Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Pesticide use and inflammatory bowel disease in licensed pesticide applicators and spouses in the Agricultural Health Study.

BACKGROUND: Pesticide exposure has been linked to some autoimmune diseases and colorectal cancer, possibly via alteration of gut microbiota or other mechanisms. While pesticides have been linked to gut dysbiosis and inflammation in animal models, few epidemiologic studies have examined pesticides in relation to inflammatory bowel disease (IBD). OBJECTIVES: We evaluated use of pesticides and incident IBD in 68,480 eligible pesticide applicators and spouses enrolled in the Agricultural Health Study. METHODS: Self-reported IBD cases were identified from follow-up questionnaires between enrollment (1993-1997) and 2022. We evaluated IBD incidence in relation to self-reported ever use of 50 pesticides among applicators and spouses. We also explored associations with intensity-weighted lifetime days (IWLD) of pesticide use among male applicators. Covariate-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression. RESULTS: We identified 454 IBD cases, including 227 among male applicators. In analyses with applicators and spouses combined, associations were positive (HR > 1.2) for ever vs. never use of five organochlorine insecticides, three organophosphate insecticides, one fungicide, and five herbicides. HRs were highest for dieldrin (HR = 1.59, 95%CI: 1.03, 2.44), toxaphene (HR = 1.61, 95%CI: 1.17, 2.21), parathion (HR = 1.42, 95%CI: 1.03, 1.95), and terbufos (HR = 1.53, 95%CI: 1.19, 1.96). We had limited power in many IWLD of pesticide use analyses and did not find clear evidence of exposure-response trends; however, we observed elevated HRs in all tertiles of IWLD use of terbufos compared to never use (T1 vs. never use HR = 1.52, 95%CI: 1.03, 2.24; T2 vs. never use HR = 1.53, 95%CI: 1.04, 2.26; T3 vs. never use HR = 1.51, 95%CI: 1.03, 2.23). CONCLUSIONS: Exposure to specific pesticides was associated with elevated hazards of IBD. These findings may have public health importance given the widespread use of pesticides and the limited number of known modifiable environmental risk factors for IBD.

Occupational farm work activities influence workers' indoor home microbiome.

BACKGROUND: Farm work entails a heterogeneous mixture of exposures that vary considerably across farms and farmers. Farm work is associated with various health outcomes, both adverse and beneficial. One mechanism by which farming exposures can impact health is through the microbiome, including the indoor home environment microbiome. It is unknown how individual occupational exposures shape the microbial composition in workers' homes. OBJECTIVES: We investigated associations between farm work activities, including specific tasks and pesticide use, and the indoor microbiome in the homes of 468 male farmers. METHODS: Participants were licensed pesticide applicators, mostly farmers, enrolled in the Agricultural Lung Health Study from 2008 to 2011. Vacuumed dust from participants' bedrooms underwent whole-genome shotgun sequencing for indoor microbiome assessment. Using questionnaire data, we evaluated 6 farm work tasks (processing of either hay, silage, animal feed, fertilizer, or soy/grains, and cleaning grain bins) and 19 pesticide ingredients currently used in the past year, plus 7 banned persistent pesticide ingredients ever used. RESULTS: All 6 work tasks were associated with increased microbial diversity levels, with a positive dose-response for the total number of tasks performed (P = 0.001). All tasks were associated with altered microbial compositions (weighted UniFrac P = 0.001) and with higher abundance of specific microbes, including soil-based commensal microbes such as Haloterrigena. Among the 19 pesticides, current use of glyphosate and past use of lindane were associated with increased microbial diversity (P = 0.02-0.04). Ten currently used pesticides and all 7 banned pesticides were associated with altered microbial composition (P = 0.001-0.04). Six pesticides were associated with differential abundance of certain microbes. DISCUSSION: Different farm activities and exposures can uniquely impact the dust microbiome inside homes. Our work suggests that changes to the home microbiome could serve as one pathway for how occupational exposures impact the health of workers and their cohabitating family members, offering possible future intervention targets.

Mosquito control exposures and breast cancer risk: analysis of 1071 cases and 2096 controls from the Ghana Breast Health Study.

