Mary Ann Butler

Prevalence in the United States of Selected Candidate Gene Variants Third National Health and Nutrition Examination Survey, 1991–1994

Population-based allele frequencies and genotype prevalence are important for measuring the contribution of genetic variation to human disease susceptibility, progression, and outcomes. Population-based prevalence estimates also provide the basis for epidemiologic studies of gene–disease associations, for estimating population attributable risk, and for informing health policy and clinical and public health practice. However, such prevalence estimates for genotypes important to public health remain undetermined for the major racial and ethnic groups in the US population. DNA was collected from 7,159 participants aged 12 years or older in Phase 2 (1991–1994) of the Third National Health and Nutrition Examination Survey (NHANES III). Certain age and minority groups were oversampled in this weighted, population-based US survey. Estimates of allele frequency and genotype prevalence for 90 variants in 50 genes chosen for their potential public health significance were calculated by age, sex, and race/ethnicity among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. These nationally representative data on allele frequency and genotype prevalence provide a valuable resource for future epidemiologic studies in public health in the United States.

Lead and cognitive function in ALAD genotypes in the third National Health and Nutrition Examination Survey.

The relationship between the blood lead concentration and cognitive function in children and adults with different ALAD genotypes who participated in the third National Health and Nutrition Examination Survey was investigated. The relationship between blood lead and serum homocysteine concentrations was also investigated. In children 12 to 16 years old, no difference in the relationship between cognitive function and blood lead concentration between genotypes was found. In adults 20 to 59 years old, mean reaction time decreased as the blood lead concentration increased in the ALAD rs1800435 CC/CG group. This represents an improvement in performance. In adults 60 years and older, no difference in the relationship between cognitive function and blood lead concentration between genotypes was found. The serum homocysteine concentration increased as the blood lead concentration increased in adults 20 to 59 years old and 60 years and older, but there were no differences between genotypes. The mean blood lead concentration of children with the ALAD rs1800435 CC/CG genotype was less than that of children with the GG genotype.

Common Variation in Genes Related to Innate Immunity and Risk of Adult Glioma

Current evidence suggests that immune system alterations contribute to the etiology of adult glioma, the most common adult brain tumor. Although previous studies have focused on variation in candidate genes in the adaptive immune system, the innate immune system has emerged as a critical avenue for research given its known link with carcinogenesis. To identify genetic markers in pathways critical to innate immunity, we conducted an association study of 551 glioma cases and 865 matched controls of European ancestry to investigate “tag” single nucleotide polymorphisms (SNP) in 148 genetic regions. Two independent U.S. case-control studies included were as follows: a hospital-based study conducted by the National Cancer Institute (263 cases, 330 controls) and a community-based study conducted by the National Institute for Occupational Safety and Health (288 cases, 535 controls). Tag SNPs (1,397) chosen on the basis of an r2 of >0.8 and minor allele frequency of >5% in Caucasians in HapMap1 were genotyped. Glioma risk was estimated by odds ratios. Nine SNPs distributed across eight genetic regions (ALOX5, IRAK3, ITGB2, NCF2, NFKB1, SELP, SOD1, and STAT1) were associated with risk of glioma with P value of <0.01. Although these associations were no longer statistically significant after controlling for multiple comparisons, the associations were notably consistent in both studies. Region-based tests were statistically significant (P < 0.05) for SELP, SOD, and ALOX5. Analyses restricted to glioblastoma (n = 254) yielded significant associations for the SELP, DEFB126/127, SERPINI1, and LY96 genetic regions. We have identified a promising set of innate immunity-related genetic regions for further investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1651–8)

Effect of perchloroethylene, smoking, and race on oxidative DNA damage in female dry cleaners.

