Publications by authors named "Laura E Beane Freeman"

203 Publications

Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study.

Environ Health Perspect 2021 Sep 13;129(9):97008. Epub 2021 Sep 13.

Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina, USA.

Background: Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides.

Objectives: We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients.

Methods: The Agricultural Lung Health Study is a case-control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina's EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009-2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users.

Results: Using family-wise error rate () or false-discovery rate (), we identified 162 differentially methylated CpGs across 8 of 9 currently marketed active ingredients (acetochlor, atrazine, dicamba, glyphosate, malathion, metolachlor, mesotrione, and picloram) and one banned organochlorine (heptachlor). Differentially methylated CpGs were unique to each active ingredient, and a dose-response relationship with lifetime days of use was observed for most. Significant CpGs were enriched for transcription motifs and 28% of CpGs were associated with whole blood -gene expression, supporting functional effects of findings. We corroborated a previously reported association between dichlorodiphenyltrichloroethane (banned in the United States in 1972) and epigenetic age acceleration.

Discussion: We identified differential methylation for several active ingredients in male farmers of European ancestry. These may serve as biomarkers of chronic exposure and could inform mechanisms of long-term health outcomes from pesticide exposure. https://doi.org/10.1289/EHP8928.
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http://dx.doi.org/10.1289/EHP8928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437246PMC
September 2021

Cancer incidence in agricultural workers: Findings from an international consortium of agricultural cohort studies (AGRICOH).

Environ Int 2021 12 27;157:106825. Epub 2021 Aug 27.

Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.

Background: Agricultural work can expose workers to potentially hazardous agents including known and suspected carcinogens. This study aimed to evaluate cancer incidence in male and female agricultural workers in an international consortium, AGRICOH, relative to their respective general populations.

Methods: The analysis included eight cohorts that were linked to their respective cancer registries: France (AGRICAN: n = 128,101), the US (AHS: n = 51,165, MESA: n = 2,177), Norway (CNAP: n = 43,834), Australia (2 cohorts combined, Australian Pesticide Exposed Workers: n = 12,215 and Victorian Grain Farmers: n = 919), Republic of Korea (KMCC: n = 8,432), and Denmark (SUS: n = 1,899). For various cancer sites and all cancers combined, standardized incidence ratios (SIR) and 95% confidence intervals (CIs) were calculated for each cohort using national or regional rates as reference rates and were combined by random-effects meta-analysis.

Results: During nearly 2,800,000 person-years, a total of 23,188 cancers were observed. Elevated risks were observed for melanoma of the skin (number of cohorts = 3, meta-SIR = 1.18, CI: 1.01-1.38) and multiple myeloma (n = 4, meta-SIR = 1.27, CI: 1.04-1.54) in women and prostate cancer (n = 6, meta-SIR = 1.06, CI: 1.01-1.12), compared to the general population. In contrast, a deficit was observed for the incidence of several cancers, including cancers of the bladder, breast (female), colorectum, esophagus, larynx, lung, and pancreas and all cancers combined (n = 7, meta-SIR for all cancers combined = 0.83, 95% CI: 0.77-0.90). The direction of risk was largely consistent across cohorts although we observed large between-cohort variations in SIR for cancers of the liver and lung in men and women, and stomach, colorectum, and skin in men.

Conclusion: The results suggest that agricultural workers have a lower risk of various cancers and an elevated risk of prostate cancer, multiple myeloma (female), and melanoma of skin (female) compared to the general population. Those differences and the between-cohort variations may be due to underlying differences in risk factors and warrant further investigation of agricultural exposures.
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http://dx.doi.org/10.1016/j.envint.2021.106825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484858PMC
December 2021

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.

Breast Cancer Res 2021 08 18;23(1):86. Epub 2021 Aug 18.

Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.

