Daniel O. Stram

Background Ultrafine particles (UFP) are unregulated air pollutants abundant in aviation exhaust. Emerging evidence suggests that UFPs may impact lung health due to their high surface area-to-mass ratio and deep penetration into airways. This study aimed to assess long-term exposure to airport-related UFPs and lung cancer incidence in a multiethnic population in Los Angeles County. Methods Within the California Multiethnic Cohort, we examined the association between long-term exposure to airport-related UFPs and lung cancer incidence. Multivariable Cox proportional hazards regression models were used to estimate the effect of UFP exposure on lung cancer incidence. Subgroup analyses by demographics, histology and smoking status were conducted. Results Airport-related UFP exposure was not associated with lung cancer risk [per one IGR …

PurposeRisk factors for pancreatic cancer include racial/ethnic disparities and smoking. However, risk trajectories by smoking history and race/ethnicity are unknown. We examined the association of smoking with pancreatic cancer by race/ethnicity to generate age-specific incidence estimates by smoking history.MethodsWe modeled pancreatic cancer incidence by race/ethnicity, age, pack-years, and years-quit using an excess relative risk model for 182,011 Multiethnic Cohort participants. We tested heterogeneity of smoking variables and pancreatic cancer by race/ethnicity and predicted incidence by smoking history.ResultsWe identified 1,831 incident pancreatic cancer cases over an average 19.3 years of follow-up. Associations of pack-years (p interaction by race/ethnicity = 0.41) and years-quit (p interaction = 0.83) with pancreatic cancer did not differ by race/ethnicity. Fifty pack-years smoked was …

Approximately 10% of smokers will develop lung cancer. Sensitive predictive biomarkers are needed to identify susceptible individuals. 1,3-Butadiene (BD) is among the most abundant tobacco smoke carcinogens. BD is metabolically activated to 3,4-epoxy-1-butene (EB), which is detoxified via the glutathione conjugation/mercapturic acid pathway to form monohydroxybutenyl mercapturic acid (MHBMA) and dihydroxybutyl mercapturic acid (DHBMA). Alternatively, EB can react with guanine nucleobases of DNA to form N7-(1-hydroxyl-3-buten-1-yl) guanine (EB-GII) adducts. We employed isotope dilution LC/ESI-HRMS/MS methodologies to quantify MHBMA, DHBMA, and EB-GII in urine of smokers who developed lung cancer (N = 260) and matched smoking controls (N = 259) from the Southern Community Cohort (white and African American). The concentrations of all three biomarkers were significantly higher in …

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10−8). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified …

Background Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. Methods We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). Results In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647 …

BackgroundA growing literature has reported associations between traffic-related air pollution and breast cancer, however there are fewer investigations into specific ambient agents and any putative risk of breast cancer development, particularly studies occurring in populations residing in higher pollution areas such as Los Angeles.ObjectivesTo estimate breast cancer risks related to ambient air toxics exposure at residential addresses.MethodsWe examined the relationships between ambient air toxics and breast cancer risk in the Multiethnic Cohort among 48,665 California female participants followed for cancer from 2003 through 2013. We obtained exposure data on chemicals acting as endocrine disruptors or mammary gland carcinogens from the National-Scale Air Toxics Assessment. Cox proportional hazards models were used to estimate breast cancer risk per one interquartile range (IQR) increase in air …

Few studies have explored the genetic underpinnings of intra-abdominal visceral fat deposition, which varies substantially by sex and race/ethnicity. Among 1,787 participants in the Multiethnic Cohort (MEC)-Adiposity Phenotype Study (MEC-APS), we conducted a genome-wide association study (GWAS) of the percent visceral adiposity tissue (VAT) area out of the overall abdominal area, averaged across L1-L5 (%VAT), measured by abdominal magnetic resonance imaging (MRI). A genome-wide significant signal was found on chromosome 2q14.3 in the sex-combined GWAS (lead variant rs79837492: Beta per effect allele = -4.76; P = 2.62 × 10−8) and in the male-only GWAS (lead variant rs2968545: (Beta = -6.50; P = 1.09 × 10−9), and one suggestive variant was found at 13q12.11 in the female-only GWAS (rs79926925: Beta = 6.95; P = 8.15 × 10−8). The negatively associated variants were most common in European Americans (T allele of rs79837492; 5%) and African Americans (C allele of rs2968545; 5%) and not observed in Japanese Americans, whereas the positively associated variant was most common in Japanese Americans (C allele of rs79926925, 5%), which was all consistent with the racial/ethnic %VAT differences. In a validation step among UK Biobank participants (N = 23,699 of mainly British and Irish ancestry) with MRI-based VAT volume, both rs79837492 (Beta = -0.026, P = 0.019) and rs2968545 (Beta = -0.028, P = 0.010) were significantly associated in men only (n = 11,524). In the MEC-APS, the association between rs79926925 and plasma sex hormone binding globulin levels reached statistical significance in females …

Background: Smoking is an established risk factor for urothelial cancer of the bladder (BC), attributed to over 50% of cases among men, however associations outside of European-descent populations are infrequently reported. Further, absolute risk of BC by smoking history has not yet been reported. Characterizing these associations will identify value of smoking cessation across non-European ancestry populations. Methods: We estimated the association between pack-years, years quit, and BC among 181,231 Multiethnic Cohort Study participants from five major racial/ethnic groups (African Americans [AA], European Americans [EA], Japanese Americans [JA], Latinos [LA], Native Hawaiians [NH]) 45-75 years old at enrollment (1993-1996). Smoking history was assessed by self-report at cohort entry and on a follow-up survey (2003-2008). Associations were estimated using an excess relative risk model to …

ImportanceLung cancer among never-smokers accounts for 25% of all lung cancers in the US; recent therapeutic advances have improved survival among patients with initial primary lung cancer (IPLC), who are now at high risk of developing second primary lung cancer (SPLC). As smoking rates continue to decline in the US, it is critical to examine more closely the epidemiology of lung cancer among patients who never smoked, including their risk for SPLC.ObjectiveTo estimate and compare the cumulative SPLC incidence among lung cancer survivors who have never smoked vs those who have ever smoked.Design, Setting, and ParticipantsThis population-based prospective cohort study used data from the Multiethnic Cohort Study (MEC), which enrolled participants between April 18, 1993, and December 31, 1996, with follow-up through July 1, 2017. Eligible individuals for this study were aged 45 to 75 years …