Perchloroethylene (PERC) is used widely as an industrial dry cleaning solvent and metal degreaser. PERC is an animal carcinogen that produces increased incidence of renal adenomas, adenocarcinomas, mononuclear cell leukemia, and hepatocellular tumors. Oxidative DNA damage and lipid peroxidation were assessed in 38 women with (dry cleaners) or without (launderers) occupational exposure to PERC. PERC exposure was assessed by collecting breathing zone samples on two consecutive days of a typical work week. PERC levels were measured in blood drawn on the morning of the second day of breathing zone sample collection in dry cleaners and before a typical workday in launderers. Blood PERC levels were two orders of magnitude higher in dry cleaners compared to launderers. A significant correlation was noted between time weighted average (TWA) PERC and blood PERC in dry cleaners (r=0.7355, P<0.002). 8-Hydroxydeoxyguanosine (8-OHdG), ng/mg deoxyguanosine (dG) in leukocyte nuclear DNA was used as an index of steady-state oxidative DNA damage. Urinary 8-OHdG, microg/g creatinine was used as an index of oxidative DNA damage repair. Urinary 8-epi-prostaglandin F(2alpha) (8-epi-PGF), ng/g creatinine was used as an index of lipid peroxidation. The mean+/-S.D. leukocyte 8-OHdG in launderers was 16.0+/-7.3 and was significantly greater than the 8.1+/-3.6 value for dry cleaners. Urinary 8-OHdG and 8-epi-PGF were not significantly different between dry cleaners and launderers. Unadjusted Pearson correlation analysis of log transformed PERC exposure indices and biomarkers of oxidative stress indicated a significant association in launderers between blood PERC and day 1 urinary 8-OHdG (r=0.4661, P<0.044). No significant associations between exposure indices and biomarkers were evident in linear models adjusted for age, body mass index, race, smoking (urinary cotinine, mg/g creatinine) and blood levels of the antioxidants Vitamin E and beta-carotene. The mean+/-S.D. leukocyte 8-OHdG value in control white women was 17.8+/-7.4 and was significantly greater than the 11.8+/-5.9 in control black women. No significant differences by race were evident for the other biomarkers. Smoking status was not significantly associated with any of the oxidative damage indices. Results indicate a reduction in oxidative DNA damage in PERC exposed dry cleaners relative to launderers, but PERC could not clearly be defined as the source of the effect.

Risk factors for oligodendroglial tumors: A pooled international study

Oligodendroglial tumors are rare subtypes of brain tumors and are often combined with other glial tumors in epidemiological analyses. However, different demographic associations and clinical characteristics suggest potentially different risk factors. The purpose of this study was to investigate possible risk factors for oligodendroglial tumors (including oligodendroglioma, anaplastic oligodendroglioma, and mixed glioma). Data from 7 case-control studies (5 US and 2 Scandinavian) were pooled. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age group, gender, and study site. Data on 617 cases and 1260 controls were available for analyses. Using data from all 7 studies, history of allergies and/or asthma was associated with a decreased risk of anaplastic oligodendroglioma (OR = 0.6; 95% CI: 0.4-0.9), and history of asthma only was associated with a decreased risk of oligodendroglioma (OR = 0.5; 95% CI: 0.3-0.9) and anaplastic oligodendroglioma (OR = 0.3; 95% CI: 0.1-0.9). A family history of brain tumors was associated with an increased risk of anaplastic oligodendroglioma (OR = 2.2; 95% CI: 1.1-4.5). Having had chicken pox was associated with a decreased risk of oligodendroglioma (OR = 0.6; 95% CI: 0.4-0.9) and anaplastic oligodendroglioma (OR = 0.5; 95% CI: 0.3-0.9) in the US studies. Although there is some overlap in risk factors between oligodendroglial tumors and gliomas as a group, it is likely that additional factors specific to oligodendroglial tumors have yet to be identified. Large, multi-institution international studies will be necessary to better characterize these etiological risk factors.

Biological exposure assessment to tetrachloroethylene for workers in the dry cleaning industry

