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Aims/hypothesis: Several studies have reported associations between specific proteins and type 2 diabetes risk in European populations. To better understand the role played by proteins in type 2 diabetes aetiology across diverse populations, we conducted a large proteome-wide association study using genetic instruments across four racial and ethnic groups: African; Asian; Hispanic/Latino; and European., Methods: Genome and plasma proteome data from the Multi-Ethnic Study of Atherosclerosis (MESA) study involving 182 African, 69 Asian, 284 Hispanic/Latino and 409 European individuals residing in the USA were used to establish protein prediction models by using potentially associated cis- and trans-SNPs. The models were applied to genome-wide association study summary statistics of 250,127 type 2 diabetes cases and 1,222,941 controls from different racial and ethnic populations., Results: We identified three, 44 and one protein associated with type 2 diabetes risk in Asian, European and Hispanic/Latino populations, respectively. Meta-analysis identified 40 proteins associated with type 2 diabetes risk across the populations, including well-established as well as novel proteins not yet implicated in type 2 diabetes development., Conclusions/interpretation: Our study improves our understanding of the aetiology of type 2 diabetes in diverse populations., Data Availability: The summary statistics of multi-ethnic type 2 diabetes GWAS of MVP, DIAMANTE, Biobank Japan and other studies are available from The database of Genotypes and Phenotypes (dbGaP) under accession number phs001672.v3.p1. MESA genetic, proteome and covariate data can be accessed through dbGaP under phs000209.v13.p3. All code is available on GitHub ( https://github.com/Arthur1021/MESA-1K-PWAS )., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk., Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated., Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10 -8 ). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10 -14 ); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10 -3 ), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk., Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use., (© 2024. The Author(s).)

Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer., Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer., Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior., Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies., Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Transcriptome-wide association studies have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large transcriptome-wide association study and an alternative splicing transcriptome-wide association study in CRC using improved genetic prediction models and performed in-depth functional investigations., Methods: We analyzed RNA-sequencing data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing and evaluated model performance using independent RNA-sequencing data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58 131 CRC cases and 67 347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for 3 selected genes in multiple CRC cell lines., Results: We identified 57 putative CRC susceptibility genes, which included the 48 genes from transcriptome-wide association studies and 15 genes from splicing transcriptome-wide association studies, at a Bonferroni-corrected P value less than .05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for 2 unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166., Conclusion: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer., Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies., (©2023 The Authors; Published by the American Association for Cancer Research.)

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), and (Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopenyl]hept-5-enoic acid (8-iso-PGF2α)] with lung cancer risk (n = 140 incident lung cancer cases over an average of 13.4 years of follow-up). Lung cancer risk was estimated using Cox proportional hazards models., Results: After adjusting for decade of birth, sex, race/ethnicity, body mass index, self-reported pack-years, creatinine, and urinary TNE (a biomarker of internal smoking dose), a one SD increase in log total 3-HCOT/cotinine (HR, 1.33; 95% CI, 1.06-1.66), 3-HPMA (HR, 1.41; 95% CI, 1.07-1.85), and Cd (HR, 1.45; 95% CI, 1.18-1.79) were each associated with increased lung cancer risk., Conclusions: Our study demonstrates that urinary total 3-HCOT/cotinine, 3-HPMA, and Cd are positively associated with lung cancer risk. These findings warrant replication and consideration as potential biomarkers for smoking-related lung cancer risk., Impact: These biomarkers may provide additional information on lung cancer risk that is not captured by self-reported smoking history or TNE. See related commentary by Etemadi et al., p. 289., (©2022 American Association for Cancer Research.)

Background: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance., Methods: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group)., Results: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity., Conclusions: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort., Impact: The proposed model has potential utility in risk-stratified colorectal cancer prevention., (©2023 American Association for Cancer Research.)