Purpose: A polygenic risk score (PRS) has demonstrated great potential in stratifying breast cancer risk in non-African ancestry populations. Several modifiable lifestyle risk factors have been identified for breast cancer, although little is known regarding their effects among women with varying genetic risk. Methods: In the Multiethnic Cohort (MEC), we conducted a nested case-control study of 3,229 breast cancer cases and 3,921 controls from five major racial/ethnic groups (White, African American, Latino, Japanese American, and Native Hawaiian). We examined a PRS of 313 variants in association with breast cancer risk and evaluated the interaction with selected modifiable lifestyle factors on the risk of breast cancer. The modifiable lifestyle factors examined included body mass index (BMI), physical activity, smoking, alcohol consumption, and five diet quality indexes, such as the Healthy Eating Index (HEI)-2010 …

PURPOSE A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer. METHODS Women with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer–specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and …

BACKGROUND AND AIM Prior epidemiologic studies have observed that the influence of smoking on lung cancer risk varies by race/ethnicity. This disparity may be partially explained by interethnic differences in the mechanism in which smoking impacts blood DNA methylation. While many studies have investigated the associations between smoking status and DNA methylation, the effect of internal smoking dose on the epigenome has been less investigated, especially across racial/ethnic populations. METHOD We conducted a two-stage epigenome-wide association study (EWAS) of internal smoking dose, as measured by urinary total nicotine equivalents (TNE), in six racial/ethnic groups across three cohort studies. The discovery phase was performed in 1,994 smokers from five racial/ethnic groups (White, African American, Latino, Japanese American and Native Hawaiian) in the Multiethnic Cohort Study …

Canadian cardiac imaging Eisenberg et al. 2011 (25) 0.3 1 x French Pediatric CT (brain tumors) Journey et al. 2016 (26) 0.7 1 1 UK Pediatric CT (brain tumors) Berrington et al. 2016 (27) 1.2 1 1 PIRATES (thyroid cancer) Lubin et al. 2017 (28) 0.96 1 1 OccupationalKorean workers Ahn et al. 2008 (29) 0.72 1 x UKNRRW Muirhead et al. 2009 (30) 0.03 1 1 Korean nuclear workers Jeong et al. 2010 (31) 0.21 1 1 Rocketdyne workers Boice et al. 2011 (32) À0. 02 0 0 Japanese workers Akiba et al. 2012 (33) 0.13 1 X Canadian nuclear workers Zablotska et al. 2014 (34) À0. 12 0 0 German nuclear workers Merzenich et al. 2014 (35) À0. 1 0 0 US nuclear workers Schubauer-Berigan et al. 2015 (36) 0.01 1 1 USRT (breast cancer) Preston et al. 2016 (12) 0.07 1 X USRT (brain cancer) Kitahara et al. 2017 (10) 0.1 1 1 USRT (skin cancer) Lee et al. 2015 (11) À0. 001 0 0 French nuclear workers Leuraud et al 2017 (37) 0.04 1 …

Background While cigarette smoking is the leading cause of lung cancer, the majority of smokers do not develop the disease over their lifetime. The inter-individual differences in risk among smokers may in part be due to variations in exposure to smoking-related toxicants. Methods Using data from a subcohort of 2,309 current smokers at the time of urine collection from the Multiethnic Cohort Study, we prospectively evaluated the association of ten urinary biomarkers of smoking-related toxicants [total nicotine equivalents (TNE), a ratio of total trans-3′-hydroxycotinine (3-HCOT)/cotinine (a phenotypic measure of CYP2A6 enzymatic activity), 4-(methylnitrosamino)-1–3-(pyridyl)-1-butanol (NNAL), S-phenylmercapturic acid (SPMA), 3-hydroxypropyl mercapturic acid (3-HPMA), phenanthrene tetraol (PheT), 3-hydroxyphenanthrene (PheOH), the ratio of PheT/PheOH, cadmium (Cd …

Inhaled particles and gases can harm health by promoting chronic inflammation in the body. Few studies have investigated the relationship between outdoor air pollution and inflammation by race and ethnicity, socioeconomic status, and lifestyle risk factors. We examined associations of particulate matter (PM) and other markers of traffic-related air pollution with circulating levels of C-reactive protein (CRP), a biomarker of systemic inflammation. CRP was measured from blood samples obtained in 1994–2016 from 7,860 California residents participating in the Multiethnic Cohort (MEC) Study. Exposure to PM (aerodynamic diameter ≤2.5 μm [PM2.5], ≤10 μm [PM10], and between 2.5 and 10 μm [PM10-2.5]), nitrogen oxides (NOx, including nitrogen dioxide [NO2]), carbon monoxide (CO), ground-level ozone (O3), and benzene averaged over one or twelve months before blood draw were estimated based on …

Patterns of microbiome diversity vary across human populations largely driven by lifestyle and environmental factors. However, differences in genetically-encoded traits in the host may also be important in shaping the microbiome and related health outcomes. We report results from a GWAS of the gut microbiome in 5,202 individuals from the Multiethnic Cohort Study, including African American, Japanese American, Native Hawaiian, Latino, and White individuals. Genotyping was derived from previous studies (n= 3,337) using various Illumina Infinium arrays (660,000 to 2.5 million SNPs) and the MEGA EX array (n= 1,865). Single nucleotide polymorphism (SNP) imputation was conducted using a cosmopolitan reference panel from the 1000 Genomes Project. The stool microbiome was assessed by paired-end sequencing (Illumina MiSeq) of the16S rRNA gene (V 1− 3). SNP-genera association tests were conducted using ordinal logistic regression with quintiles of bacterial abundance regressed on SNPs, adjusted for age, ancestry estimates, season of sample collection, batch, and genotyping study, using a genome-wide statistical significance threshold of p< 5* 10− 8. We identified associations between 53 SNPs in 11 human chromosomes and 16 bacterial/archaeal genera at p< 5* 10− 8. The SNPs in coding regions were categorized into broad categories: human genes known to be exploited by bacterial pathogens; genes involved in nutrition, obesity, diabetes, and cancer; and immune function. Most significantly, Bifidobacterium abundance was associated with 2 known SNPs on chromosome 2 (rs182549 p= 3.8* 10− 11; rs4988235 4.8* 10 …

Background Frailty status has been sparsely studied in some groups including Native Hawaiians and Asian Americans. Methods We developed a questionnaire-based deficit accumulation frailty index (FI) in the Multiethnic Cohort (MEC) and examined frailty status (robust, FI 0 to <0.2, prefrail, FI 0.2 to <0.35, and frail FI ≥ 0.35) among 29 026 men and 40 756 women. Results After adjustment for age, demographic, lifestyle factors, and chronic conditions, relative to White men, odds of being frail was significantly higher (34%–54%) among African American, Native Hawaiian, and other Asian American men, whereas odds was significantly lower (36%) in Japanese American men and did not differ in Latino men. However, among men who had high school or less, none of the groups displayed significantly higher odds of prefrail or frail compared with White men …

