BACKGROUND:Integrating genetic and lifestyle information has the potential to greatly improve the prediction of colorectal cancer (CRC) risk. However, racial and ethnic minorities are generally underrepresented in gene-environment studies of CRC risk. METHODS:We investigated the interplay of genetics and lifestyle on CRC risk in a prospective analysis of 68 397 African American, Japanese American, Latino, Native Hawaiian, and White individuals from the Multiethnic Cohort Study. Genetic predisposition was assessed using a 205-variant polygenic risk score. Lifestyle was assessed using a lifestyle risk score based on smoking, alcohol consumption, body mass index, physical activity, and diet. The independent and joint associations of the polygenic risk score and lifestyle risk score on CRC risk were evaluated using Cox regression. RESULTS:We identified 1303 incident CRC cases (median 15.1-year follow-up). The highest quintile of the polygenic risk score was associated with a 2.4-fold increase in CRC risk compared with the lowest quintile (Q5 vs Q1: hazard ratio [HR] = 2.40, 95% confidence interval [CI] = 1.99 to 2.89). The highest quintile of the lifestyle risk score was associated with a 54% increased risk (Q5 vs Q1: HR = 1.54, 95% CI = 1.26 to 1.88). This association was stronger among those with high genetic risk (polygenic risk score  ≥ 50%; Q5 vs Q1: HR = 1.82, 95% CI = 1.41 to 2.35) and statistically nonsignificant among those with low genetic risk (polygenic risk score  < 50%; Q5 vs Q1: HR = 1.20, 95% CI = 0.88 to 1.64; P for interaction = 0.01). Results were similar across race and ethnicity. CONCLUSIONS:Our study suggests that lifestyle modification may offer greater risk reduction among those at higher genetic risk. Future research is warranted to enhance the integration of genetics and lifestyle in CRC risk stratification and screening approaches across populations.

Abstract Background: Chronic inflammation is implicated in ovarian carcinogenesis, but how different inflammation-related exposures individually or jointly affect histotype-specific associations remains unclear. Materials and Methods: We pooled data from 16 case-control studies in the Ovarian Cancer Association Consortium to evaluate associations of eight inflammation-related factors (anti-inflammatory: aspirin use, tubal ligation (TL); pro-inflammatory: endometriosis, obesity, lifetime ovulatory cycles (LOC), smoking, pelvic inflammatory disease (PID), polycystic ovary syndrome (PCOS)) with epithelial ovarian cancer (OvC) by histologic subtype. We examined individual associations and clustering of risk factors across histotypes and computed population attributable risk (PAR) for each factor. We assessed additive and multiplicative interactions for exposure combinations. Results: Associations with OvC risk differed by histotype (e.g., high-grade serous: aspirin: OR=0.90; 95%CI 0.82, 0.99; TL: OR=0.80; 95%CI 0.73, 0.88; overall serous: endometriosis: OR=1.17; 95%CI 1.03, 1.31; high LOC: OR=1.42; 95%CI 1.28, 1.58; obesity (low-grade serous): OR=1.50; 95%CI 1.14, 1.98). Clustering analyses showed highly correlated risk profiles in endometrioid and clear cell (r=0.91). High-grade serous and mucinous profiles were moderately correlated with endometrioid and clear cell (r=0.60) tumors. The profile for low-grade serous (r=0.36) tumors was distinct from other histotypes. PAR estimates suggested modifying aspirin use, TL, and LOCs could substantially reduce burdens of endometrioid, clear cell and mucinous tumors. Out of 28 exposure combinations tested in overall OvC and 189 by histotype, we observed 12 interactions. Not using aspirin regularly showed positive additive interactions with obesity and high LOCs, particularly in endometrioid tumors (obesity relative excess risk due to interaction (RERI)=0.74, 95%CI 0.31, 1.18; Pint=0.001 for; LOCs RERI=0.80, 95%CI 0.03, 1.56; Pint=0.04). Not using aspirin regularly also showed a positive additive interaction with endometriosis in clear cell tumors (RERI=1.77, 95%CI 0.03, 3.52; Pint=0.05). Lack of TL showed positive interactions with obesity in endometrioid (RERI=0.86, 95%CI 0.17, 1.53; Pint=0.01) and mucinous (RERI=1.10, 95%CI 0.23, 1.97; Pint=0.01) tumors, while negative additive interactions were observed for smoking and endometriosis in endometrioid tumors (RERI=-1.12, 95%CI -2.19, -0.05; Pint=0.04). A multiplicative interaction was observed between obesity and endometriosis in mucinous tumors (Pint=0.01). Conclusion: The findings suggest ovarian tumorigenesis is strongly shaped by pro- and anti-inflammatory pathways that act largely independently. Further examining these pathways may clarify the origins of histotype heterogeneity and guide prevention strategies. Citation Format: Maxwell Akonde, Britton Trabert, SHELLEY TWOROGER, Allan Jensen, Kathryn L. Terry, Joshua Sampson, Hoda Anton-Culver, David Bowtell, Elisa V. Bandera, Angela Brooks-Wilson, Andrew Berchuck, Daniel William Cramer, Linda S. Cook, Julie M. Cunningham, Jennifer A. Doherty, Ellen L. Goode, Marc T. Goodman, Holly Ruth Harris, Susanne K. Kjaer, Nhu Le, Alice Wen-Ron Lee, Francesmary Modugno, Kirsten B. Moysich, Celeste Pearce, Malcolm C. Pike, Harvey A. Risch, Mary A. Rossing, Joellen M. Schildkrau, Daniel O. Stram, Rebecca Sutphen, David Van Den Berg, Penelope M. Webb, Anna Wu, Argyrios Ziogas, Nicolas A. Wentzensen. Inflammation-related exposures and histotype- specific ovarian cancer risk in the Ovarian Cancer Association Consortium (OCAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6261.

