Abstract Polygenic risk scores (PRSs) may enhance risk stratification for pancreatic ductal adenocarcinoma (PDAC), but existing models vary widely in design, predictive performance, and cross-ancestry transferability. We developed genome-wide PRSs using Bayesian methods (LDpred2 and PRS-CS) and p value thresholding (PRSice-2) and systematically evaluated these alongside 13 published PRSs to identify models with robust predictive performance across ancestries. Using GWAS summary statistics from 7531 cases and 10,631 controls, we derived the PRSs and tested associations in an independent sample of 4508 PDAC cases and 46,189 controls, with adjustment for well-established PDAC risk factors. Among all models, the genome-wide LDpred2-based PRS showed the strongest association with PDAC (OR = 1.57 per standard deviation increase; 95% CI: 1.51–1.62) and significantly improved discrimination beyond established risk factors alone (AUC = 0.74–0.76; p < 0.0001). Importantly, the genome-wide LDpred2 PRS demonstrated consistent associations across African, Admixed American, and European ancestry groups, whereas the best-performing published PRS was associated with PDAC risk only in individuals of European ancestry. These findings support genome-wide PRSs as a promising framework for multi-ancestry risk stratification for PDAC and to inform targeted early detection strategies.

Understanding associations between pesticide exposure and chronic disease requires long-term, chemical-specific estimates. To characterize non-occupational pesticide exposure in the Agricultural Health Study (AHS), we previously developed a quantitative algorithm that estimated active ingredient-specific exposure to estimate exposure for the take-home, agricultural drift, and residential use pathways, with weights derived from indoor pesticide dust concentrations in agricultural homes from ten studies published through 2015. Here, we describe an update. First, we expanded our meta-analysis to include data from nine additional studies published through 2024. We then calculated relative differences (RD) in pesticide concentrations, with sensitivity analyses for AHS data, for known use of the specific pesticide, and for herbicides vs. insecticides. For take-home, the RD was 2.6 (95% confidence interval (CI): 1.9-3.4) between homes with a resident likely vs. not likely to have occupational exposure to pesticides, increasing to 3.7 (95%CI: 1.9-7.4) with known use of the pesticide. For agricultural drift, we observed non-linear trends with distance from treated fields; the RD was 1.9 (95%CI: 1.2-2.8) for homes located <100 vs. >440 yards from field, increasing to 4.2 (95%CI: 1.7-10) with known use of the pesticide. For residential use, we observed trends with increasing probability the pesticide was used, with a RD of 1.6 (95%CI: 1.3-2.0) with ≥20% probability. Our updated findings were used to re-conceptualize the algorithm; we illustrate its application for chlorpyrifos and atrazine. These refinements provide increased confidence in our exposure characterization and will help advance our knowledge of potential health risks related to non-occupational pesticide exposures.

BACKGROUND:The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. METHODS:We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. RESULTS:Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. CONCLUSIONS:Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 (CLPTM1L, rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10-8), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance:To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

BACKGROUND:Occupational exposure to endotoxin has been associated with reduced lung cancer risk. The mechanisms underlying this association are unclear, though immunological alterations likely play a role. Farmers who perform certain tasks (eg, raising hogs) can be highly exposed to endotoxin. We, therefore, leveraged measurements of circulating immune markers from a prior investigation among male farmers in the Biomarkers of Exposure and Effect in Agriculture study to evaluate associations with newly developed estimates of endotoxin exposure. METHODS:Our investigation included 122 non-smoking farmers from Iowa, oversampling those raising hogs. Serum levels of 60 markers were measured using multiplex bead-based assays and ELISA. Based on an algorithm linking measurement-based task intensity estimates with self-reported task frequency, we estimated cumulative endotoxin exposure in the 30 days up to sample collection. We used multivariable linear regression to estimate geometric mean ratios of immune markers across exposure quartiles. RESULTS:Higher endotoxin exposure in the last 30 days was associated with increased levels of fibroblast growth factor-2, macrophage inflammatory protein-3 alpha/CCL20 and sIL-4R (Ptrend≤0.02) and decreased levels of macrophage-derived chemokine/CCL22 (Ptrend=0.02). We also identified novel associations with several additional markers; those with the highest (vs lowest) exposure to endotoxin had decreased levels of TARC/CCL17, sCD27 and IL-1B. CONCLUSIONS:Several circulating immune markers were associated with endotoxin levels in an exposure-response manner. Our findings are consistent with prior work on hog farming and suggest possible biological mechanisms through which endotoxin may confer a reduced risk of lung cancer.