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.
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http://dx.doi.org/10.1186/s13058-021-01450-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371820PMC
August 2021

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

Br J Cancer 2021 Oct 2;125(8):1135-1145. Epub 2021 Aug 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

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), 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.
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http://dx.doi.org/10.1038/s41416-021-01432-8DOI Listing
October 2021

Agricultural Pesticides and Shingles Risk in a Prospective Cohort of Licensed Pesticide Applicators.

Environ Health Perspect 2021 Jul 28;129(7):77005. Epub 2021 Jul 28.

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.

Background: Some pesticides are immunotoxic and have been associated with an increased risk of immune-mediated diseases. The risk of shingles, the clinical reactivation of varicella-zoster virus, increases with aging and immunosuppression; little is known about its associations with pesticides.

Objective: We examined the use of agricultural pesticides in relation to incident shingles in a prospective cohort of licensed pesticide applicators.

Methods: The study sample included 12,820 (97% male) farmers (enrolled in 1993-1997 in North Carolina and Iowa), who were followed for a median of 12 y (interquartile range: 11-13). Shingles was self-reported at enrollment and at follow-up. We evaluated ever-use of 48 agricultural pesticides reported at study enrollment in relation to shingles risk and considered exposure-response for intensity-weighted lifetime days (IWLDs) of use. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models, adjusting for state, and allowing estimates to vary by median attained age (60 y).

Results: Incident shingles was reported by 590 participants. Associations were positive () for ever- vs. never-use of eight insecticides, three fumigants, two fungicides, and five herbicides, and exposure-response trends were seen across increasing quartiles (Q3 and ) or tertiles (T3 and ) of IWLDs for four insecticides [permethrin (crops), coumaphos, malathion, and lindane], two fumigants (carbon tetrachloride/carbon disulfide and methyl bromide), and three herbicides [alachlor, trifluralin () and 2,4-dichlorophenoxyacetic acid]. Shingles was not associated with total years or days per year mixed or applied any pesticides, but in older participants, shingles was associated with a history of a high pesticide exposure event [ (95% CI: 1.45, 2.45)].

Conclusions: Several specific pesticides were associated with increased risk of shingles in farmers, especially at higher levels of cumulative use. These novel findings, if replicated in other populations, could have broader implications for the potential effects of pesticides on vaccine efficacy and susceptibility to other infections. https://doi.org/10.1289/EHP7797.
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http://dx.doi.org/10.1289/EHP7797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317610PMC
July 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 10;114(4):1408-1417

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488877PMC
October 2021

Pesticide use and kidney function among farmers in the Biomarkers of Exposure and Effect in Agriculture study.

Environ Res 2021 08 11;199:111276. Epub 2021 May 11.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Electronic address:

Background: Pesticides have been reported to be associated with malignant and non-malignant kidney disease. Few studies have examined the relationship between individual pesticides and kidney dysfunction.

Objective: We evaluated the associations of pesticide use with measured kidney function among male pesticide applicators in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study, a subcohort in the Agricultural Health Study.

Methods: Serum creatinine was measured in 1545 BEEA participants and estimated glomerular filtration rate (eGFR) was calculated with the chronic kidney disease epidemiology collaboration (CKD-EPI) equation. Using reported information on lifetime use of 41 pesticides, multivariable linear and logistic regression was used to examine associations with eGFR modeled continuously and with CKD (eGFR <60 mL/min/1.73 m), respectively. Models were adjusted for possible confounding factors related to kidney function and correlated pesticides.

Results: Lower eGFR was observed among pesticide applicators who ever used the herbicides pendimethalin (-3.7%, 95% confidence interval (CI): 5.8%, -1.5%), atrazine (-3.7%, 95% CI: 6.9%, -0.4%), and dicamba (-2.8%, 95% CI: 5.3%, -0.2%) compared with never users of each pesticide. Ever use of pendimethalin (odds ratio (OR)=1.6, 95% CI: 1.1, 2.2) and atrazine (OR=1.8, 95% CI: 1.0, 3.0) was also associated with elevated odds of CKD, with an exposure-response association between intensity-weighted lifetime days of pendimethalin use and CKD among active farmers (N=1302; p=0.04). Atrazine use within the last year was associated with lower eGFR and elevated odds of CKD when compared with never users, and we observed exposure-response associations with intensity-weighted lifetime days among recent users. Use of several other pesticides was associated with higher eGFR.