Background Data on diet quality and pancreatic cancer are limited. We examined the relationship between diet quality, assessed by the Healthy Eating Index-2015 (HEI-2015), the Alternative Healthy Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED) score, the Dietary Approaches to Stop Hypertension (DASH) score and the energy-adjusted Dietary Inflammatory Index (E-DII), and pancreatic cancer incidence in the Multiethnic Cohort Study. Methods Diet quality scores were calculated from a validated food frequency questionnaire administered at baseline. Cox models were used to calculate HR and 95% confidence intervals (CI) adjusted for age, sex, race/ethnicity, education, diabetes, family history of pancreatic cancer, physical activity, smoking variables, total energy intake, body mass index (BMI), and alcohol consumption. Stratified analyses by sex …

8532Background: Health effects associated with particles less than 2.5 μm in diameter (PM2.5) have been well studied, leading to the establishment of air quality standards and routine monitoring. Additionally, there is growing experimental evidence that ultrafine particles (UFPs), defined as particles less than 0.1µm in diameter, may adversely affect lung health, eliciting greater injury than larger particles due to deeper penetration into airways and longer retention in the lung parenchyma. Only two epidemiological studies have investigated this topic, finding no associations between ambient UFPs and respiratory mortality or overall lung cancer incidence respectively. Given the limited epidemiologic investigation of UFPs and lung cancer, we examined the association between airport-related UFPs and lung cancer incidence in a large, racially and ethnically diverse cohort. Methods: We estimated airport-related UFP …

Wide exposure to endocrine-disrupting chemicals (EDCs) poses a great risk on human health. However, few large-scale cohort studies have comprehensively estimated the association between EDCs exposure and mortality risk. This study aimed to investigate the association of urinary EDCs exposure with mortality risk and quantify attributable mortality and economic loss. Multivariable Cox proportional hazards regression models were performed to investigate the association of 38 representative EDCs exposure with mortality risk in the National Health and Nutrition Examination Survey (NHANES). During a median follow-up of 7.7 years, 47,279 individuals were enrolled. All-cause mortality was positively associated with 1-hydroxynaphthalene, 2-hydroxynaphthalene, cadmium, antimony, cobalt, and monobenzyl phthalate. Cancer mortality was positively associated with cadmium. Cardiovascular disease (CVD …

Objective: To date, genome-wide association studies (GWAS), which are primarily conducted in Europeans, have identified a large number of validated DNA methylation quantitative trait loci (meQTLs) acting in both cis and trans. However, it is recognized that there are racial differences in genetic architectures such as allele frequencies and linkage equilibrium patterns, which may differentially influence DNA methylation levels. This points to a critical need to conduct a methylome wide association study (MWAS) to identify meQTLs across multiethnic populations including understudied African Americans (AAs), Latinos, Japanese Americans (JAs), and Native Hawaiians (NHs). Methods: We are performing a GWAS to identify meQTLs in blood leukocytes in a multiethnic population using data from the Multiethnic Cohort Study (MEC). In MEC, “genome-wide” germline genetic variants and DNA methylation levels of …

Background: Benzene is classified as a Group 1 carcinogen in humans. A major pathway of benzene exposure is through the inhalation of ambient air contaminated by emissions from motor vehicle exhaust, gas stations, industries, tobacco smoke, and other consumer products. Past studies on benzene and breast cancer based on job titles or occupational history have yielded mixed results and the role of ambient benzene and breast cancer risk has been sparsely studied. Within the California component of the Multiethnic Cohort study, we examined the association between outdoor exposure to benzene and breast cancer risk among four major U.S. racial/ethnic groups―African Americans, Latinos, Japanese Americans, and Whites. Methods: Outdoor ambient benzene exposure was estimated from U.S. EPA measurements from air monitoring stations that were within 15 km of residences of 57,589 female MEC …

One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, and 7% Hawaiian) across 25 key cardiometabolic traits and relevant tissues to identify 102 novel associations. We then compared associations …

Evidence regarding the association of cigarette smoking and prostate cancer (PCa) risk has been mixed and mostly based on studies in White populations. To provide additional information on the topic, we assessed the relation between smoking and PCa risk and mortality in a large multi-ethnic population, while considering the effect of PSA screening. We included 74,598 White, African American, Native Hawaiian, Japanese American, and Latino men from the Multiethnic Cohort Study in Hawaii and California (1993-2017). During 21.5 years of follow-up, we documented 8,696 PCa cases and 1,171 deaths from PCa. Smoking status, pack years, and age at initiation were obtained at baseline. Total nicotine equivalents (TNE) for smokers were imputed by an algorithm developed based on a subset of participants (n=2,239) who measured urine TNE. We used multivariable-adjusted Cox proportional hazard …

PurposeScientific Committee 6–9 was established by the National Council on Radiation Protection and Measurements (NCRP), charged to provide guidance in the derivation of organ doses and their uncertainty, and produced a report, NCRP Report No. 178, Deriving Organ Doses and their Uncertainty for Epidemiologic Studies with a focus on the Million Person Study of Low-Dose Radiation Health Effects (MPS). This review summarizes the conclusions and recommendations of NCRP Report No. 178, with a concentration on and overview of the dosimetry and uncertainty approaches for the cohorts in the MPS, along with guidelines regarding the essential approaches used to estimate organ doses and their uncertainties (from external and internal sources) within the framework of an epidemiologic study.ConclusionsThe success of the MPS is tied to the validity of the dose reconstruction approaches to provide …

Introduction: African Americans and Native Hawaiians have a higher risk of lung cancer and greater mortality rate than other racial/ethnic groups in the US. The guidelines for lung cancer screening by low-dose CT scan were derived from clinical trial data conducted primarily in white men. In 2021, to address the underlying ethnic/racial disparities in eligibility for lung cancer screening the United States Preventive Services Task Force (USPSTF) updated the 2013 guidelines from 55-80 years of age, current or former smokers (quit ≤15 years) with a 30 pack-year smoking history to include ever smokers ≥50 years of age and with a ≥20 pack-year history. We hypothesize that the disparities in eligibility across race/ethnicity will remain due to the greater age-specific risk and lower pack-years among African Americans and Native Hawaiians. Methods: We used the Multiethnic Cohort study (MEC) data to examine …