Epidemiologic data on insecticide exposures and breast cancer risk are inconclusive and mostly from high-income countries. Using data from 1071 invasive pathologically confirmed breast cancer cases and 2096 controls from the Ghana Breast Health Study conducted from 2013 to 2015, we investigated associations with mosquito control products to reduce the spread of mosquito-borne diseases, such as malaria. These mosquito control products were insecticide-treated nets, mosquito coils, repellent room sprays, and skin creams for personal protection against mosquitos. Multivariable and polytomous logistic regression models were used to estimate odds ratios (ORadj) and 95% confidence intervals (CI) with breast cancer risk-adjusted for potential confounders and known risk factors. Among controls, the reported use of mosquito control products were mosquito coils (65%), followed by insecticide-treated nets (56%), repellent room sprays (53%), and repellent skin creams (15%). Compared to a referent group of participants unexposed to mosquito control products, there was no significant association between breast cancer risk and mosquito coils. There was an association in breast cancer risk with reported use of insecticide-treated nets; however, that association was weak and not statistically significant. Participants who reported using repellent sprays were at elevated risks compared to women who did not use any mosquito control products, even after adjustment for all other mosquito control products (OR = 1.42, 95% CI=1.15-1.75). We had limited power to detect an association with repellent skin creams. Although only a few participants reported using repellent room sprays weekly/daily or < month-monthly, no trends were evident with increased frequency of use of repellent sprays, and there was no statistical evidence of heterogeneity by estrogen receptor (ER) status (p-het > 0.25). Our analysis was limited when determining if an association existed with repellent skin creams; therefore, we cannot conclude an association. We found limited evidence of risk associations with widely used mosquito coils and insecticide-treated nets, which are reassuring given their importance for malaria prevention. Our findings regarding specific breast cancer risk associations, specifically those observed between repellent sprays, require further study.

A latent functional approach for modeling the effects of multidimensional exposures on disease risk.

Understanding the relationships between exposure and disease incidence is an important problem in environmental epidemiology. Typically, a large number of these exposures are measured, and it is found either that a few exposures transmit risk or that each exposure transmits a small amount of risk, but, taken together, these may pose a substantial disease risk. Further, these exposure effects can be nonlinear. We develop a latent functional approach, which assumes that the individual effect of each exposure can be characterized as one of a series of unobserved functions, where the number of latent functions is less than or equal to the number of exposures. We propose Bayesian methodology to fit models with a large number of exposures and show that existing Bayesian group LASSO approaches are a special case of the proposed model. An efficient Markov chain Monte Carlo sampling algorithm is developed for carrying out Bayesian inference. The deviance information criterion is used to choose an appropriate number of nonlinear latent functions. We demonstrate the good properties of the approach using simulation studies. Further, we show that complex exposure relationships can be represented with only a few latent functional curves. The proposed methodology is illustrated with an analysis of the effect of cumulative pesticide exposure on cancer risk in a large cohort of farmers.

Joint associations between established genetic susceptibility loci, pesticide exposures, and risk of prostate cancer.

More than 200 genetic variants have been independently associated with prostate cancer risk. Studies among farmers have also observed increased prostate cancer risk associated with exposure to specific organophosphate (fonofos, terbufos, malathion, dimethoate) and organochlorine (aldrin, chlordane) insecticides. We examined the joint associations between these pesticides, established prostate cancer loci, and prostate cancer risk among 1,162 cases (588 aggressive) and 2,206 frequency-matched controls nested in the Agricultural Health Study cohort. History of lifetime pesticide use was combined with a polygenic risk score (PRS) generated using 256 established prostate cancer risk variants. Logistic regression models estimated the joint associations of the pesticides, the PRS, and the 256 individual genetic variants with risk of total and aggressive prostate cancer. Likelihood ratio tests assessed multiplicative interaction. We observed interaction between ever use of fonofos and the PRS in relation to total and aggressive prostate cancer risk. Compared to the reference group (never use, PRS < median), men with ever use of fonofos and PRS > median had elevated risks of total (OR 1.35 [1.06-1.73], p-interaction = 0.03) and aggressive (OR 1.49 [1.09-2.04], p-interaction = 0.19) prostate cancer. There was also suggestion of interaction between pesticides and individual genetic variants occurring in regions associated with DNA damage response (CDH3, EMSY genes) and with variants related to altered androgen receptor-driven transcriptional programs critical for prostate cancer. Our study provides evidence that men with greater genetic susceptibility to prostate cancer may be at higher risk if they are also exposed to pesticides and suggests potential mechanisms by which pesticides may increase prostate cancer risk.

An algorithm for quantitatively estimating occupational endotoxin exposure in the biomarkers of exposure and effect in agriculture study: II. Application to the study population.