Discussion: These results suggest that two widely used herbicides, pendimethalin and atrazine, may be associated with altered kidney function among pesticide applicators. Our findings for these herbicides are consistent with observed associations with end-stage renal disease in the Agricultural Health Study.
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http://dx.doi.org/10.1016/j.envres.2021.111276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489787PMC
August 2021

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

Thorax 2021 May 7. Epub 2021 May 7.

Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA

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 FEV, FVC and FEV/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) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r=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). The inverse association of the GRS with FEV/FVC was stronger for current smokers (p=0.017) or former smokers (p=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (p=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.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215624DOI Listing
May 2021

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Cancer Res 2021 06 11;81(11):3134-3143. Epub 2021 Feb 11.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and < 5 × 10 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, = 3.08 × 10). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178175PMC
June 2021

Spatial Heterogeneity in Positional Errors: A Comparison of Two Residential Geocoding Efforts in the Agricultural Health Study.

Int J Environ Res Public Health 2021 02 9;18(4). Epub 2021 Feb 9.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Geocoding is a powerful tool for environmental exposure assessments that rely on spatial databases. Geocoding processes, locators, and reference datasets have improved over time; however, improvements have not been well-characterized. Enrollment addresses for the Agricultural Health Study, a cohort of pesticide applicators and their spouses in Iowa (IA) and North Carolina (NC), were geocoded in 2012-2016 and then again in 2019. We calculated distances between geocodes in the two periods. For a subset, we computed positional errors using "gold standard" rooftop coordinates (IA; N = 3566) or Global Positioning Systems (GPS) (IA and NC; N = 1258) and compared errors between periods. We used linear regression to model the change in positional error between time periods (improvement) by rural status and population density, and we used spatial relative risk functions to identify areas with significant improvement. Median improvement between time periods in IA was 41 m (interquartile range, IQR: -2 to 168) and 9 m (IQR: -80 to 133) based on rooftop coordinates and GPS, respectively. Median improvement in NC was 42 m (IQR: -1 to 109 m) based on GPS. Positional error was greater in rural and low-density areas compared to in towns and more densely populated areas. Areas of significant improvement in accuracy were identified and mapped across both states. Our findings underscore the importance of evaluating determinants and spatial distributions of errors in geocodes used in environmental epidemiology studies.
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http://dx.doi.org/10.3390/ijerph18041637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915413PMC
February 2021

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev 2021 04 26;30(4):623-642. Epub 2021 Jan 26.

Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026532PMC
April 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Br J Cancer 2021 02 26;124(4):842-854. Epub 2021 Jan 26.

Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

Lifetime Pesticide Use and Monoclonal Gammopathy of Undetermined Significance in a Prospective Cohort of Male Farmers.

Environ Health Perspect 2021 01 6;129(1):17003. Epub 2021 Jan 6.

Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: Farmers have a higher incidence of multiple myeloma, and there is suggestive evidence of an elevated prevalence of its precursor, monoclonal gammopathy of undetermined significance (MGUS), relative to the general population. Pesticide exposures are suspected to play a role; however, the biologic plausibility for associations with multiple myeloma remains unclear.

Objectives: Our objectives were to examine the prevalence of MGUS and evaluate associations with a wide range of pesticides in a large sample of farmers.

Methods: We obtained sera and assessed MGUS among 1,638 male farmers of age in the Agricultural Health Study (AHS), a prospective cohort in Iowa and North Carolina. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate associations with MGUS for recent use (within the 12 months before phlebotomy) and cumulative intensity-weighted lifetime days of use of specific pesticides.