Background: Studies in men of European ancestry suggest prostate-specific antigen (PSA) as a marker of early prostate cancer development that may help to risk-stratify men earlier in life., Methods: We examined PSA levels in men measured up to 10+ years before a prostate cancer diagnosis in association with prostate cancer risk in 2,245 cases and 2,203 controls of African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. We also compared the discriminative ability of PSA to polygenic risk score (PRS) for prostate cancer., Results: Excluding cases diagnosed within 2 and 10 years of blood draw, men with PSA above the median had a prostate cancer OR (95% CIs) of 9.12 (7.66-10.92) and 3.52 (2.50-5.03), respectively, compared with men with PSA below the median. A PSA level above the median identified 90% and 75% of cases diagnosed more than 2 and 10 years after blood draw, respectively. The associations were significantly greater for Gleason ≤7 versus 8+ disease. At 10+ years, the association of prostate cancer with PSA was comparable with that with the PRS [OR per SD increase: 1.88 (1.45-2.46) and 2.12 (1.55-2.93), respectively]., Conclusions: We found PSA to be an informative marker of prostate cancer risk at least a decade before diagnosis across multiethnic populations. This association was diminished with increasing time, greater for low grade tumors, and comparable with a PRS when measured 10+ years before diagnosis., Impact: Our multiethnic investigation suggests broad clinical implications on the utility of PSA and PRS for risk stratification in prostate cancer screening practices., (©2022 American Association for Cancer Research.)

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II A muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention., (© 2022. The Author(s).)

Objective: While cardiometabolic abnormalities are associated with elevated risk of morbidity, they may not occur in all individuals with obesity. Less is known about associations with mortality, especially cancer mortality. This study examined associations between cardiometabolic-weight categories and mortality from cardiovascular disease (CVD), cancer, and all causes. Methods: Cox proportional hazards regressions of time to all-cause, CVD, and cancer mortalities were used to examine associations with cardiometabolic-weight status, in the Multiethnic Cohort ( n =157,865). Cardiometabolic-weight status categories were: Metabolically Healthy Normal Weight, Metabolically Healthy Obese, Metabolically Healthy Overweight, Metabolically Unhealthy Normal Weight, Metabolically Unhealthy Obese, and Metabolically Unhealthy Overweight. Results: Higher mortality, especially for all-cause and CVD, was found for all metabolically unhealthy groups no matter the weight classification when compared to the Metabolically Healthy Normal Weight category across sex-ethnic groups. For all-cause mortality, a reduction in mortality was seen for males in the Metabolically Healthy Overweight category (HR: 0.88, 95% CI: 0.84, 0.93), especially for African American, Native Hawaiian, and Latino males. Mortality was elevated in the Metabolically Healthy Obese category for all-cause and CVD mortality in both sexes (HR range : 1.08-1.93). Few associations were seen with cancer mortality. Conclusions: Past examinations of cardiometabolic-weight status and mortality have been hampered by a lack of diversity. In a racially/ethnically diverse population, metabolically unhealthy groups exhibited a substantially higher risk of death from all causes and CVD than metabolically healthy groups. A reduction in all-cause mortality was seen for some males classified as Metabolically Healthy Overweight; however, being classified as Metabolically Healthy Obese elevated mortality risk for males and females compared to Metabolically Healthy Normal Weight. Future research is needed to examine how sex-ethnic differences in body fat distribution and changes in weight over time influence associations between cardiometabolic-weight status and mortality.

Background: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches., Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status., Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74-0.77) in the training and 0.77 (95% CI, 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients., Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC., Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing., (©2022 American Association for Cancer Research.)

Background: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome., Patients and Methods: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10 -5 ), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas., Results: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10 -7 ). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10 -2 ) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10 -8 ). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10 -2 )., Conclusions: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis., Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC., Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs., Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association., Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association., (Published by Oxford University Press on behalf of the American Society for Nutrition 2021.)