Growing evidence links air pollution to colorectal cancer (CRC) incidence. We examined this association within the large Multiethnic Cohort Study (MEC). Geocoded residential addresses for 98,675 California MEC participants were appended to ambient air pollution measures of PM2.5 (particulate matter [PM] with an aerodynamic diameter <2.5 μm), PM10 (PM < 10 μm), nitrogen dioxide (NO2), nitrogen oxides (NOx), carbon monoxide (CO), and ozone (O3), generated from enrollment (1993-1996) to December 31, 2018. Multivariable-adjusted Cox proportional hazards models evaluated associations of time-varying air pollutants with CRC incidence (n = 3217 cases). We assessed heterogeneity in associations by demographics, tumor stage, and anatomical subsite. CRC incidence increased with PM2.5 exposure (per 10 μg/m3; hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 0.96-1.33), mainly among female (HR = 1.29, 95% CI = 1.03-1.62) but not among male participants (Pheterogeneity = 0.08). CRC incidence also increased with NOx exposure among female (HR = 1.22, 95% CI = 1.01-1.48) but not male participants (Pheterogeneity = 0.07). Increased incidence associated with PM2.5 (HR = 1.36, 95% CI = 1.05-1.76), NO2 (per 20 parts per billion [ppb]; HR = 1.32, 95% CI = 1.05-1.68) and CO (per 1000 ppb; HR = 1.36, 95% CI = 1.01-1.84) exposures were observed for left colon and rectal cancers combined, but not right colon cancers (Pheterogeneity by site = 0.08, 0.06 and 0.13, respectively). Associations of PM2.5 and NO2 with rectal cancer incidence differed by population group (Pheterogeneity = 0.04 and 0.03, respectively), and was mostly driven by positive associations among Latino participants. In summary, increasing PM2.5, NO2, NOx, and CO exposures were suggestively associated with increased CRC incidence, particularly among female and Latino participants and for left colon and rectal cancers.