Rationale: Although the contribution of air pollution to lung cancer risk is well characterized, few studies have been conducted in racially, ethnically, and socioeconomically diverse populations. Objectives: To examine the association between traffic-related air pollution and risk of lung cancer in a racially, ethnically, and socioeconomically diverse cohort. Methods: Among 97,288 California participants of the Multiethnic Cohort Study, we used Cox proportional hazards regression to examine associations between time-varying traffic-related air pollutants (gaseous and particulate matter pollutants and regional benzene) and lung cancer risk (n = 2,796 cases; average follow-up = 17 yr), adjusting for demographics, lifetime smoking, occupation, neighborhood socioeconomic status (nSES), and lifestyle factors. Subgroup analyses were conducted for race, ethnicity, nSES, and other factors. Measurements and Main …

Background Age‐related loss in skeletal muscle mass, quality, and strength, known as sarcopenia, is a well‐known phenomenon of aging and is determined clinically using methods such as dual‐energy X‐ray absorptiometry (DXA). However, these clinical methods to measure sarcopenia are not practical for population‐based studies, and a five‐question screening tool known as SARC‐F has been validated to screen for sarcopenia. Methods We investigated the relationship between appendicular skeletal lean mass/height2 (ALM/HT2) (kg/m2) assessed by DXA and SARC‐F in a subset of 1538 (778 men and 760 women) participants in the Multiethnic Cohort (MEC) Study after adjustment for race/ethnicity, age, and body mass index (BMI) at the time of DXA measurement. We then investigated the association between SARC‐F and mortality among 71 283 (41 757 women and 29 526 men) participants in the MEC …

The Multiethnic Cohort Study has demonstrated that the risk for lung cancer in cigarette smokers among three ethnic groups is highest in Native Hawaiians, intermediate in Whites, and lowest in Japanese Americans. We hypothesized that differences in levels of DNA adducts in oral cells of cigarette smokers would be related to these differing risks of lung cancer. Therefore, we used liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry to quantify the acrolein-DNA adduct (8R/S)-3-(2′-deoxyribos-1′-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dGuo, 1) and the lipid peroxidation-related DNA adduct 1,N6-etheno-dAdo (εdAdo, 2) in DNA obtained by oral rinse from 101 Native Hawaiians, 101 Whites, and 79 Japanese Americans. Levels of urinary biomarkers of nicotine, acrolein, acrylonitrile, and a mixture of crotonaldehyde, methyl vinyl …

BackgroundWithin the Multiethnic Cohort (MEC), we examined the association between air pollution and mortality among African American, European American, Japanese American, and Latina American women diagnosed with breast cancer.MethodsWe used a land use regression (LUR) model and kriging interpolation to estimate nitrogen oxides (NOx , NO2) and particulate matter (PM2.5, PM10) exposures for 3,089 breast cancer cases in the MEC, who were diagnosed from 1993 through 2013 and resided largely in Los Angeles County, California. Cox proportional hazards models were used to examine the association of time-varying air pollutants with all-cause, breast cancer, cardiovascular disease (CVD), and non-breast cancer/non-CVD mortality, accounting for key covariates.ResultsWe identified 1,125 deaths from all causes (474 breast cancer, 272 CVD, 379 non-breast cancer/non-CVD deaths) among …

Introduction The nicotine metabolite ratio and nicotine equivalents are measures of metabolism rate and intake. Genome-wide prediction of these nicotine biomarkers in multiethnic samples will enable tobacco-related biomarker, behavioral, and exposure research in studies without measured biomarkers. Aims and Methods We screened genetic variants genome-wide using marginal scans and applied statistical learning algorithms on top-ranked genetic variants, age, ethnicity and sex, and, in additional modeling, cigarettes per day (CPD), (in additional modeling) to build prediction models for the urinary nicotine metabolite ratio (uNMR) and creatinine-standardized total nicotine equivalents (TNE) in 2239 current cigarette smokers in five ethnic groups. We predicted these nicotine biomarkers using model ensembles and evaluated external validity using dependence measures in 1864 treatment-seeking smokers in …

Exposure to bisphenol A (BPA), triclosan and parabens is widespread but their impact on breast cancer risk remains unclear. This nested case‐control study investigated endocrine‐disrupting chemicals (EDCs) and breast cancer risk within the Multiethnic Cohort (MEC). We measured prediagnostic urinary BPA, triclosan and parabens in 1032 postmenopausal women with breast cancer (48 African American, 77 Latino, 155 Native Hawaiian, 478 Japanese American and 274 White) and 1030 individually matched controls, using a sensitive and validated liquid chromatography mass spectrometry assay. Conditional logistic regression was used to examine risk with these EDCs with adjustment for creatinine and potential confounders. In all women, breast cancer risk was not associated with BPA (Ptrend = 0.53) and was inversely associated with triclosan (ORT3 vs T1 = 0.83, 95% CI: 0.66‐1.04, Ptrend = 0.045) and …

1,3-Butadiene (BD) is a known human carcinogen used in the synthetic polymer industry and also found in cigarette smoke, automobile exhaust and wood burning smoke. BD is metabolically activated by cytochrome P450 monooxygenases (CYP) 2E1 and 2A6 to 3,4-epoxy-1-butene (EB), which can be detoxified by GST-catalyzed glutathione conjugation or hydrolysis. We have previously observed ethnic differences in urinary levels of EB–mercapturic acids in white, Japanese American and Native Hawaiian smokers. In the present study, similar analyses were extended to urinary BD–DNA adducts. BD-induced N7-(1-hydroxy-3-buten-2-yl) guanine (EB–GII) adducts were quantified in urine samples obtained from smokers and non-smokers belonging to three racial/ethnic groups: white, Japanese American and Native Hawaiian. After adjusting for sex, age, nicotine equivalents, body mass index and batch, we …

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60–77 years, with 12–53% overall adiposity (BMI of 17.8–46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD …

BackgroundPrior studies examining the association between ambient air pollutants and pancreatic cancer have been conducted in racially/ethnically homogeneous samples and have produced mixed results, with some studies supporting evidence of an association with fine particulate matter.MethodsTo further investigate these findings, we estimated exposure levels of particulate matter (PM2.5, PM10) and oxides of nitrogen (NOX, and NO2) using kriging interpolation for 100,527 men and women from the Multiethnic Cohort Study, residing largely in Los Angeles County from 1993 through 2013. We measured the association between these air pollutants and incident pancreatic cancer using Cox proportional hazards models with time-varying pollutant measures, with adjustment for confounding factors.ResultsA total of 821 incident pancreatic cancer and 1,660,488 person-years accumulated over the study period …