Background: There is limited prior investigation of the combined influence of personal and community-level socioeconomic factors on racial/ethnic disparities in individual risk of coronavirus disease 2019 (COVID-19)., Methods: We performed a cross-sectional analysis nested within a prospective cohort of 2,102,364 participants from March 29, 2020 in the United States (US) and March 24, 2020 in the United Kingdom (UK) through December 02, 2020 via the COVID Symptom Study smartphone application. We examined the contribution of community-level deprivation using the Neighborhood Deprivation Index (NDI) and the Index of Multiple Deprivation (IMD) to observe racial/ethnic disparities in COVID-19 incidence. ClinicalTrials.gov registration: NCT04331509., Findings: Compared with non-Hispanic White participants, the risk for a positive COVID-19 test was increased in the US for non-Hispanic Black (multivariable-adjusted odds ratio [OR], 1.32; 95% confidence interval [CI], 1.18-1.47) and Hispanic participants (OR, 1.42; 95% CI, 1.33-1.52) and in the UK for Black (OR, 1.17; 95% CI, 1.02-1.34), South Asian (OR, 1.39; 95% CI, 1.30-1.49), and Middle Eastern participants (OR, 1.38; 95% CI, 1.18-1.61). This elevated risk was associated with living in more deprived communities according to the NDI/IMD. After accounting for downstream mediators of COVID-19 risk, community-level deprivation still mediated 16.6% and 7.7% of the excess risk in Black compared to White participants in the US and the UK, respectively., Interpretation: Our results illustrate the critical role of social determinants of health in the disproportionate COVID-19 risk experienced by racial and ethnic minorities., Competing Interests: JC reports personal fees from Zoe Ltd. during the conduct of the study and outside the submitted work and is an employee of Zoe Ltd. TDS is a consultant to Zoe Ltd. LLM reports grants from National Cancer Institute during the conduct of the study. SO reports grants from Wellcome Trust, grants from Innovate UK (UKRI), grants from Chronic Disease Research Foundation (CDRF) outside the submitted work. DAD reports grants from National Institutes of Health, grants from American Gastroenterological Association during the conduct of the study and that he previously served as an investigator for a clinical trial of diet and lifestyle using a separate mobile application that was supported by Zoe Ltd. RD reports grants from Department of Health and Social Care (UK), personal fees from Zoe Ltd. during the conduct of the study and outside the submitted work and is an employee of Zoe Ltd. CJS reports grants from Chronic Disease Research Foundation during the conduct of the study. CHS reports grants from Alzheimer's Society during the conduct of the study. CMA reports grants from National Institutes of Health K23 DK120899 and Boston Children's Hospital Office of Faculty Development Career Development Award during the conduct of the study. ATC reports personal fees from Bayer Pharma AG, Pfizer Inc., Boehringer Ingelheim, and grants from Zoe Ltd. outside the submitted work and that he previously served as an investigator for a clinical trial of diet and lifestyle using a separate mobile application that was supported by Zoe Ltd. JW is the CEO of Zoe Ltd. Other authors have no conflict of interest to declare., (© 2021 The Author(s).)

Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival., Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components., Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years; P = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location., Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival., Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed., (©2021 American Association for Cancer Research.)

Background: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses., Methods: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR., Results: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses., Conclusions: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development., Impact: Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development. See related commentary by Hang and Shen, p. 1302 ., (©2021 American Association for Cancer Research.)

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown., Objective: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes., Methods: Carriers of pathogenic variants of MLH1 ( path&#95;MLH1 ) and MSH2 ( path&#95;MSH2 ) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity., Results: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately., Conclusion: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path&#95;MSH2 .

Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite., Methods: Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite., Results: Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P  = .04)., Conclusion: In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease., (© The Author(s) 2021. Published by Oxford University Press.)

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 also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (p heterogeneity = 3.85 × 10 -20 ). Comparing individuals in the top GRS risk category (40%-60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.

Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data ( N = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial ( N = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92-3.00; P = 1.80 × 10 -14 ] in the validation set ( P trend = 5.26 × 10 -20 ). The OR per SD of PRS increase was 1.26 (95% CI = 1.20-1.32; P = 9.69 × 10 -23 ) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy. SIGNIFICANCE: Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening., (©2021 American Association for Cancer Research.)

It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes-people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1 , 314 MSH2 , 126 MSH6 , 71 PMS2 , and 22 EPCAM ) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P  >   .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided P  =   .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer., (© The Author(s) 2021. Published by Oxford University Press.)

Background/objective: As dietary intake and endocrine metabolism are vastly different by sex, we evaluated differences in the association of diet quality with body composition between men and women., Subjects/methods: Close to 2000 participants from the Multiethnic Cohort completed calibrated quantitative food frequency questionnaires at cohort entry (1993-96) and clinic visit (2013-16), from which the Healthy Eating Index (HEI-2010) was computed. Adiposity measures were obtained through DXA and MRI at clinic visit. Multivariable-adjusted mean adiposity measures were estimated by tertiles of HEI-2010 scores using general linear regression. The associations of diet quality with high visceral fat (VAT) and nonalcoholic fatty liver disease (NAFLD) were examined by logistic regression. To assess sex differences, cross-product terms with the HEI-2010 were added to the models., Results: Mean HEI-2010 scores were higher for women than men at cohort entry (67.4 vs. 64.0) and clinic visit (73.6 vs. 71.0). Past and current diet quality was inversely associated with adiposity measures in men and women. Although interaction terms were not significant, the magnitude of the slopes and differences in adjusted means across tertiles suggested a stronger association for women than men. When comparing individuals who maintained a high vs. poor quality diet over 20 years, women but not men showed significantly lower risks for high VAT, whereas high HEI-2010 scores predicted a lower risk of NAFLD in both sexes., Conclusions: The inverse association of diet quality with adiposity was similar in both sexes, but diet quality appeared to have a stronger influence on VAT in women than men.