Results: The age-standardized MGUS prevalence was significantly elevated among AHS farmers (7.7%) compared with demographically similar men in the National Health and Nutrition Examination Survey (2.8%) or Olmsted County, Minnesota (3.8%; ). Recent use of permethrin was associated with MGUS [recent use vs. no recent use, (95% CI: 1.06, 3.13)], especially among those who had also used it in the past [recent and past use vs. never use, (95% CI: 1.32, 4.69)]. High intensity-weighted lifetime use of the organochlorine insecticides aldrin and dieldrin was associated with MGUS relative to those who never used either of these pesticides [ (95% CI: 1.29, 4.54); ]. We also observed a positive association with high lifetime use of petroleum oil/distillates as an herbicide, as well as an inverse association with fonofos use.

Discussion: This is the largest investigation of MGUS in farmers and the first to identify an association with MGUS for permethrin, a pyrethroid insecticide previously associated with multiple myeloma. Given the continued widespread use of permethrin in various residential and commercial settings, our findings may have important implications for exposed individuals in the general population. https://doi.org/10.1289/EHP6960.
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http://dx.doi.org/10.1289/EHP6960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787072PMC
January 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Pesticide exposure and incident thyroid cancer among male pesticide applicators in agricultural health study.

Environ Int 2021 01 27;146:106187. Epub 2020 Oct 27.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Many pesticides are known to have thyroid-disrupting properties. However, few studies have evaluated the association between specific pesticide ingredients and risk of thyroid cancer. We investigated self-reported pesticide use and incident thyroid cancer in the Agricultural Health Study (AHS), a large cohort of occupationally-exposed male pesticide applicators.

Methods: The AHS is a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. At enrollment (1993-1997) and follow-up (1999-2005), participants reported use of 50 pesticides. We characterized exposure as ever use (44 pesticides with ≥5 exposed cases) and by cumulative intensity-weighted lifetime days (22 pesticides with ≥10 exposed cases), a metric that accounts for factors that influence exposure. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression for incident thyroid (n = 85 cases) cancer among male participants using follow-up through 2014/2015.

Results: Use of the fungicide metalaxyl (HR = 2.03, CI:1.16-3.52) and the organochlorine insecticide lindane (HR = 1.74, CI:1.06-2.84) was associated with increased risk of thyroid cancer. The herbicide chlorimuron-ethyl was inversely associated with risk when we restricted to papillary thyroid cancer, the most common subtype (HR = 0.52, CI:0.28-0.96). High use of the insecticide carbaryl (>median intensity-weighted days) was inversely associated with thyroid cancer (HR = 0.20, CI:0.08-0.53, p = 0.001).

Conclusions: In this large cohort study, we observed increased risk of thyroid cancer associated with use of metalaxyl and lindane, and an inverse association with carbaryl. More work is needed to understand the potential role of these chemicals in thyroid carcinogenesis.
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http://dx.doi.org/10.1016/j.envint.2020.106187DOI Listing
January 2021

Occupational pesticide use and self-reported olfactory impairment in US farmers.

Occup Environ Med 2020 Oct 23. Epub 2020 Oct 23.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

Objectives: Pesticide exposure may impair human olfaction, but empirical evidence is limited. We examined associations between occupational use of 50 specific pesticides and olfactory impairment, both self-reported, among 20 409 participants in the Agricultural Health Study, a prospective cohort of pesticide applicators (mostly farmers, 97% male).

Methods: We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between pesticide use at enrolment (1993-1997) and olfactory impairment reported two decades later (2013-2016), adjusting for baseline covariates.