BACKGROUND AND OBJECTIVES:Meta-analysis results, based largely among Whites, suggested that fine particulate matter (PM2.5) exposure increases the risk of clinical dementia. This study investigated the association of air pollution and incidence of Alzheimer's disease and related dementias (ADRD) by race and ethnicity. METHODS:We investigated incidence of AD (n = 4,010) and other dementia (n = 4,971) among 44,954 California Multiethnic Cohort (MEC) participants (28% African American, 14% Japanese American, 44% Latino, 14% White adults) who were enrolled in the fee-for-service component of Medicare (2001-2016). We used Cox proportional hazards regression to examine associations between exposure to PM, airport-related ultrafine particles (aUFP) and gaseous pollutants and incidence of AD, other dementia, and ADRD in a minimally- and fully-adjusted model, considering 12 established ADRD risk factors. We conducted stratified analyses to examine associations by sex, and race/ethnicity. RESULTS:ADRD incidence was associated with PM2.5 (per 2 µg/m3), airport-related UFP (aUFP, per 4400 particles/cm3) and nitrogen dioxide (NO2, per 10 µg/m3) with hazard ratios (HRs, 95%CI), respectively, of 1.04 (1.02-1.06), 1.03 (1.01-1.05) and 1.09 (1.06-1.12). The AD-associations with PM2.5 and NO2, were stronger than the corresponding associations with other dementia (Pheterogeneity ≤ 0.003). Similar patterns of results were observed by sex and across race and ethnicity. Statistically significant findings for ADRD with PM2.5, aUFP and NO2 were observed among African American (respective HRs 1.03, 1.04, 1.09), and Latino and White participants for NO2 (HR 1.10, 1.08). Results in all and African American participants remained statistically significant in fully-adjusted models. Although the effect of PM2.5 was diluted in a co-pollutant with NO2, both PM2.5 and aUFP were significantly associated with ADRD incidence in a co-pollutant model, and NO2 and aUFP (but not PM2.5) remained associated in a multipollutant model. We did not observe consistent modifying effects for any of the 12 established ADRD risk factors. CONCLUSIONS:In this multiethnic population, incidence of ADRD increased with exposures to PM2.5, aUFP, and NO2 in all subjects and this pattern was most prominent among African American adults. These results emphasize that ADRD prevention should include not only individual-level factors but also population-wide policies and regulation to curb air pollution.

Genome-wide association studies (GWAS) have identified numerous genetic variants linked to breast cancer risk, but most discoveries come from European populations, limiting their applicability to other populations. Here, we show that the choice of genotype imputation reference panel, an essential step for GWAS, affects variant detection in Asian populations. Using two large breast cancer datasets from the Breast Cancer Association Consortium (n = 38 954 Asian samples), we compared the 1000 Genomes (1KG) reference panel with SG10K_Health (SG10K), an Asian-specific panel. SG10K imputed more rare variants and achieved higher accuracy for rare alleles (MAF < 0.001), while 1KG performed better for common variants in some contexts. Differences in panel performance influenced association signals, including breast cancer candidate loci such as FGFR2, TOX3, and ESR1. Together, these findings support the use of population-specific imputation panels as a means to improve variant discovery in underrepresented populations.

OBJECTIVE:Estimate breast cancer risk associated with residential industrial air pollutant exposure. METHODS:We analyzed 53,313 women in the California Multiethnic Cohort (1993-1996) for associations between 15 industrial pollutants and breast cancer incidence. Using Environmental Protection Agency Toxic Release Inventory data, sites were linked to geocoded residential histories via quadratic decay models to estimate 5-year lagged exposures. Cox models calculated risk per interquartile range increase, stratified by race/ethnicity and hormone receptor status. RESULTS:Increased risk was associated with dichloromethane (hazard ratio [HR] = 1.17, 95% confidence interval [CI]: 1.05-1.29), tetrachloroethylene (HR = 1.53, CI: 1.39-1.69), 1,1,1-trichloroethane (HR = 1.77, CI: 1.65-1.91), diethanolamine (HR = 1.06, CI: 0.98-1.15), lead (HR = 1.02, CI: 1.00-1.03), and methyl ethyl ketone (HR = 1.27, CI: 1.15-1.41). Formaldehyde was associated only with hormone receptor-negative tumors (HR = 1.44, CI: 1.15-1.73). CONCLUSIONS:Residential exposure to certain industrial pollutants may increase breast cancer risk.