BACKGROUND: We developed an algorithm to quantitatively estimate endotoxin exposure for farmers in the Biomarkers of Exposure and Effect in Agriculture (BEEA) Study. METHODS: The algorithm combined task intensity estimates derived from published data with questionnaire responses on activity duration to estimate task-specific cumulative endotoxin exposures for 13 tasks during four time windows, ranging from "past 12 months" to "yesterday/today." We applied the algorithm to 1681 participants in Iowa and North Carolina. We examined correlations in endotoxin metrics within- and between-task. We also compared these metrics to prior day full-shift inhalable endotoxin concentrations from 32 farmers. RESULTS: The highest median task-specific cumulative exposures were observed for swine confinement, poultry confinement, and grind feed. Inter-quartile ranges showed substantial between-subject variability for most tasks. Time window-specific metrics of the same task were moderately-highly correlated. Between-task correlation was variable, with moderately-high correlations observed for similar tasks (e.g., between animal-related tasks). Prior day endotoxin concentration increased with the total metric and with task metrics for swine confinement, clean other animal facilities, and clean grain bins. SIGNIFICANCE: This study provides insight into the variability and sources of endotoxin exposure among farmers in the BEEA study and summarizes exposure estimates for future investigations in this population.

An algorithm for quantitatively estimating occupational endotoxin exposure in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study: I. Development of task-specific exposure levels from published data.

BACKGROUND/OBJECTIVE: Farmers conduct numerous tasks with potential for endotoxin exposure. As a first step to characterize endotoxin exposure for farmers in the Biomarkers of Exposure and Effect in Agriculture (BEEA) Study, we used published data to estimate task-specific endotoxin concentrations. METHODS: We extracted published data on task-specific, personal, inhalable endotoxin concentrations for agricultural tasks queried in the study questionnaire. The data, usually abstracted as summary measures, were evaluated using meta-regression models that weighted each geometric mean (GM, natural-log transformed) by the inverse of its within-study variance to obtain task-specific predicted GMs. RESULTS: We extracted 90 endotoxin summary statistics from 26 studies for 9 animal-related tasks, 30 summary statistics from 6 studies for 3 crop-related tasks, and 10 summary statistics from 5 studies for 4 stored grain-related tasks. Work in poultry and swine confinement facilities, grinding feed, veterinarian services, and cleaning grain bins had predicted GMs > 1000 EU/m3 . In contrast, harvesting or hauling grain and other crop-related tasks had predicted GMs below 100 EU/m3 . SIGNIFICANCE: These task-specific endotoxin GMs demonstrated exposure variability across common agricultural tasks. These estimates will be used in conjunction with questionnaire responses on task duration to quantitatively estimate endotoxin exposure for study participants, described in a companion paper.

Elevated 2,4-dichlorophenoxyacetic acid (2,4-D) herbicide concentrations in the household dust of farmers with recent occupational use.

Pesticide dust concentrations in homes have been previously associated with occupational and home/garden use of pesticides, hygiene practices, and other factors. This study evaluated the relationship between self-reported use of 2,4-dichlorophenoxyacetic acid (2,4-D) and house dust concentrations and these factors in the Biomarkers of Exposure and Effect in Agriculture (BEEA) Study, a molecular epidemiologic study of farmers in Iowa and North Carolina. The vacuum dust from the homes of 35 BEEA participants was analyzed for the presence of 2,4-D. Participants provided detailed information on occupational and home/garden pesticide use during the past 12 months and reported household characteristics via questionnaires. Linear regression models were used to examine the association between 2,4-D concentrations and four exposure metrics for occupational use in the last 12 months (yes/no, days since last use, days of use, intensity-weighted days of use), home/garden use (yes/no), as well as several household characteristics. 2,4-D was detected in all homes and was used occupationally by 54% of the participants. In a multi-variable model, compared to homes with no occupational or home/garden 2,4-D use reported in the past 12 months, concentrations were 1.6 (95% confidence interval (CI): 0.5, 4.9) times higher in homes with low occupational 2,4-D use (intensity-weighted days < median) and 3.1 (95% CI: 1.0, 9.8) times higher in homes of participants with high use (≥median intensity-weighted days) (p-trend = 0.06). Similar patterns were observed with other occupational metrics. Additionally, 2,4-D dust concentrations were non-significantly elevated (relative difference (RD) = 1.8, 95% CI: 0.5, 6.2) in homes with home/garden use and were significantly lower in homes that did not have carpets (RD = 0.20, 95% CI: 0.04, 0.98). These analyses suggest that elevated 2,4-D dust concentrations were associated with several metrics of recent occupational use and may be influenced by home/garden use and household characteristics.

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

High Pesticide Exposure Events and Dream-Enacting Behaviors Among US Farmers.