Results: About 10% of participants reported olfactory impairment. The overall cumulative days of any pesticide use at enrolment were associated with a higher odds of reporting olfactory impairment (OR (highest vs lowest quartile): 1.17 (95% CI: 1.02 to 1.34), p-trend = 0.003). In the analyses of 50 specific pesticides, ever-use of 20 pesticides showed modest associations with olfactory impairment, with ORs ranging from 1.11 to 1.33. Of these, higher lifetime days of use of 12 pesticides were associated with higher odds of olfactory impairment compared with never use (p-trend ≤ 0.05), including two organochlorine insecticides (dichlorodiphenyltrichloroethane and lindane), two organophosphate insecticides (diazinon and malathion), permethrin, the fungicide captan and six herbicides (glyphosate, petroleum distillates, 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid and metribuzin), although many of these did not exhibit clear, monotonic exposure-response patterns.

Conclusion: Overall, we found relatively broad associations between pesticides and olfactory impairment, involving many individual pesticides and covering several chemical classes, suggesting that pesticides could affect olfaction through multiple pathways. Future epidemiological studies with objective measurement of olfaction are required to confirm these findings.
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http://dx.doi.org/10.1136/oemed-2020-106818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062570PMC
October 2020

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 12 23;29(12):2735-2739. Epub 2020 Sep 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.

Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710600PMC
December 2020

Pesticide use and incident Parkinson's disease in a cohort of farmers and their spouses.

Environ Res 2020 12 10;191:110186. Epub 2020 Sep 10.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Electronic address:

Background: Extensive literature suggests an association between general pesticide use and Parkinson's disease (PD). However, with few exceptions, little is known about associations between specific pesticides and PD.

Objective: We evaluated use of pesticides and incident PD in 38,274 pesticide applicators and 27,836 of their spouses in the Agricultural Health Study cohort followed over 20 years.

Methods: We used self-reported information on ever-use of 50 specific pesticides as of enrollment for both applicators and spouses, and considered intensity-weighted lifetime days (IWLD) reported at enrollment and through the first 5-year follow-up among applicators. We estimated covariate-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression. We also examined heterogeneity in associations by history of head injury and chemical resistant glove use.

Results: A total of 373 applicators and 118 spouses self-reported incident doctor-diagnosed PD. Ever-use of the insecticide terbufos (HR:1.31, 95%CI:1.02-1.68) and the herbicides trifluralin (HR:1.29, 95%CI: 0.99-1.70) and 2,4,5-T (HR:1.57, 95%CI:1.21-2.04) was associated with elevated PD risk. On the other hand, diazinon (HR:0.73, 95%CI: 0.58-0.94) and 2,4,5-TP (HR:0.39, 95%CI:0.25-0.62) were associated with reduced risk. We observed heterogeneity in ever-use associations by head injury and chemical-resistant glove use for some pesticides, with higher risk among those who reported a history of head injury, or who did not use gloves. PD risk was also elevated for applicators in the highest category of IWLD for dichlorvos, permethrin (animal use), and benomyl.

Conclusions: We found evidence of increased PD risk for some pesticides. Our results also suggest higher susceptibility for pesticide-associated PD among individuals with head injury as well as protection with use of chemical resistant gloves, although further research is needed to understand the impact of head injury. Research on current and newer pesticides, including mechanisms relevant to PD, is important given widespread pesticide use.
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http://dx.doi.org/10.1016/j.envres.2020.110186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822498PMC
December 2020

Occupational Pesticide Use and Risk of Renal Cell Carcinoma in the Agricultural Health Study.

Environ Health Perspect 2020 06 12;128(6):67011. Epub 2020 Jun 12.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Rockville, Maryland, USA.

Background: Agricultural work and occupational pesticide use have been associated with increased risk of renal cell carcinoma (RCC), the most common form of kidney cancer. However, few prospective studies have investigated links to specific pesticides.

Objective: We evaluated the lifetime use of individual pesticides and the incidence of RCC.

Methods: We evaluated the associations between intensity-weighted lifetime days (IWDs) of 38 pesticides and incident RCC in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. Among 55,873 applicators, 308 cases were diagnosed between enrollment (1993-1997) and the end of follow-up (2014-2015). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounding factors, with lagged and unlagged pesticide exposures.