OBJECTIVE:To evaluate the effects of ambient air pollution on rheumatoid arthritis (RA) incidence in a racially and ethnically diverse population. METHODS:This analysis included 42,152 California Multiethnic Cohort participants, aged ≥65 years (>70% African American and Latino adults) who were enrolled in the Fee For Service component of Medicare (2001-2018). We employed multivariable Cox proportional hazards regression to examine the associations of time-varying air pollutants based on spatiotemporal models with RA incidence (n = 2,027) after adjusting for demographics, neighborhood socioeconomic status, smoking, work, and other exposures. RESULTS:RA incidence increased with exposure to fine particulate matter (PM) with diameter ≤2.5 μm (PM2.5) (hazard ratio [HR] per 2 μg/m3 = 1.20 [95% confidence interval (CI) 1.16-1.23]) and nitrogen dioxide (NO2) (HR per 10 μg/m3 = 1.44 [95% CI 1.35-1.52]). Air pollutant levels and risk associations were higher in African American and Latino than in Japanese American and White adults (Pheterogeneity < 0.05). The RA-PM2.5 association was higher in men (HR 1.23 [95% CI 1.15-1.32]) than in women (HR 1.17 [95% CI 1.12-1.21]; Pheterogeneity = 0.06). RA associations with PM2.5 (and NO2) did not differ by demographics, smoking, or other lifestyle factors, but the HR associated with PM2.5 was higher among those with high-risk work (longest occupation in labor/craftsman work and exposed to ≥10 years in one or more of 13 industries; HR 1.29 [95% CI 1.18-1.41]) than those without high-risk work exposures (HR 1.16 [95% CI 1.12-1.21]; Pheterogeneity = 0.04). CONCLUSION:Exposure to PM and gaseous pollution associates with increased RA incidence after age 65 years, particularly among African American and Latino adults. Further characterization of air pollution's contribution to racial and ethnic disparities in RA risk is warranted.

Among cigarette smokers, higher internal smoking dose is associated with elevated lung cancer risk and mortality, independent of smoking pack-years. Some measures of epigenetic age acceleration (EAA) are associated with cigarette smoking status and exposure, as well as lung cancer risk and overall mortality. No study has examined the association between EAA measures and internal smoking dose (total nicotine equivalents (TNE; nmol/mL)), and their shared relationship with lung cancer incidence and mortality in a multiethnic population. From a subgroup of Multiethnic Cohort Study participants who smoked cigarettes at the time of biospecimen collection (n = 1969), six epigenetic clocks were computed using blood-based DNA methylation (DNAm) array data. EAA measures were computed by calculating the residuals that results from regressing an epigenetic clock on chronological age. The association of urinary TNE with EAA measures were assessed using linear regression models, adjusted for age, sex, body mass index (BMI; kg/m2), DNAm-based estimates of blood cell composition, population stratification, and self-reported pack-years of cigarette smoking. To evaluate the associations of EAA with incident lung cancer risk (n = 176 cases) and all-cause mortality (n = 780 deaths) (from 13 years of follow-up), Cox proportional hazard models, with age as the time metric, adjusted for decade of birth, sex, BMI, years of education, creatinine, DNAm-based estimates of blood cell composition, population stratification, self-reported pack-years, and urinary TNE, were used. A standard deviation (SD) increase of log-TNE was statistically significantly associated with increased AgeAccelPheno (beta = 0.416, 95

Polygenic risk scores (PRS) hold prognostic value for identifying individuals at higher risk of type 2 diabetes (T2D). However, further characterization is needed to understand the generalizability of T2D PRS in diverse populations across various contexts. We characterized a multi-ancestry T2D PRS among 244,637 cases and 637,891 controls across eight populations from the Population Architecture Genomics and Epidemiology (PAGE) Study and 13 additional biobanks and cohorts. PRS performance was context dependent, with better performance in those who were younger, male, with a family history of T2D, without hypertension, and not obese or overweight. Additionally, the PRS was associated with various diabetes-related cardiometabolic traits and T2D complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between T2D and other diseases. These findings highlight the need to account for context when evaluating PRS as a tool for T2D risk prognostication and potentially generalizable associations of T2D PRS with diabetes-related traits despite differential performance in T2D prediction across diverse populations.

Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score.