BACKGROUND: Dream-enacting behavior is a characteristic feature of rapid eye movement sleep behavior disorder, the most specific prodromal marker of synucleinopathies. Pesticide exposure may be associated with dream-enacting behaviors, but epidemiological evidence is limited. OBJECTIVES: To examine high pesticide exposure events in relation to dream-enacting behaviors among farmers in the Agricultural Health Study. METHODS: We conducted multivariable logistic regression analyses to examine high pesticide exposure events reported from 1993 to 1997 in relation to dream-enacting behaviors assessed from 2013 to 2015 among 11,248 farmers (age 47 ± 11 years). RESULTS: A history of dream-enacting behaviors was reported by 939 (8.3%) farmers. Compared with farmers who did not report any high pesticide exposure event, those who reported were more likely to endorse dream-enacting behaviors 2 decades later (odds ratio = 1.75; 95% confidence interval [CI], 1.49-2.05). The association appeared stronger when there was a long delay in washing with soap and water after the event (2.63 [95% CI, 1.62-4.27] for waiting >6 hours vs. 1.71 [95% CI, 1.36-2.15] for washing within 30 minutes) and when the exposure involved the respiratory or digestive tract (2.04 [95% CI, 1.62-2.57] vs. 1.58 [95% CI, 1.29-1.93] for dermal contact only). In the analyses of specific pesticides involved, we found positive associations with two organochlorine insecticides (dichlorodiphenyltrichloroethane and lindane), four organophosphate insecticides (phorate, ethoprop, terbufos, and parathion), two herbicides (alachlor and paraquat), and fungicides as a group. CONCLUSIONS: This study provides the first epidemiological evidence that high pesticide exposures may be associated with a higher risk of dream-enacting behaviors. © 2022 International Parkinson and Movement Disorder Society.

Use of permethrin and other pyrethroids and mortality in the Agricultural Health Study.

OBJECTIVES: Pyrethroid insecticides have been linked with multiple health outcomes. One study reported an association with increased all-cause and cardiovascular mortality. Given the widespread use of pyrethroids, these findings warrant confirmation. We explored associations of permethrin/pyrethroid use with overall and cause-specific mortality among 50 665 licensed pesticide applicators in the Agricultural Health Study. METHODS: At enrolment (1993-1997), participants self-reported information on permethrin/pyrethroid use. Information on causes of death came from linkage with death registries through 2016. We used Cox proportional hazards models to estimate HRs and 95% CIs with adjustment for potential confounders. RESULTS: Over an average 21 years of follow-up, 19.6% (9,955) of the cohort died. We found no clear evidence that ever-use of permethrin/pyrethroid was associated with elevated overall mortality or with mortality from most causes examined. There was suggestive evidence, based on a small number of deaths among those exposed, for elevated pyrethroid-associated mortality from some neurological, respiratory and genitourinary diseases in the overall sample and from lung cancer among never-smokers. CONCLUSION: Although based on mortality, which is also affected by survival, rather than incidence, these findings are biologically plausible, and future investigations in other populations may be warranted.

Allergic and non-allergic wheeze among farm women in the Agricultural Health Study (2005-2010).

BACKGROUND: Farms represent complex environments for respiratory exposures including hays, grains and pesticides. Little is known about the impact of these exposures on women's respiratory health. We evaluated the association of farm exposures with allergic and non-allergic wheeze among women in the Agricultural Health Study, a study of farmers and their spouses based in Iowa and North Carolina. METHODS: We used self-reported data (2005-2010) on current use (≤12 months) of 15 pesticides (selected based on frequency of use) and occupational farm activities from 20 164 women. We defined allergic wheeze as reporting wheeze and doctor-diagnosed hay fever (7%) and non-allergic wheeze as wheeze but not hay fever (8%) in the past 12 months. Using polytomous logistic regression, we evaluated associations of wheeze subtypes with pesticides and other farm exposures (eg, raising farm animals) using no wheeze/hay fever as the referent, adjusting for age, body mass index, state, current asthma, glyphosate use and smoking. RESULTS: Current use of any pesticide, reported by 7% of women, was associated with both allergic (OR: 1.36, 95% CI: 1.10 to 1.67) and non-allergic (OR: 1.25, 95% CI: 1.04 to 1.51) wheeze. Four pesticides were associated with at least one wheeze subtype: glyphosate, with both wheeze subtypes; diazinon and fly spray with only allergic wheeze; carbaryl with only non-allergic wheeze. Working weekly with mouldy hay was associated with allergic (OR: 1.88, 95% CI: 1.26 to 2.80) and non-allergic wheeze (OR: 1.69, 95% CI: 1.18 to 2.42). CONCLUSION: Use of specific pesticides and certain farm activities may contribute to wheeze among farm women.

Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study.

OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

House dust microbiota in relation to adult asthma and atopy in a US farming population.

BACKGROUND: Bacterial exposure from house dust has been associated with asthma and atopy in children but whether these relationships are present in adults remains unclear. OBJECTIVE: We sought to examine associations of house dust microbiota with adult asthma, atopy, and hay fever. METHODS: Vacuumed bedroom dust samples from the homes of 879 participants (average age, 62 years) in the Agricultural Lung Health Study, a case-control study of asthma nested within a farming cohort, were subjected to 16S rRNA amplicon sequencing to characterize bacterial communities. We defined current asthma and hay fever using questionnaires and current atopy by blood specific IgE level > 0.70 IU/mL to 1 or more of 10 common allergens. We used linear regression to examine whether overall within-sample bacterial diversity differed by outcome, microbiome regression-based kernel association test to evaluate whether between-sample bacterial community compositions differed by outcome, and analysis of composition of microbiomes to identify differentially abundant bacterial taxa. RESULTS: Overall diversity of bacterial communities in house dust was similar by asthma status but was lower (P < .05) with atopy or hay fever. Many individual bacterial taxa were differentially abundant (false-discovery rate, <0.05) by asthma, atopy, or hay fever. Several taxa from Cyanobacteria, Bacteroidetes, and Fusobacteria were more abundant with asthma, atopy, or hay fever. In contrast, several taxa from Firmicutes were more abundant in homes of individuals with adequately controlled asthma (vs inadequately controlled asthma), individuals without atopy, or individuals without hay fever. CONCLUSIONS: Microbial composition of house dust may influence allergic outcomes in adults.

Observed vs. self-reported agricultural activities: Evaluating 24-hr recall in a pilot study.

Few studies have evaluated the validity of self-report of work activities because of challenges in obtaining objective measures. In this study, farmers' recall of the previous day's agricultural activities was compared to activities observed by field staff during air monitoring. Recall was assessed in 32 farmers from the Biomarkers of Exposure and Effect in Agriculture Study, a subset of a prospective cohort study. The farmers participated in 56 visits that comprised air monitoring the day before an interview. The answers for 14 agricultural activities were compared to activities observed by field staff during air monitoring (median duration 380 min, range 129-486). For each task, evaluated as yes/no, overall agreement, sensitivity, specificity, and kappa were calculated. Median prevalence of the 14 activities was 8% from observation and 13% from participants (range: 2-54%). Agreement was generally good to perfect, with a median overall agreement of 95% (range: 89-100%), median sensitivity of 84% (50-100%), median specificity of 95% (88-100%), and median kappa of 0.65 (0.31-1.0). Reasons for disagreement included activities occurring when the field staff was not present (i.e., milking cows), unclear timing notes that made it difficult to determine whether the activity occurred the day of and/or day before the interview, definition issues (i.e., participant included hauling in the definition of harvesting), and difficulty in observing details of an activity (i.e., whether hay was moldy). This study provides support for accurate participant recall the day after activities.

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

BACKGROUND: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. METHODS: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. RESULTS: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. CONCLUSION: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin.

RATIONALE: Genome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene-environment interactions, but studies are few. METHODS: We analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case-control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10-9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions. RESULTS: Each trait was highly significantly associated with its GRS (all three p values<8.9×10-8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin. CONCLUSIONS: Evaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.

Associations Between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Postmenopausal Women.

BACKGROUND AND AIMS: In almost all countries, incidence rates of liver cancer (LC) are 100%-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of LC cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with LC risk, overall and by histology, by leveraging resources from five prospective cohorts. APPROACH AND RESULTS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography/tandem mass spectrometry and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 postmenopausal female LC cases (HCC, n = 83; ICC, n = 56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and LC were calculated using multivariable-adjusted conditional logistic regression. A doubling in the concentration of 4-androstenedione (4-dione) was associated with a 50% decreased LC risk (OR = 0.50; 95% CI = 0.30-0.82), whereas SHBG was associated with a 31% increased risk (OR = 1.31; 95% CI = 1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR = 1.40; 95% CI = 1.05-1.89), but not HCC (OR = 1.12; 95% CI = 0.81-1.54). CONCLUSIONS: This study provides evidence that higher levels of 4-dione may be associated with lower, and SHBG with higher, LC risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease LC risk. Indeed, estradiol may be associated with an increased ICC risk.