Supplementary Table S5 shows results of univariate analysis for 77 chronically elevated serum alanine aminotransferase (cALT)-defined nonalcoholic fatty liver disease in the Pancreatic Cancer Case-Control Consortium (PanC4) data

Carbaryl is a common carbamate insecticide in the United States (USA). Previous epidemiologic investigations, including within the Agricultural Health Study (AHS), have suggested potential associations between carbaryl use and cancer risk. The AHS is a prospective cohort study of licensed pesticide applicators in North Carolina (NC) and Iowa (IA), USA. Information on lifetime pesticide use was reported at enrollment (1993-1997) and follow-up (1999-2005). We evaluated cancer risks associated with ever- and intensity-weighted lifetime days (IWLD) of carbaryl use. Among 52,625 applicators, 8713 incident cancer cases were identified from linkages with state cancer registries through 2014 (NC) or 2017 (IA). We used Poisson regression to estimate rate ratios (RR) and 95 % confidence intervals (CI), controlling for confounders, and evaluated lagged exposures. Approximately 51 % of applicators reported using carbaryl. Increasing IWLD of carbaryl use was associated with increased stomach cancer risk (third tertile vs. never use; RRT3 = 2.07, 95 % CI: 1.05-4.07, p-trend = 0.02), persisting when exposure was lagged by 5-years (RRT3 = 2.20, 95 % CI: 1.12-4.33). We noted elevated risks of esophageal (RR = 1.52, 95 % CI: 1.01-2.27) and tongue (RR = 1.91, 95 % CI: 0.95-3.81) cancers with ever-use. There was an increased risk of aggressive prostate cancer when carbaryl exposure was lagged by 30 years (RRlag30Q4 = 1.56, 95 % CI: 1.18-2.08, p-trend = 0.002). This is the largest and most comprehensive prospective evaluation of carbaryl and cancer risk to date. We provide novel evidence of associations between carbaryl exposure and specific cancers. There is a need for additional studies to confirm these findings and to elucidate the biological mechanisms underlying the observed associations.

Supplementary Table S3 shows results of univariate analysis for 36 biopsy-confirmed nonalcoholic fatty liver disease SNPs in the PanScan sample

Previous epidemiological studies have reported increased risks of certain cancers in relation to pesticide exposures. Although the biologic mechanisms underlying these associations are not well understood, altered telomere length has been hypothesized to play a role. We examined associations between occupational use of specific pesticides and leukocyte telomere length in the Biomarkers of Exposure and Effect in Agriculture study, a molecular epidemiological investigation of pesticide applicators in Iowa and North Carolina. Relative telomere length (RTL) was measured using quantitative polymerase chain reaction in leukocytes from 1539 male pesticide applicators >= 50 years of age. We evaluated lifetime use of 47 pesticides in terms of self- reported ever use and intensity-weighted lifetime days (IWLDs), a metric integrating lifetime days of use and other factors influencing exposure. Multivariable linear regression was used to estimate percent difference in geometric mean RTL in relation to ever (vs. never) use, IWLDs of use, and timing of use [recent (last 12 months) and former vs. never use]. Mean RTL was significantly longer among ever users of the insecticides lindane (percent difference = 2.20%, 95%CI: 0.45%, 3.99%) and aldicarb (percent difference = 3.27%, 95%CI: 0.23%, 6.40%). Longer RTL was also associated with increasing IWLDs of lindane (highest quartile vs. never use: percent difference = 4.51%, 95%CI:-0.22%, 9.46%; p-trend = 0.048) and the insecticide diazinon (4.77%, 95%CI: 0.17%, 9.58%; p-trend = 0.055), and with recent use of the insecticide dichlorvos (vs. never use: 8.15%, 95%CI: 1.31%, 15.46%). Increasing IWLDs of the insecticide heptachlor and the herbicide 2,4,5-TP and recent use of the herbicide metolachlor were significantly associated with shorter RTL. Our findings provide novel evidence suggesting that use of certain pesticides is associated with altered leukocyte telomere length. Notably, diazinon and lindane have previously been associated with increased risks of lung and lymphoid malignancies, respectively, and longer leukocyte telomere length has been implicated in the development of these cancers.