Ultrafine particles (UFP; diameter less than or equal to 100 nm) may reach the brain via systemic circulation or the olfactory tract and have been implicated in the risk of brain tumors. The effects of airport-related UFP on the risk of brain tumors are not known. Here we determined the association between airport-related UFP and risk of incident malignant brain cancer (n = 155) and meningioma (n = 420) diagnosed during 16.4 years of follow-up among 75,936 men and women residing in Los Angeles County from the Multiethnic Cohort study. UFP exposure from aircrafts was estimated for participants who lived within a 53 km × 43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993–1996) through December 31, 2013. Cox proportional hazards models were used to estimate the effects of time-varying, airport-related UFP exposure on risk of malignant brain …

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the TGFB1 gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p=2.06 × 10−8), which replicated in independent studies of African ancestry (p = 6.26 × 10−23). We identified a multiethnic risk variant in the BACE2 gene (rs13052926, RAF=14.1%, OR=1.08, p=5.75 × 10−9), which also replicated in independent studies (p = 3.45 × 10−4). We …

MethodsWe prospectively evaluated the association of 12 urinary biomarkers of nicotine metabolism and tobacco smoking toxicants with lung cancer risk among a subcohort of 2,309 Multiethnic Cohort Study participants who were current smokers at time of urine collection. Participants were followed from the time of urine collection to one of the following endpoints: lung cancer diagnosis, death, or end of follow-up (December 31, 2017). After an average of 13.4 years of study follow-up, 140 incident lung cancer cases were diagnosed. Urinary biomarkers were normalized using a log base 2 transformation. Risk of lung cancer was estimated by the hazard ratios (HR) and 95% confidence intervals (CIs) using Cox proportional hazards models where age was the time metric.ResultsAfter adjusting for decade of birth, sex, race/ethnicity, body mass index, self-reported pack-years, and urinary creatinine, we found that …

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89–1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a …

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 (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47 …

Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of ten established breast cancer predisposition genes based on a consensus call from six state-of-the-art SV callers. Overall, no significant case–control difference was found in the frequency of these deletions. However, 1.0% of cases and 0.3% of controls carried any of the eight putative protein-truncating rare deletions located in BRCA1, BRCA2, CDH1, TP53, NF1, RAD51D, RAD51C and CHEK2, resulting in an odds ratio (OR) of 3.29 (95% CI 0.74–30.16). We also identified a low-frequency deletion in NF1 …

The role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2,309 cases and 2,814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for de novo AML and MDS (OR = 1.38, 95% CI, 1.26-1.51, Pmeta = 2.8 × 10–12) in patients carrying the T allele at s12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS (OR = 3.90, 95% CI, 2.36-6.44, Pmeta = 1.0 × 10–7). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.

The workers at the Mayak nuclear facility near Ozyorsk, Russia are a primary source of information about exposure to radiation at low-dose rates, since they were subject to protracted exposures to external gamma rays and to internal exposures from plutonium inhalation. Here we re-examine lung cancer mortality rates and assess the effects of external gamma and internal plutonium exposures using recently developed Monte Carlo dosimetry systems. Using individual lagged mean annual lung doses computed from the dose realizations, we fit excess relative risk (ERR) models to the lung cancer mortality data for the Mayak Workers Cohort using risk-modeling software. We then used the corrected-information matrix (CIM) approach to widen the confidence intervals of ERR by taking into account the uncertainty in doses represented by multiple realizations from the Monte Carlo dosimetry systems. Findings of this …

Background The epidemiologic evidence from observational studies on breast cancer risk and phthalates, endocrine disrupting chemicals, has been inconsistent. In the only previous study based on pre-diagnostic urinary phthalates and risk of breast cancer, results were null in mostly white women. Methods We examined the association between pre-diagnostic urinary phthalates and breast cancer in a nested case-control study within the Multiethnic Cohort (MEC) study, presenting the first data from five major racial/ethnic groups in the USA. We measured 10 phthalate metabolites and phthalic acid, using a sensitive liquid chromatography mass spectrometry assay on 1032 women with breast cancer (48 African Americans, 77 Latinos, 155 Native Hawaiians, 478 Japanese Americans, and 274 Whites) and 1030 matched controls. Conditional logistic …

BackgroundIdentification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT.MethodsWe performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000–2011.FindingsUsing meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10−8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24–1.56, p = 3.3 × 10−8 …

Introduction Compared to non‐Hispanic Whites, Japanese Americans, Native Hawaiians, and African Americans have higher incidences of pancreatic cancer (PCa) that are not entirely explained by rates of obesity but may be explained by weight changes throughout adulthood. Methods The multiethnic cohort is a population‐based prospective cohort study that has followed 155,308 participants since its establishment between 1993 and 1996. A total of 1,328 incident cases with invasive PCa were identified through 2015. We conducted separate multivariable Cox proportional hazards models for self‐reported weight‐change and BMI‐change (age 21 to cohort entry) to determine the association with PCa risk, adjusting for potential confounders including weight or BMI at age 21. Results The mean age at cohort entry was 59.3 years (SD 8.9). An increased risk of PCa was associated with: 1) weight (HR per10 lbs …

The Multiethnic Cohort Study (MEC) has demonstrated racial/ethnic differences in smoking-associated lung cancer risk. As part of the ongoing effort to characterize exposure to cigarette smoke constituents and better understand risk differences, we evaluated Cd exposure as it is a known lung carcinogen. We quantified urinary cadmium (Cd) by inductively coupled plasma mass spectrometry in a subset of 1956 current smokers from MEC. Ethnic-specific geometric means (GM) were compared adjusting for age at urine collection, sex, creatinine (natural log), education, and smoking (urinary total nicotine equivalents [TNE] and smoking duration). Self-reported questionnaire data, including occupation, were also considered. Latinos and Native Hawaiians had the highest GM urinary Cd (0.871 and 0.836 ng/mL, respectively) followed by Japanese Americans and African Americans (0.811 ng/mL and 0.807, respectively) and Whites (0.736 ng/mL). Patterns in race/ethnicity were consistent by sex such that females had the highest GM urinary Cd. When further adjusting for categorical occupational Cd exposure, racial/ethnic differences of Cd remained (p = 0.009). Findings suggest differences in urinary Cd among smokers across different racial/ethnic groups exist and highlight the importance in considering environmental sources of Cd exposure beyond smoking. These finding lay ground for future studies of individual characteristics that are associated with lower risk for cancer despite higher carcinogenic exposures.

Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group.Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA, and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site.Results: In GWAS analysis …

Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and oxides of nitrogen were estimated by kriging (NOx, NO2, PM10, PM2.5), land use regression (LUR, NOx, NO2) and California Line Source Dispersion model (CALINE4, NOx, PM2.5) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993–1996) through 2010. Cox proportional hazards models were used to examine the associations between time‐varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion [ppb]) and NO2 (per 20 ppb) determined by …

Background:Menopausal estrogen-alone therapy is a risk factor for endometrial and ovarian cancers. When a progestin is included with the estrogen daily (continuous estrogen–progestin combined therapy), there is no increased risk of endometrial cancer. However, the effect of continuous estrogen–progestin combined therapy on risk of ovarian cancer is less clear.Methods:We pooled primary data from five population-based case–control studies in the Ovarian Cancer Association Consortium, including 1509 postmenopausal ovarian cancer cases and 2295 postmenopausal controls. Information on previous menopausal hormonal therapy use, as well as ovarian cancer risk factors, was collected using in-person interviews. Logistic regression was used to assess the association between use of continuous estrogen–progestin combined therapy and risk of ovarian cancer by duration and recency of use and disease …

Background: There is a 2-3-fold excess of both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) among African Americans (AAs) compared to non-Hispanic whites (NHWs) for unknown reasons. It is unclear if risk of progression from MGUS to MM is similar across racial/ethnic groups. We identified MGUS patients and controls from the Multiethnic Cohort (MEC), a population-based cohort study in Los Angeles and Hawaii, described characteristics of and examined risk factors for MGUS among different racial/ethnic groups.Methods: A total of 637 MEC participants with a diagnosis of MGUS by CMS billing codes and 1,065 race/ethnicity-matched MM-free and presumed MGUS-free controls were identified. Screening for monoclonal proteinemia was performed at the USC Clinical Laboratories using serum protein electrophoresis (SPEP) with reflex to immunofixation (IFX …

Background Ionizing radiation is an established carcinogen, but risks from low-dose exposures are controversial. Since the Biological Effects of Ionizing Radiation VII review of the epidemiological data in 2006, many subsequent publications have reported excess cancer risks from low-dose exposures. Our aim was to systematically review these studies to assess the magnitude of the risk and whether the positive findings could be explained by biases. Methods Eligible studies had mean cumulative doses of less than 100 mGy, individualized dose estimates, risk estimates, and confidence intervals (CI) for the dose-response and were published in 2006–2017. We summarized the evidence for bias (dose error, confounding, outcome ascertainment) and its likely direction for each study. We tested whether the median excess relative risk (ERR) per unit dose equals zero and …

Background: Phthalates (Phth), known endocrine-disruptors, may play a role in breast carcinogenesis. Low-molecular-weight phthalates (LMWPhth) are commonly found in personal care products while high MWPhth (HMWPhth) are used primarily as plasticizers. Individual Phth may disrupt normal mammary gland development and promote tumorigenesis by binding to and activating the estrogen receptor (ER).Methods: We prospectively examined the association between pre-diagnostic urinary levels of Phth metabolites and breast cancer risk in a case-control study nested within the Multiethnic Cohort (MEC). We measured 11 Phth metabolites and phthalic acid from overnight/first morning urine samples of 798 women with invasive breast cancer (355 Japanese Americans, 218 Whites, 125 Native Hawaiians, 62 Latinos, and 38 African Americans; the latter three groups were combined due to small numbers) and …

Familial studies were among the first to indicate that breast cancer prognosis has a heritable component. Subsequently many variants associated with prognosis have been identified using a range of techniques including genome-wide association studies (GWAs). Despite these advances, much of the heritability remains unexplained. In young women, breast cancer is characterised by a higher incidence of adverse pathological features, unique tumour gene expression profiles and worse survival. In addition, the association of risk with conventional epidemiological exposures is less clear in women with early onset. We hypothesise that some of these difference between early and late onset could be influenced by germline variation.To identify additional variants that influence breast cancer prognosis we conducted a two stage meta-analysis of four GWAs consisting of 6,042 patients from the UK (POSH), Finland …

Introduction: California has one of the highest levels of air pollution in the nation. Vehicle exhaust contains a mixture of gases and particulate matter that are known to have mutagenic and carcinogenic effects. Our objective was to examine the association between specific traffic-related air pollutants and lung cancer risk by race/ethnicity and sex among participants of the Multiethnic Cohort Study (MEC), residing predominately in Los Angeles County.Methods: Residential addresses from baseline, 1993-1996, through 2013 for over 112,000 California MEC participants were geocoded to latitude and longitude coordinates and used to estimate air pollutant exposures of NO2, NOX, PM10, CO, and O3 based on Bayesian kriging interpolation of state and national government air monitoring data. A total of 2,994 incident lung cancer cases (1,415 African Americans, 732 Latinos, 516 Whites, and 327 Japanese Americans …

Patterns of microbiome diversity vary across human populations, and although variation is largely driven by diet and lifestyle, genetically encoded differences between hosts may be important in shaping the microbiome and health outcomes, including cancer. We report preliminary results from a GWAS of the gut microbiome in 6,217 individuals from the Multiethnic Cohort Study, including African Americans, Japanese Americans, Native Hawaiians, Latinos, and Whites. Genome-wide SNP data was based on existing data from a variety of Illumina Infinium arrays (500,000 to 2.5 million single nucleotide polymorphisms (SNPs); n=4,363) as well as genotyping 1,853 individuals using the Illumina MEGA EX array. SNP imputation was conducted using a cosmopolitan reference panel of all 1000 Genomes samples. The stool microbiome was assessed by paired-end sequencing (Illumina MiSeq) of the16S rRNA gene (V1 …

Background: There are limited studies that have investigated the association between ambient gaseous and particulate matter (PM) air pollutants and risk of pancreatic cancer. Results from published studies are inconsistent, the strongest evidence was a significant, 16% increase in risk of pancreatic cancer mortality per 10 µg/m3 increase in PM <2.5 µm (PM2.5) in China. We used data from the Multiethnic Cohort Study to examine prospectively associations between ambient air pollutants and incident pancreatic cancer, while adjusting for a comprehensive list of confounding factors. Methods: Kriging Interpolation was used to estimate individual, time varying, monthly, air pollutant exposure levels of nitrogen oxides (NOX, NO2) and PM (PM2.5, PM10) pollutants for 100,527 men and women, who resided largely in Los Angeles County at the time of enrollment (1993-1996) through 2014. We observed 844 incident …

