some HLA-DPB1*E69 variants convey higher risk of beryllium sensitization and chronic beryllium disease than others. To do this, two approaches were pursued: first, detailed analysis of the findings from the published literature was performed, and second, computational chemistry was used to seek clues concerning the physical properties of the HLA protein molecules for which these alleles code. Among the 40 HLA-DPB1 gene variants that code for E69, molecular epidemiological studies have suggested a risk hierarchy, where some variants appear to convey low to moderate risk of chronic beryllium disease (e.g., HLA-DPB1*0201, approximately 3-fold increased risk), some convey an intermediate risk (e.g., HLA-DPB1*1901, approximately 5-fold) and others convey high risk (e.g., HLA-DPB1*1701, >10-fold). Molecular modeling has been used to further investigate a potential mechanistic basis for these observations. We found a strong correlation between the hierarchical order of risk of chronic beryllium disease associated with specific alleles and the predicted surface electrostatic potential and charge of the corresponding isotypes. Therefore, when alleles were grouped by the relative negative charge on the molecules for which they code, the data suggest that those alleles associated with the most negatively charged proteins carry the greatest risk of beryllium sensitization and disease.

CYP3A4 polymorphisms--potential risk factors for breast and prostate cancer: a HuGE review.

The steroid hydroxylase CYP3A4 is the most abundant P-450 enzyme in the human liver, and CYP3A enzymes metabolize more than 50% of prescription drugs. The CYP3A4 gene is expressed in the liver, gut, colon, prostate, and breast. Individual variation in CYP3A4 may play a role in breast and prostate carcinogenesis through modulation of sex hormone metabolite levels. Alternatively, CYP3A4 can metabolically activate exogenous carcinogens. CYP3A4 activity varies widely in humans, and more than 78 DNA sequence polymorphisms are known. These observations prompted the hypothesis that variant CYP3A4 may be involved in breast and prostate cancer. Two epidemiologic studies of breast cancer and five of prostate cancer examined CYP3A4 genotypes. A US study showed that inheritance of CYP3A4*1B correlates with early menarche, a breast cancer risk factor. However, an Australian breast cancer case-control study found no association with CYP3A4*1B. Two Scottish prospective studies showed CYP3A4*1B to be a risk factor for prostate cancer among men with benign prostatic hyperplasia. Three other studies were undertaken in the United States: two were case-only studies and the other was a case-sibling control study. Although results for African Americans were inconsistent, these studies suggested that CYP3A4*1B was associated with markers of advanced disease. These observations support the notion that development of robust, conventional molecular epidemiologic case-control studies to address these questions, including gene-gene and gene-environment interactions, will be timely.

The association between HLA-DPB1Glu69 and chronic beryllium disease and beryllium sensitization.

BACKGROUND: Several case-control studies have found an association between chronic beryllium disease (CBD) and HLA-DPB1 gene variants. However, the relationship between HLA-DPB1 and beryllium sensitization, and whether the presence of one or two HLA-DPB1(Glu69) alleles is differentially associated with CBD and beryllium sensitization have not been completely resolved. METHODS: Restriction fragment length polymorphism (RFLP) analysis was used to address these questions in a large population-based cohort consisting of 884 beryllium workers (90 with CBD, 64 beryllium sensitized). RESULTS: HLA-DPB1(Glu69) was associated with both CBD (OR = 9.4; 95% CI = 5.4, 16.6) and sensitization (OR = 3.3, 95% CI = 1.9, 5.9). Further, workers with CBD and sensitization were more likely to be homozygous HLA-DPB1(Glu69) compared to workers without disease or sensitization (P < 0.001). CONCLUSIONS: Follow-up of this cohort, scrutiny of HLA-DPB1 haplotypes, and evaluation of gene-environment and gene-gene interactions will be important for fully understanding the immunogenetic nature of this occupational disease.

HLA-DPB1 and chronic beryllium disease: a HuGE review.

The human leukocyte antigen (HLA) complex is a series of genes located on chromosome 6 that are important in normal immune function. Susceptibility to chronic beryllium disease, a granulomatous lung disease that appears in workers exposed to beryllium, is modified by genetic variants of the HLA-DP subregion. Evaluation of HLA-DPB1 sequence motifs in current and former beryllium workers implicated a glutamic acid residue at position 69 (HLA-DPB1(Glu69)) in chronic beryllium disease. This finding has since been extended to specific HLA-DPB1(Glu69) alleles. Specific job tasks have also been implicated in degree of risk, and in this paper the authors explore gene-environment interaction. The utility of this genetic information for prospective, current, and former beryllium workers must be weighed against the potential for employment and insurance discrimination. Continued research in the beryllium-exposed population will be important for improving personal risk assessment and identifying high-risk genes associated with disease progression.

Waf-1 (p21) and p53 polymorphisms in breast cancer.

p53 is a transcription factor for Waf-1/p21, a cyclin-dependent kinase inhibitor. Certain polymorphic variants of Waf-1 and p53 have been evaluated for their association with cancer risk. Previous studies indicated that certain p53 polymorphisms confer an increased risk of breast cancer [odds ratios (ORs) and 95% confidence intervals (CIs) = 2.9, 1.4-6.3 Carcinogenesis (Lond.), 17: 1313, 1996; 2.5, 1.3-4.8 Cancer Epidemiol. Biomark. Prev., 6: 105, 1997; and 1.5, 1.1-2.0, Anticancer Res., 18: 2095, 1998). The primary objectives of this study were to test the hypotheses that the serine variant (codon 31 polymorphism) of Waf-1 is also involved in this process and that there is an interaction between Waf-1 and p53 polymorphisms. To do this, Waf-1 and p53 genotypes were determined for women enrolled in a breast cancer case-control study (Caucasians, African-Americans and Latinas; 487 Waf-1 and 504 p53 genotypes were obtained). Multivariate logistic regression was used to evaluate possible associations between Waf-1 and p53 polymorphisms, race, and menopause. The primary aim was to determine whether an interaction between Waf-1 and p53(1-2-1) existed. Whereas multivariate analysis suggested associations between breast cancer and inheritance of Waf-1(ser31) in African-Americans (OR, 2.32; 95% CI = 0.66-5.60; n = 37 cases and 65 controls) and Latinas (OR, 2.22; 95% CI = 0.71-6.89; n = 30 cases and 75 controls), and inheritance of p53(1-2-1) in Caucasians (OR, 3.15; 95% CI = 1.14-8.89; n = 93 cases and 187 controls), we did not see an interaction between Waf-1(ser31) and p53(1-2-1). Consistent with the finding that p53(1-2-1) is a risk factor for Caucasian women was the observation of a strong interaction between race and p53 (P < 0.01).