Globally, in 2019, chronic obstructive pulmonary disease (COPD) was the third leading cause of death. While tobacco smoking is the predominant risk factor, the role of long-term air pollution exposure in increasing risk of COPD remains unclear. Moreover, there are few studies that have been conducted in racial and ethnic minoritized and socioeconomically diverse populations, while accounting for smoking history and other known risk factors. To evaluate the association for ambient air pollution and COPD in a multiethnic population in California. Among 38,654 African American, Japanese American, Latino and White California participants in the Multiethnic Cohort study enrolled in the fee-for-service component of Medicare, we used Cox proportional hazards regression to estimate the association of time-varying ambient air pollutants: particulate matter with diameter ≤2.5 μm or 10 μm (PM2.5, PM10), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), benzene and ultrafine particles (UFP) with COPD risk (n=10,915 cases; 8.8 years of follow-up). Subgroup analyses were conducted by race and ethnicity, sex, smoking status at MEC baseline questionnaire, and neighborhood socioeconomic status (nSES). We observed positive associations for NOx (per 50 ppb) with risk of COPD (hazards ratios (HR)=1.45; 95% CI: 1.35-1.55). The associations for NO2 (per 20 ppb), PM2.5 (10ug/m3), PM10 (10ug/m3), CO (1000 ppb), and UFP (IQR=5241.7 particles/cm3) with risk of COPD were in similar directions as these air pollutants are highly correlated with NOx. These associations were found in African American, Latino, and Japanese American participants, but not in whites (p-heterogeneity across race and ethnicity<0.04). These associations also differed by nSES with effects being stronger in racial and ethnic minoritized populations and residents of low SES neighborhoods. Long-term ambient air pollutant exposure is associated with COPD risk in a multiethnic, older adult (>65 years of age), population.

While there is a well-established link between ionizing radiation and cancer, there are uncertainties with effects following low doses delivered at low dose rates. To address these gaps, the ongoing Million Person Study of Radiation Workers and Veterans (MPS) is investigating the likelihood of a variety of cancer and non-cancer effects following chronic exposure to low dose-rate ionizing radiation. One challenge is and will be combining and harmonizing diverse cohorts with widely different measures of socio-economic status, birth cohorts, dose distributions and sex ratios. Herein, we have evaluated non-cancer mortality in three cohorts for which dose reconstructions have been completed: Rocketdyne (Atomics International, California, 1948-2008), Mound (Dayton, Ohio, 1944-2009) and nuclear weapons test participants (Atomic Veterans, 1945-2012). These three cohorts represent a small fraction of the overall MPS but provide valuable insight into methods of combining and harmonizing data from multiple diverse cohorts that can later be considered for all MPS cohorts. Heart disease mortality, including both underlying and contributing causes of death, was chosen for illustrating the statistical approaches. In all three cohorts, radiation dose estimates were distributed very differently by different measures of socio-economic status. Further, the effect of birth cohort was significantly different for heart disease mortality in all three cohorts, with all studies showing that later birth cohorts have lower rates of heart disease mortality than the earlier. The goal of this paper is not to quantify radiation effects based on these combined cohorts and it would be inappropriate to do so. Rather these cohorts are used to illustrate approaches for combining multiple data sets that incorporate the full set of individual confounder and cofactor information available from each cohort, though widely different. We identified five different methods to combine the results of these three datasets: the simple pooled analysis (PA), PA including study interactions, traditional stratified analysis, and both fixed and random effects meta-analysis. We describe the similarities and differences between the combined results using these approaches.