Background: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk., Methods: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing., Results: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (P G×E = 1.96 × 10 -4 ), KRT16 (P G×E = 2.3 × 10 -4 ), CD14 (P G×E = 9.38 × 10 -4 ), and CYP27A1 (P G×E = 1.44 × 10 -3 ). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (P G×E = 3.23 × 10 -5 ). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2., Conclusions: By incorporating functional information, we discovered several novel genes that interacted with NSAID use., Impact: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer., (©2020 American Association for Cancer Research.)

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

Background: People with diabetes are at an increased risk of developing pancreatic cancer. However, it is unclear whether diabetes-related complications are associated with risk of pancreatic cancer., Methods: A nested matched case-control analysis was conducted among the fee-for-service Medicare participants of the prospective Multiethnic Cohort (n = ∼123 000). Between 2001 and 2014, 433 incident cases of pancreatic ductal adenocarcinoma were matched to 1728 controls by birth year, sex, race and ethnicity, and age at cohort entry. Participants were linked to data from the California and Hawaii cancer registries and Medicare claims. We used the diabetes complications severity index (DCSI) for the presence of 7 complications within 2 years prior to the diagnosis date of the index case. Multivariable conditional logistic regression was used to examine the association of DCSI with pancreatic cancer incidence., Results: Diabetes was present among 45.4% of cases and 34.1% of controls. Cases had higher DCSI score compared with controls (score ≥4: 32.8% in cases; 21.2% in controls). The most prevalent diabetes-related complications for cases were cardiovascular disease (61.2%), nephropathy (31.2%), and cerebrovascular disease (21.7%). Individuals with diabetes (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.14 to 1.91), nephropathy (OR = 1.75, 95% CI = 1.32 to 2.33), cardiovascular disease (OR = 1.88, 95% CI = 1.45 to 2.44), and metabolic complications (OR = 6.61, 95% CI = 2.49 to 17.50) were at increased risk of pancreatic cancer. For every 1-unit increase in DCSI score, participants had 18% greater risk of pancreatic cancer (OR = 1.18, 95% CI = 1.11 to 1.25)., Conclusions: Participants with diabetes-related complications have an elevated risk of pancreatic cancer. Identifying diabetes-related complications may help identify high-risk groups who can be studied for development of early markers for this fatal cancer., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk., Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined., Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [OR LA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10 -4 ] and α-linolenic acid (OR ALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10 -5 ), whereas modest increased risks were observed for arachidonic (OR AA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10 -5 ), eicosapentaenoic (OR EPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10 -3 ), and docosapentaenoic acids (OR DPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10 -2 ). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses., Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk., Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer., (©2020 American Association for Cancer Research.)

Purpose: Reducing colorectal cancer incidence and mortality through early detection would improve efficacy if targeted. We developed a colorectal cancer risk prediction model incorporating personal, family, genetic, and environmental risk factors to enhance prevention., Methods: A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history (FH), family structure, probabilities of mutation in major colorectal cancer susceptibility genes, and a polygenic component. We developed risk models, including individuals' FRP or binary colorectal cancer FH, and colorectal cancer risk factors collected at enrollment using population-based colorectal cancer cases ( N = 4,445) and controls ( N = 3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based ( N = 12,052) and clinic-based ( N = 5,584) relatives with no cancer history at recruitment to assess model calibration [expected/observed rate ratio (E/O)] and discrimination [area under the receiver-operating-characteristic curve (AUC)]., Results: The E/O [95% confidence interval (CI)] for FRP models for population-based relatives were 1.04 (0.74-1.45) for men and 0.86 (0.64-1.20) for women, and for clinic-based relatives were 1.15 (0.87-1.58) for men and 1.04 (0.76-1.45) for women. The age-adjusted AUCs (95% CI) for FRP models for population-based relatives were 0.69 (0.60-0.78) for men and 0.70 (0.62-0.77) for women, and for clinic-based relatives were 0.77 (0.69-0.84) for men and 0.68 (0.60-0.76) for women. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08 (0.01-0.15) for men and 0.10 (0.04-0.16) for women, and for clinic-based relatives were 0.11 (0.05-0.17) for men and 0.11 (0.06-0.17) for women., Conclusions: Both models calibrated well. The FRP-based model provided better risk stratification and risk discrimination than the FH-based model., Impact: Our findings suggest detailed FH may be useful for targeted risk-based screening and clinical management., (©2020 American Association for Cancer Research.)