PurposeMultiple myeloma (MM) treatment has changed tremendously, with significant improvement in patient out-comes. One group with a suboptimal benefit is patients with high-risk cytogenetics, as tested by conventional karyotyping or fluorescence in situ hybridization (FISH). Methodology for these tests has been published, but not necessarily standardized.MethodsWe address variability in the testing and reporting methodology for MM cytogenetics in the United States using the ongoing African American Multiple Myeloma Study (AAMMS). We evaluated clinical and cytogenetic data from 1,221 patients (1,161 with conventional karyotyping and 976 with FISH) tested between 1998 and 2016 across 58 laboratories nationwide.ResultsInterlab and intralab variability was noted for the number of cells analyzed for karyotyping, with a significantly higher number of cells analyzed in patients in whom cytogenetics were …

Background: The etiology of malignant brain cancer remains largely unknown. The two established risk factors, ionizing radiation and a history of allergies or atopic disease, explain less than 10% of the disease. In 2012, the International Agency for Research on Cancer classified air pollution and particulate matter (PM) as carcinogenic to humans (Group 1). The carcinogenic effects of air pollution may reach the brain via the systemic circulation, crossing the blood-brain barrier. There are increasing concerns about the potential impact of air pollution on outcomes of central nervous system (CNS), including chronic brain inflammation and microglia cell activation, but evidence of its carcinogenic effects is still limited. Methods: Kriging interpolation of air pollution data from monitoring stations were used to estimate long-term exposures of particulate matter pollutants (PM2.5, PM10), gaseous pollutants (oxides of nitrogen …

This article addresses issues relevant to interpreting findings from 26 epidemiologic studies of persons exposed to low-dose radiation. We review the extensive data from both epidemiologic studies of persons exposed at moderate or high doses and from radiobiology that together have firmly established radiation as carcinogenic. We then discuss the use of the linear relative risk model that has been used to describe data from both low- and moderate- or high-dose studies. We consider the effects of dose measurement errors; these can reduce statistical power and lead to underestimation of risks but are very unlikely to bring about a spurious dose response. We estimate statistical power for the low-dose studies under the assumption that true risks of radiation-related cancers are those expected from studies of Japanese atomic bomb survivors. Finally, we discuss the interpretation of confidence intervals and …

1,3-Butadiene (BD) is a known human carcinogen found in cigarette smoke, automobile exhaust, and urban air. Workers occupationally exposed to BD in the workplace have an increased incidence of leukemia and lymphoma. BD undergoes cytochrome P450-mediated metabolic activation to 3,4-epoxy-1-butene (EB), 1,2,3,4-diepoxybutane (DEB) and 1,2-dihydroxy-3,4-epoxybutane (EBD), which form covalent adducts with DNA. We have previously reported a quantitative nanoLC/ESI+-HRMS3 method for urinary N7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) adducts as a mechanism-based biomarker of BD exposure. In the present study, the method was updated to include high throughput 96-well solid phase extraction (SPE) and employed to establish urinary EB-GII biomarker stability and association with smoking. Urinary EB-GII levels were measured bimonthly for 1 year in 19 smokers to determine …

Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US with differential risk across race/ethnicity groups and increases lung cancer risk. In the Multiethnic Cohort (MEC), an ethnically diverse prospective cohort (>215,000) established in the early 1990’s in California and Hawaii, we found COPD prevalence was highest in African Americans, followed by European Americans, Native Hawaiians, Latinos and Japanese Americans. Family history and smoking are strong risk factors for COPD with heritability estimates ranging from 20-40%. However, large scale genomic studies (GWAS) have primarily focused on Europeans. Thus, ethnic-specific calibration of polygenic risk scores (PRS) for predicting COPD has the potential to identify those with greatest need for recommended screening and targeted prevention. Methods: Incident COPD case status was identified from …

Background There are increasing concerns about the potential impact of air pollution on chronic brain inflammation and microglia cell activation, but evidence of its carcinogenic effects is limited. Methods We used kriging interpolation and land use regression models to estimate long-term air pollutant exposures of oxides of nitrogen (NOx, NO2), kriging interpolation for ozone (O3), carbon monoxide, and particulate matter (PM2.5, PM10), and nearest monitoring station measurements for benzene for 103 308 men and women from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993–1996) through 2013. We used Cox proportional hazards models to examine the associations between time-varying pollutants and risk of malignant brain cancer (94 men, 116 women) and meningioma (130 men, 425 women) with adjustment for sex, race and …

ObjectiveTo examined the impact of reproductive factors on the relationship between radiation treatment (RT) for a first breast cancer and risk of contralateral breast cancer (CBC).MethodsThe Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based case-control study where cases are women with asynchronous CBC (N = 1521) and controls are women with unilateral breast cancer (N = 2211). Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression to assess the independent and joint effects of RT (ever/never and location-specific stray radiation dose to the contralateral breast [0, >0-<1Gy, ≥1Gy]) and reproductive factors (e.g., parity).ResultsNulliparous women treated with RT (≥1Gy dose) were at increased risk of CBC compared with nulliparous women not treated with RT, although this relationship did not …

Conclusion: In a large, prospective, European real-life study of tertiary care outpatient hepatology clinics, 25% of pts are currently referred for known or suspected NAFLD which is confirmed in 77% of cases after multiple diagnostic procedures. 40–62% have advanced fibrosis and 8.4–12% cirrhosis. Diagnostic practices vary widely between countries and pt referral for comorbidities is low. NAFLD is becoming a major burden on hepatology outpatient clinics in Europe

Over the past 10 years, there has been substantial progress in the study and implementation of lung cancer screening using low-dose computed tomography (LDCT). The National Lung Screening Trial, the recently reported NELSON (NEderlands-Leuvens Longkanker Screenings ONderzoek) trial, and other European trials provide strong evidence for the efficacy of LDCT to reduce lung cancer mortality. This has resulted in the United State's Preventative Task Force and numerous professional medical societies adopting lung cancer screening recommendations. Despite the general acceptance of the positive effect of screening, low adoption and implementation rates remain nationally. In this article, the authors discuss the evolution and current state of the evidence for LDCT screening for lung cancer. The authors will also review the associated risks, cost, and challenges of implementation of an LDCT screening …

Background: Lung cancer is the most common cancer in the U.S. and leading cause of cancer-related death. We demonstrated in the Multiethnic Cohort Study that for the same number of cigarettes smoked, Native Hawaiians and African Americans have the highest risk compared to whites, while Japanese Americans and Latinos are at lower risk of disease. We showed that internal smoking dose (as measured by total nicotine equivalents (TNE)) per cigarette differs across race/ethnicity; in part explaining why African Americans have a higher risk of disease and Japanese Americans have a lower risk. DNA methylation of CpG sites from cigarette smoking is one of the most common epigenetic modifications linked to lifestyle. Although many smoking-related DNA methylated CpG sites have been identified, these studies have been primarily conducted in populations of European ancestry. Moreover, the influence of …

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.