Increased leukemia incidence or mortality is a well-known effect of acute radiation exposure. Less is known about the risks associated with protracted exposure, such as those arising in occupational exposure settings. We used excess relative risk models to investigate the strength of evidence for and the shape of the dose response for mortality from leukemia (excluding chronic lymphocytic leukemia, CLL) in the Russian Mayak Worker Cohort. The cohort includes 25,757 workers followed for cancer mortality from 1948 to 2015 who were subject to both external low-dose-rate gamma ray and internal exposures (from alpha particles emitted by inhaled plutonium). The red bone marrow external dose estimates were based on individual readings from film badges or TLD dosimeters. The mean external marrow dose was 584 mGy for workers hired before 1959 and 105 mGy for those hired between 1959 and 1982. Internal exposures were described using red bone marrow alpha-particle dose for workers who were subject to plutonium monitoring and potential plutonium exposure categories for unmonitored workers. The mean marrow dose from internal exposure for monitored workers was 2.1 mGy for those hired before 1959 and 0.16 mGy for those hired between 1959 and 1982. Radiation effects were described using both excess relative rate (ERR) and excess absolute rate (EAR) models. The excess relative rates for the 96 deaths from non-CLL leukemia were described using a time-since-exposure-dependent quadratic response in cumulative external low LET dose with effect modification by attained age. While the largest ERRs [2.45 at 1 Gy, 95% confidence interval (CI) 0.33 to 11.9] were associated with external doses received between 2 and 5 years before death, there was also a significant increase in rates for doses received 5 or more years before death (ERR 0.28 at 1 Gy, 95% CI 0.06 to 0.72) and an indication of increased rates associated with doses within two years of death (ERR 1.47 at 1 Gy, 95% CI 0.06 to 10.6). Uncertainties in these excess relative rate estimates from the primary models were adjusted for dose uncertainty. Excess absolute rate (EAR) models were also used to describe the leukemia death rates. The pattern of the EAR variation with time-since-exposure was like that for the ERR Doses received 2 to 4 years before death had the largest EAR (ERR 4.78 per 10,000 person years per Gy2, 94% CI 1.75 to 10.7) with increased rates for doses received within two years of death (3.66, 95% CI 9.26 to 11.2), and for doses received 5 or more years before death (0.34, 95% CI 0.11 to 0.7). However, while the ERR decreased with increasing attained age, there was no indication of an attained age dependence in the EAR. The external-exposure radiation-associated leukemia risk appeared to be largely from acute myeloid leukemia. There was no evidence of external exposure effects on the risks of death from chronic lymphocytic leukemia, lymphoma, or multiple myeloma. There was no evidence of internal exposure effects on the rates of leukemia or other lymphohematopoietic malignancies. These analyses extend earlier studies of leukemia mortality in the Mayak worker cohort, with additional years of follow-up, utilize the latest bone marrow dose estimates, and include an assessment of the effect of shared dose uncertainty on risk uncertainty. Our results show significant excess risk for non-CLL leukemia mortality with a complex interaction between attained age, time since exposure, and age at exposure. The highest risk per unit dose was associated with exposures received 2-5 years before the time at risk. In addition, for a given total cumulative dose, the risk decreases rapidly with increasing attained age. We discuss the differences between the patterns of risk related to acute exposures in the Life Span Study of survivors of the atomic bombings in Hiroshima and Nagasaki, and chronic exposure in the Mayak Worker Cohort as well as differences between risk estimates in our study and others involving prolonged low-dose external gamma ray exposure.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with Hispanic/Latino children having a higher incidence of ALL than other racial/ethnic groups. Among the genetic variants previously implicated in ALL risk, a number of them were found to be enriched in Indigenous American (IA)-like ancestries and inherited by many Hispanic/Latino individuals. However, due to potential confounding from environmental factors, the association between IA-like ancestry and risk for ALL has remained unclear. In this study, we characterized the impact of IA-like ancestry on overall ALL risk and on the frequency and effect size of known risk alleles, while accounting for non-genetic correlates of ancestry. Contrary to previous findings, we found that global IA-like ancestry was not significantly associated with ALL risk after adjusting for socioeconomic indicators. However, locally at known ALL risk regions, we uncovered that increasing copies of the IA-like haplotype were positively and significantly associated with ALL risk (e.g., the IA-like haplotype had ∼1.33 times the odds of harboring the risk allele compared to non-IA-like haplotypes), but we found no evidence of interaction between genotype and ancestry in relation to ALL. Admixture mapping identified replicable association signals at chr7p12.2 and chr10q21.2, consistent with the benefit of leveraging genetic ancestry in identifying genetic risk loci. Our results suggest that increased risk of ALL in Hispanic/Latino children may be conferred by the higher frequency of risk alleles within IA-like ancestry and that local ancestry-based analyses are robust strategies to elucidate genetic etiology of disease.