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 (NO x , NO 2 ), kriging interpolation for ozone (O 3 ), carbon monoxide, and particulate matter (PM 2.5 , PM 10 ), 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 ethnicity, neighborhood socioeconomic status, smoking, occupation, and other covariates. Stratified analyses were conducted by sex and race and ethnicity., Results: Brain cancer risk in men increased in association with exposure to benzene (hazard ratio [HR] = 3.52, 95% confidence interval [CI] = 1.55 to 7.55) and PM 10 (HR = 1.80, 95% CI = 1.00 to 3.23). Stronger associations with PM 10 (HR = 3.02, 95% CI = 1.26 to 7.23), O 3 (HR = 2.93, 95% CI = 1.09 to 7.88), and benzene (HR = 4.06, 95% CI = 1.17 to 18.2) were observed among Latino men. Air pollution was unrelated to risk of meningioma except that O 3 exposure was associated with risk in men (HR = 1.77, 95% CI = 1.02 to 3.06). Brain cancer risk in women was unrelated to air pollution exposures., Conclusions: Confirmation of these sex differences in air pollution-brain cancer associations and the stronger findings in Latino men in additional diverse populations is warranted., (© The Author(s) 2020. Published by Oxford University Press.)

Intake of heterocyclic amines (HCAs) and other mutagenic compounds formed during cooking has been hypothesized to be responsible for the positive association observed between red meat and colorectal cancer. We evaluated whether well-done/very well-done preferences for various meat and fish items, higher intakes of meat and fish, and meat-derived and fish-derived HCA are associated with the risk of colorectal adenoma (CRA) in a Japanese-Brazilian population. We selected 302 patients with adenoma and 403 control individuals who underwent total colonoscopy between 2007 and 2013, and collected information on aspects of meat intake using a detailed questionnaire. We also estimated HCA intake of the study participants using an HCA database that matched the cooking methods of this population. Latent class analysis on the basis of response to doneness preferences for different cooking methods of commonly consumed meat and fish items identified four distinct subgroups. Compared with the subgroup characterized by a preference for rare/medium well-done cooking for most meat and fish items, the odds ratio of CRA for the well-done/very well-done preference subgroup was 1.19 (95% confidence interval: 0.51-2.75). High intake of mixed-meat dishes was suggestively associated inversely with CRA, whereas a high intake of poultry was associated positively with CRA. No clear association with intake of total or specific HCAs and no effect modification by N-acetyltransferase 2 acetylation genotype were observed. We found no statistically significant associations between meat and HCA intake and CRA. These findings do not support a positive association between meat and meat-derived HCA intake and the risk of CRA.

Background: The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species., Methods: To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study., Results: We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk., Conclusions: In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The purpose of this study was to examine associations of sociodemographic and lifestyle factors with diet quality in a multiethnic population., Methods: The analysis included 160 353 African American, Native Hawaiian, Japanese American, Latino, and non-Hispanic white participants aged 45 to 75 y who entered the Multiethnic Cohort study by completing a comprehensive questionnaire in 1993 to 1996 and did not report cancer or heart disease. Diet quality was assessed using four diet quality indexes (DQIs): the Healthy Eating Index 2010, the Alternative Healthy Eating Index 2010, the alternate Mediterranean Diet, and the Dietary Approaches to Stop Hypertension., Results: For three DQIs, the Healthy Eating Index 2010, Alternative Healthy Eating Index 2010, and Dietary Approaches to Stop Hypertension, mean scores were significantly higher in women than men, whereas the mean score of the alternate Mediterranean Diet was significantly higher in men than women. In both men and women, older age, higher education, being physically active, and multivitamin use were associated with scores above the median of DQIs, whereas overweight/obesity, current smoking, and heavy alcohol consumption (≥2 drinks/d) were associated with scores less than the median of DQIs. Race/ethnicity had inconsistent associations according to the DQIs. Being widowed, being a previous smoker, and having a low body mass index (<20 kg/m 2 ) were associated with scores less than the median of DQIs in men but not in women., Conclusions: Diet quality was associated with sociodemographic and lifestyle characteristics in men and women. The associations with several factors, such as marital status, body mass index, and smoking status, differed by sex. These findings may help to identify at-risk populations for nutritional screening and to develop nutritional intervention strategies and educational materials., (Copyright © 2018 Elsevier Inc. All rights reserved.)