Results: There was a statistically significant increased risk of RCC among the highest users of 2,4,5-T compared with never users [unlagged (95% CI: 1.65, 5.17; )], with similar risk estimates for lagged exposure [20-y lag (95% CI: 1.83, 6.22; )]. In 20-y lagged analyses, we also found exposure-response associations with chlorpyrifos [ (95% CI: 1.05, 2.70; )], chlordane [ (95% CI: 1.10, 3.87; )], atrazine [ (95% CI: 1.00, 2.03; )], cyanazine [ (95% CI: 1.03, 2.50; )], and paraquat [ (95% CI: 1.03, 3.70; )].

Conclusions: This is, to our knowledge, the first prospective study to evaluate RCC risk in relation to various pesticides. We found evidence of associations with RCC for four herbicides (2,4,5-T, atrazine, cyanazine, and paraquat) and two insecticides (chlorpyrifos and chlordane). Our findings provide insights into specific chemicals that may influence RCC risk among pesticide applicators. Confirmation of these findings and investigations of the biologic plausibility and potential mechanisms underlying the observed associations are warranted. https://doi.org/10.1289/EHP6334.
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http://dx.doi.org/10.1289/EHP6334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292387PMC
June 2020

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.

Cancer Res 2020 09 8;80(18):4004-4013. Epub 2020 Jul 8.

Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC ( = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease ( = 0.22) and primary sclerosing cholangitis ( = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861352PMC
September 2020

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

J Allergy Clin Immunol 2021 03 29;147(3):910-920. Epub 2020 Jun 29.

Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, NC. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jaci.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770060PMC
March 2021

Herbicide, fumigant, and fungicide use and breast cancer risk among farmers' wives.

Environ Epidemiol 2020 Jun 27;4(3):e097. Epub 2020 May 27.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland.

Evidence from epidemiologic and laboratory studies relating pesticides to breast cancer risk is inconsistent. Women engaging in agricultural work or living in agricultural areas may experience appreciable exposures to a wide range of pesticides, including herbicides, fumigants, and fungicides.

Methods: We examined exposure to herbicides, fumigants, and fungicides in relation to breast cancer risk among farmers' wives with no prior history of breast cancer in the Agricultural Health Study. Women provided information on pesticide use, demographics, and reproductive history at enrollment (1993-1997) and at a 5-year follow-up interview. We used Cox proportional hazards regression to estimate associations (hazard ratios [HRs] and 95% confidence intervals [CIs]) between the women's and their husbands' self-reported use of individual pesticides and incident breast cancer risk.

Results: Out of 30,594 women, 38% reported using herbicides, fumigants, or fungicides and 1,081 were diagnosed with breast cancer during a median 15.3 years of follow-up. We found elevated risk in relation to women's ever use of the fungicide benomyl (HR = 1.6; 95% CI = 0.9, 2.7) and the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) (HR = 1.6; 95% CI = 0.8, 3.1) and to their husbands' use of the herbicide 2-(2,4,5-trichlorophenoxy) propionic acid (2,4,5-TP) (HR = 1.5; 95% CI = 0.9, 2.7). We observed few other chemical associations and little evidence of differential risk by tumor estrogen receptor status or linear exposure-response relationships.

Conclusion: We did not observe clear excesses between use of specific pesticides and breast cancer risk across exposure metrics, although we did observe elevated risk associated with women's use of benomyl and 2,4,5-T and husbands' use of 2,4,5-TP.
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http://dx.doi.org/10.1097/EE9.0000000000000097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289136PMC
June 2020

Insecticide use and risk of non-Hodgkin lymphoma subtypes: A subset meta-analysis of the North American Pooled Project.

Int J Cancer 2020 12 31;147(12):3370-3383. Epub 2020 Jul 31.

Occupational Cancer Research Centre, Cancer Care Ontario, Toronto, Ontario, Canada.