Background: There are now 3.1 million breast cancer (BC) survivors with 4.5 million survivors projected by 2030. This high and growing burden speaks to the need of identifying modifiable factors that influence BC survival. Particulate matter (PM) air pollutants have been associated with increased mortality for cardiovascular disease (CVD) and several cancers. However, few studies have examined the impact of air pollution on mortality among BC cases. Within the Multiethnic Cohort (MEC), we examined the association between outdoor air pollution and mortality among African American (AA), Latino (LA), Japanese American (JA), and White (WH) women diagnosed with BC. Methods: Kriging interpolation of air pollution data from air monitoring stations was used to estimate PM2.5, PM10, and nitrogen oxides (NOx, NO2) exposures for 3,089 BC cases in the MEC, residing largely in Los Angeles County, linked to …

Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer–associated genes is unknown. In a population-based case-control study, we examined the association between RT; variants in ATM, BRCA1/2, or CHEK2*1100delC; and CBC risk. We analyzed 708 cases of women with CBC and 1399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2000 and aged younger than 55 years at diagnosis and screened for variants in breast cancer–associated genes. Rate ratios (RR) and 95% confidence intervals (CIs) were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (eg, BRCA1/2 pathogenic variant carriers without RT: RR = 3.52, 95% CI = 1.76 to 7.01 …

The global rise in fatty liver is a major public health problem. Thus, it is critical to identify both global and population‐specific genetic variants associated with liver fat. We conducted a genome‐wide association study (GWAS) of percent liver fat and nonalcoholic fatty liver disease (NAFLD) assessed by magnetic resonance imaging in 1,709 participants from the population‐based Multiethnic Cohort Adiposity Phenotype Study. Our participants comprised older adults of five U.S. racial/ethnic groups: African Americans (n = 277), Japanese Americans (n = 424), Latinos (n = 348), Native Hawaiians (n = 274), and European Americans (n = 386). The established missense risk variant rs738409 located in patatin‐like phospholipase domain containing 3 (PNPLA3) at 22q13 was confirmed to be associated with percent liver fat (P = 3.52 × 10−15) but more strongly in women than men (P heterogeneity = 0.002). Its frequency …

Background: Benzene is classified as a Group 1 carcinogen in humans. A major pathway of benzene exposure is through inhalation of ambient air contaminated by emissions from motor vehicle exhaust, gas stations, industry, tobacco smoke, and other consumer products. Prior studies of benzene and lung cancer have been limited largely to occupational studies. We examined the association between outdoor air exposure to benzene and lung cancer risk in the large population-based Multiethnic Cohort Study (MEC), including four major U.S. racial/ethnic groups—African Americans, Latinos, Japanese Americans, and Whites. Methods: Ambient benzene exposure was estimated from EPA data from air monitoring stations that were within 20 km of residences of 97,288 MEC participants, largely from Los Angeles County, from the time-period of recruitment (1993-1996) through 12/31/2013. Cox proportional hazards …

Backgrounds: There are striking racial/ethnic differences in pancreatic cancer incidence in the United States. Studies have reported positive associations between intake of red meat and pancreatic cancer risk; however, less evidence exists for ethnic/racial minorities, including African Americans who have elevated risks of this fatal cancer. In this study, we assessed the association between red meat consumption and pancreatic cancer incidence in two large cohort studies: the Multiethnic Cohort Study (MEC) and the Southern Community Cohort Study (SCCS). Methods: Demographics, dietary data and other risk factors were assessed at cohort enrollment. Total red meat intake was assessed using a quantitative food frequency questionnaire and categorized using cohort-specific quartiles. Incident cases of pancreatic cancer were identified via linkage to state cancer registries and the National Death Index. Cox …

To improve risk stratification and treatment decisions for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We used SNP-array data from the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT peripheral blood (collected 2–4 weeks before the administration of conditioning regimen) from 1974 AML patients who received HCT between 2000 and 2011. All aberrations detected in ≥ 10 patients were tested for their association with overall survival (OS), separately by remission status, using the Kaplan–Meier estimator. Cox regression models were used for multivariable analyses. Follow-up was through January 2019. We identified 701 unique chromosomal aberrations in 285 patients (7% of 1438 in complete remission (CR) and 36% of 536 not in CR). Copy-neutral loss-of-heterozygosity (CNLOH) in chr17p in CR patients (3-year OS = 20% vs. 50 …

Spatiotemporal air pollution models are increasingly being used to estimate health effects in epidemiological studies. Although such exposure prediction models typically result in improved spatial and temporal resolution of air pollution predictions, they remain subject to shared measurement error, a type of measurement error common in spatiotemporal exposure models which occurs when measurement error is not independent of exposures. A fundamental challenge of exposure measurement error in air pollution assessment is the strong correlation and sometimes identical (shared) error of exposure estimates across geographic space and time. When exposure estimates with shared measurement error are used to estimate health risk in epidemiological analyses, complex errors are potentially introduced, resulting in biased epidemiological conclusions. We demonstrate the influence of using a three …

Background: The WNT signaling pathway is involved in a wide range of developmental events and maintenance of homeostasis in adult tissue, including lung development and health. WNT signaling genes have also been suggested to play a role in pathogenesis of lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma.Aims and Objectives: The aim of this meta-analysis was to identify consistent disease markers for COPD, asthma, forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) in nine genes of the WNT signaling cascade pathway (WNT10b, WIF1, WISP1, SFRP2, SFRP5, DKK1, Axin2, TCF7L2, and FZD3) using genome-wide association data from six European cohort studies.Methods: The six European cohort studies included are: B58C (UK), ECRHS (multicentre), EGEA (France), GINI / LISA (Germany), NFBC1966 (Finland), and SAPALDIA …

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.

Purpose: Japanese Americans, Native Hawaiians and African Americans have a higher incidence of pancreatic cancer compared to non-Hispanic whites that cannot be explained by the rates of obesity or absolute body weight. While absolute body weight in adulthood is positively associated with pancreatic cancer risk, the effect of weight change throughout adulthood, particularly among a racially diverse population, is not well documented for this high-risk group. Methods: This population-based prospective cohort study included 155,308 participants enrolled in the Multiethnic Cohort from 1993-1996 (median follow-up = 20.2 years). We identified 1,328 participants diagnosed with incident primary invasive pancreatic cancer from the linked cohort data with the Hawaii and California SEER registries. Participants diagnosed with other cancers were excluded from the cohort analysis. Body weight at 21 years old and at …