BACKGROUND:Cadmium (Cd), classified as an International Agency for Research on Cancer (IARC) Group 1 human carcinogen, is present in cigarette smoke. Recent studies have illustrated the potential role of genetics in influencing Cd biomarker levels. METHODS:We conducted a genome-wide association study (GWAS) of urinary Cd levels in 1977 current smokers from the Multiethnic Cohort Study, comprising participants from five different racial and ethnic groups. Linear regression models were adjusted for age at urine collection, sex, self-reported race/ethnicity, and the top ten leading principal components. RESULTS:Among the 11 710 497 single nucleotide polymorphisms (SNP) analyzed, no associations with urinary Cd reached genome-wide significance (P < 5.0 × 10-8). Notably, five variants demonstrated suggestive associations with urinary Cd levels (P < 1.0 × 10-6). Lead variants included: rs10097646 in the SCARA gene at 8q13.2 (P = 2.62 × 10-7); rs7444817 in the NIPBL gene at 5p13.2 (P = 3.10 × 10-7), rs830422 in the SPINK4 gene at 9q13.2 (P = 4.89 × 10-7); chrX:145489901 in the SLC9A7 gene at Xq121.1 (P = 5.38 × 10-7); and rs73074456 at 5p13.3 (P = 5.86 × 10-7). CONCLUSIONS:Our GWAS of urinary Cd levels in a diverse population of people who smoke, revealed suggestive associations with variants in SCARA5, NIPBL, SPINK4, SLC9A7, and 5p13.3. These findings underscore the potential role of genetic factors in understanding and mitigating the health risks associated with internal dose of carcinogens, particularly in the context of tobacco-related carcinogens.

Rationale: Globally, chronic obstructive pulmonary disease (COPD) was the third leading cause of death in 2019. Although tobacco smoking is the predominant risk factor, the role of long-term air pollution exposure in increasing the risk of COPD remains unclear. Moreover, few studies that account for smoking history and other known risk factors have been conducted in racially and ethnically minoritized and socioeconomically diverse populations. Objectives: We sought to evaluate the association of ambient air pollution with COPD in a multiethnic population in California. Methods: In the Multiethnic Cohort Study of 38,654 African-American, Japanese-American, Latino, and White California participants who were enrolled in the fee-for-service component of Medicare, we used Cox proportional hazards regression to estimate the association of time-varying ambient air pollutants-particulate matter with an aerodynamic diameter ⩽2.5 μm or ⩽10 μm, nitrogen dioxide, carbon monoxide, ozone, benzene, and ultrafine particles (UFPs)-with COPD risk (n = 10,915 cases; 8.8 yr of follow up). Subgroup analyses were conducted by race and ethnicity, sex, smoking status as recorded on the Multiethnic Cohort Study baseline questionnaire, and neighborhood socioeconomic status. Results: We observed a positive association of nitrogen oxide (per 50 ppb) with risk of COPD (hazard ratio = 1.45; 95% confidence interval = 1.35-1.55). The associations of nitrogen dioxide (per 20 ppb), particulate matter with an aerodynamic diameter ⩽2.5 μm (10 μg/m3) or ⩽10 μm (10 μg/m3), carbon monoxide (1,000 ppb), and UFPs (interquartile range = 5,241.7 particles/cm3) with risk of COPD were in similar directions, as these air pollutants are highly correlated with nitrogen oxide. These associations were found in African-American, Latino, and Japanese-American participants, but not in Whites (P heterogeneity across race and ethnicity <0.04). These associations also differed by neighborhood socioeconomic status, with effects being stronger in racially and ethnically minoritized populations and residents of low-SES neighborhoods. Conclusions: Long-term ambient air pollutant exposure is associated with COPD risk in a multiethnic, older adult (age >65 yr) population.

Supplemental Table 1. Coefficients of Variation for Biomarker analysis

Supplemental Table 7. Association of urinary biomarkers and lung cancer risk in Southern Community Cohort participants stratified by histologic cell-type

Supplemental Table 3. Pearson Correlation Coefficients (R) for smoking-related urinary biomarkers

Supplementary Table 3 shows an analysis of the association between Airport-Related UFP and Lung Cancer Risk by Smoking Status and Histology among California MEC Participants between 1993-2013.