BackgroundThe purpose of this study was to assess the feasibility of conducting biological tetrachloroethylene (perchloroethylene, PCE) exposure assessments of dry cleaning employees in conjunction with evaluation of possible PCE health effects.MethodsEighteen women from four dry cleaning facilities in southwestern Ohio were monitored in a pilot study of workers with PCE exposure. Personal breathing zone samples were collected from each employee on two consecutive work days. Biological monitoring included a single measurement of PCE in blood and multiple measurements of pre- and post-shift PCE in exhaled breath and trichloroacetic acid (TCA) in urine.ResultsPost-shift PCE in exhaled breath gradually increased throughout the work week. Statistically significant correlations were observed among the exposure indices. Decreases in PCE in exhaled breath and TCA in urine were observed after two days without exposure to PCE. A mixed-effects model identified statistically significant associations between PCE in exhaled breath and airborne PCE time weighted average (TWA) after adjusting for a random participant effect and fixed effects of time and body mass index.ConclusionAlthough comprehensive, our sampling strategy was challenging to implement due to fluctuating work schedules and the number (pre- and post-shift on three consecutive days) and multiplicity (air, blood, exhaled breath, and urine) of samples collected. PCE in blood is the preferred biological index to monitor exposures, but may make recruitment difficult. PCE TWA sampling is an appropriate surrogate, although more field intensive. Repeated measures of exposure and mixed-effects modeling may be required for future studies due to high within-subject variability. Workers should be monitored over a long enough period of time to allow the use of a lag term.

Gliomas and farm pesticide exposure in men: the upper midwest health study.

Abstract The National Institute for Occupational Safety and Health evaluated farm pesticide exposure and glioma risk in a study that included 457 glioma cases and 648 population-based controls, all adult men (18–80 yr old) and nonmetropolitan residents of Iowa, Michigan, Minnesota, and Wisconsin. Multiple logistic regressions were used to control for farm residence, age, age group, education, and exposure to other pesticides. No associations were found between glioma and 12 specific pesticides. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (Cls) and found reduced glioma risk for insecticides (OR = 0.53, Cl = 0.37–0.77), fumigants (OR = 0.57, Cl = 0.34–0.95), and organochlorines (OR = 0.66, Cl = 0.47–0.94). In analyses excluding proxy respondents (47% of cases) most Cls included 1.0. No positive association of farm pesticide exposure and glioma was found. Other farm exposures may explain the excess brain cancer risk seen in previous studies.

Known glioma risk loci are associated with glioma with a family history of brain tumours -- a case-control gene association study.

Familial cancer can be used to leverage genetic association studies. Recent genome‐wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first‐ or second‐degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty‐one glioma cases and 2,868 cancer‐free controls were identified from four case–control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case–control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A‐CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25–0.61; Bonferroni adjusted ptrend, 1.7 × 10−4). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.

Detection of DNA damage in workers exposed to JP-8 jet fuel.

The genotoxicity of jet propulsion fuel 8 (JP-8) was assessed in the leukocytes of archived blood specimens from U.S. Air Force personnel using the comet assay. No differences in mean comet assay measurements were found between low, moderate, and high exposure groups before or after a 4h work shift. Before the work shift, mean tail DNA and mean tail (Olive) moment increased as the concentration of benzene measured in end-exhaled breath increased, indicating that prior environmental or work-related exposures to benzene produced DNA damage. The number of cells with highly damaged DNA decreased as the pre-shift benzene concentration in breath increased. It is not clear why the decrease is occurring. Mean tail DNA and mean tail (Olive) moment decreased as the concentrations of benzene and naphthalene measured in breath immediately after the work shift increased. These inverse relationships may reflect a slower rate of absorption or a faster rate of expiration of benzene in the lung. The number of cells with highly damaged DNA increased as the concentration of urinary (2-methoxyethoxy)acetic acid (MEAA) increased. This relationship was not seen in urinary MEAA adjusted for creatinine. MEAA is a metabolite of the deicing agent 2-(2-methoxyethoxy)ethanol contained in JP-8. MEAA or a component of JP-8 correlated with MEAA may have a toxic effect on DNA.

Immunoglobulin Genes Influence the Magnitude of Humoral Immunity to Cytomegalovirus Glycoprotein B

Human cytomegalovirus (HCMV) is a risk factor for many human diseases, but among exposed individuals, not everyone is equally likely to develop HCMV-spurred diseases, implying the presence of host genetic factors that might modulate immunity to this virus. Here, we show that antibody responsiveness to HCMV glycoprotein B (gB) is significantly associated with particular immunoglobulin GM (γ marker) genotypes. Anti-HCMV gB antibody levels were highest in GM 17/17 homozygotes, intermediate in GM 3/17 heterozygotes, and lowest in GM 3/3 homozygotes (28.2, 19.0, and 8.1 µg/mL, respectively; P=.014). These findings provide mechanistic insights in the etiopathogenesis of HCMV-spurred diseases.