Insecticide use has been linked to increased risk of non-Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self-reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype-specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20-2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17-2.16: FL, SLL) and DDT (OR = 1.36, 1.06-1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (P = 1.7 × 10 ), chlordane (P = 1.0 × 10 ) and DDT (P = 4.2 × 10 ), however, the exposure-response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45-9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75-16.53; P = 3.6 × 10 ). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure.
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http://dx.doi.org/10.1002/ijc.33164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689728PMC
December 2020

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

Cancer Epidemiol Biomarkers Prev 2020 09 16;29(9):1784-1791. Epub 2020 Jun 16.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.

Methods: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics.

Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the (family with sequence similarity 63 member A) gene (significance threshold < 1.25 × 10) was observed in the meta-analysis ( = 1.2 ×10, = 4.2 ×10).

Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.

Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483330PMC
September 2020

Associations between Genetically Predicted Blood Protein Biomarkers and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 07 21;29(7):1501-1508. Epub 2020 May 21.

Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments.

Methods: To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci.

Results: We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by , which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production.

Conclusions: We identified 38 candidates of protein biomarkers for PDAC risk.

Impact: This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334065PMC
July 2020

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

J Hepatol 2020 10 11;73(4):863-872. Epub 2020 May 11.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay Summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
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http://dx.doi.org/10.1016/j.jhep.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901003PMC
October 2020

Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study.

Eur Respir J 2020 09 3;56(3). Epub 2020 Sep 3.

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, NC, USA

Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma; however, studies in adults are rare and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study (EWAS) of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a United States agricultural cohort. Atopy was defined by serum specific immunoglobulin E (IgE). Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous cytosine-phosphate-guanine (CpG) sites were differentially methylated in non-atopic asthma (eight at family-wise error rate (FWER) p<9×10, 524 at false discovery rate (FDR) less than 0.05) and implicated 382 novel genes. More CpG sites were identified in atopic asthma (181 at FWER, 1086 at FDR) and implicated 569 novel genes. 104 FDR CpG sites overlapped. 35% of CpG sites in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpG sites in non-atopic and atopic asthma. Many CpG sites from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease, as well as implicate novel genes associated with non-atopic and atopic asthma.
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http://dx.doi.org/10.1183/13993003.00217-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469973PMC
September 2020

Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank.

Br J Cancer 2020 07 7;123(2):316-324. Epub 2020 May 7.

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

Background: Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC.

Methods: We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases).

Results: Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors.

Conclusions: This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.
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http://dx.doi.org/10.1038/s41416-020-0835-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374167PMC
July 2020

The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action.

Cancer Epidemiol Biomarkers Prev 2020 07 5;29(7):1283-1289. Epub 2020 May 5.

Social & Scientific Systems, Durham, North Carolina.

The rapid pace of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) pandemic presents challenges to the real-time collection of population-scale data to inform near-term public health needs as well as future investigations. We established the COronavirus Pandemic Epidemiology (COPE) consortium to address this unprecedented crisis on behalf of the epidemiology research community. As a central component of this initiative, we have developed a COVID Symptom Study (previously known as the COVID Symptom Tracker) mobile application as a common data collection tool for epidemiologic cohort studies with active study participants. This mobile application collects information on risk factors, daily symptoms, and outcomes through a user-friendly interface that minimizes participant burden. Combined with our efforts within the general population, data collected from nearly 3 million participants in the United States and United Kingdom are being used to address critical needs in the emergency response, including identifying potential hot spots of disease and clinically actionable risk factors. The linkage of symptom data collected in the app with information and biospecimens already collected in epidemiology cohorts will position us to address key questions related to diet, lifestyle, environmental, and socioeconomic factors on susceptibility to COVID-19, clinical outcomes related to infection, and long-term physical, mental health, and financial sequalae. We call upon additional epidemiology cohorts to join this collective effort to strengthen our impact on the current health crisis and generate a new model for a collaborative and nimble research infrastructure that will lead to more rapid translation of our work for the betterment of public health.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357669PMC
July 2020
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