Supplementary Table S4 shows results of univariate analysis for 17 imaging and biopsy validated SNPs in the PanScan sample

Supplementary Table S9 shows descriptive Statistics for PanScan sample

Supplementary Table S10 shows descriptive Statistics for PanC4 sample

Glyphosate-based herbicides are the most widely applied pesticides worldwide and have been implicated in the development of certain hematologic malignancies; however, the underlying biological mechanisms are not well-understood. High lifetime use of glyphosate-based herbicides, hereafter referred to as glyphosate, was previously associated with mosaic loss of chromosome Y (mLOY), a biomarker of genomic instability potentially linked to cancer and immune dysregulation, in circulating blood of male farmers from a subcohort of the Agricultural Health Study (AHS). Here, we further investigated the association between glyphosate use and mLOY using buccal-derived DNA among 1,868 male pesticide applicators in an independent AHS study. We detected mLOY using genotyping array intensity data in the male-specific region of the Y chromosome. Information on cumulative lifetime use of glyphosate was derived from questionnaires. Logistic regression analyses were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations of glyphosate use with overall mLOY and mLOY affecting a high cell fraction (≥ median), adjusted for potential confounders. Overall, mLOY was detected in buccal samples of 298 (16 %) pesticide applicators. High intensity-weighted lifetime days of glyphosate use was associated with overall mLOY (ORhighest vs. lowest quartile of glyphosate use = 1.54; 95 % CI: 1.01, 2.37), although the exposure-response trend was not statistically significant (Ptrend = 0.40). For mLOY affecting a high fraction of cells, positive associations were observed for both high lifetime days (ORhighest vs. lowest quartile of glyphosate use = 1.76; 95 % CI: 1.04, 2.99; Ptrend = 0.06) and high intensity-weighted lifetime days (ORhighest vs. lowest quartile of glyphosate use = 2.02; 95 % CI: 1.12, 3.64; Ptrend = 0.16). Together, these findings support previous evidence linking glyphosate and mLOY and help inform our understanding of the biological impact of glyphosate on human health and its potential role in carcinogenesis.

BACKGROUND:Organochlorine (OC) insecticides are a class of environmentally persistent chemicals linked to risk of several cancers, including non-Hodgkin lymphoma and prostate cancer. In vitro and animal studies suggest some OCs may be genotoxic, but evidence in humans is limited. Mosaic loss of the Y chromosome (mLOY) is a marker of genotoxicity and genomic instability that has been associated with certain cancers and may reflect intermediate effects of pesticide exposure. We examined associations between OC use and mLOY in circulating blood of male farmers. METHODS:This investigation included 1653 male farmers from Iowa and North Carolina in the Biomarkers of Exposure and Effect in Agriculture study, a subcohort of the Agricultural Health Study. Ever use, total lifetime days, and intensity-weighted lifetime days of use of seven OCs (DDT, lindane, aldrin, dieldrin, chlordane, heptachlor, toxaphene) were derived from questionnaires. We detected mLOY using genotyping array intensity data in the pseudoautosomal regions of the sex chromosomes. Logistic regression was used to estimate associations between OC use and mLOY, adjusted for pre-specified confounders. Stratified analyses were performed by factors associated with mLOY (age, smoking status, obesity) and state of residence. RESULTS:mLOY was detected in 357 farmers (21.6 %). We observed positive associations with mLOY for ever use of DDT (OR = 1.44 [95 % CI = 1.08-1.92]) and lindane (OR = 1.31 [0.99-1.73]). Associations were stronger among farmers without obesity (DDT: OR = 1.61 [1.12-2.33], p-interaction = 0.20; lindane: OR = 1.82 [1.28-2.59], p-interaction<0.01). For lindane, there was evidence of a positive exposure-response among farmers ≥70 years of age (p-trend = 0.03) and those without obesity (p-trend = 0.05). Other OCs were not consistently associated with mLOY. CONCLUSIONS:Use of DDT and lindane was associated with mLOY, particularly in certain subgroups of farmers (e.g., non-obese or age ≥70 years). Our findings suggest that these pesticides could confer genotoxic effects and provide new mechanistic evidence for their associations with cancer risk.

Supplementary Table S2 shows results of univariate analysis for 22 imaging-defined nonalcoholic fatty liver disease SNPs in the PanScan sample

Supplementary Table S6 shows results of univariate analysis for 22 imaging defined nonalcoholic fatty liver disease SNPs in the PanC4 sample

Supplementary Table S1 shows results of univariate analysis for 77 chronically elevated serum alanine aminotransferase (cALT)-defined nonalcoholic fatty liver disease SNPs in the Pancreatic Cancer Cohort Consortium (PanScan) data

Supplementary Table S7 shows results of univariate analysis for 36 biopsy-confirmed nonalcoholic fatty liver disease SNPs in the PanC4 sample