Metabolites Associated with Polygenic Risk of Breast Cancer.

While hundreds of germline genetic variants have been associated with breast cancer risk, the mechanisms underlying the impacts of most of these variants on breast cancer remain uncertain. Metabolomics may offer valuable insights into the mechanisms underlying genetic risks of breast cancer. Among 143 cancer-free female participants, we used linear regression analyses to explore associations between the genetic risk of breast cancer, as determined by a previously developed polygenic risk score (PRS) that included 266 single-nucleotide polymorphisms (SNPs), and 223 measures of metabolites obtained from blood samples using nuclear magnetic resonance (NMR). A false discovery rate of 10% was applied to account for multiple comparisons. PRS was statistically significantly associated with 45 metabolite measures. These were primarily measures of very low-density lipoproteins (VLDLs) and high-density lipoproteins (HDLs), including triglycerides, cholesterol, and phospholipids. For example, the strongest effect was observed with the percent ratio of medium VLDL triglycerides to total lipids (0.53 unit increase in mean-standardized ln-transformed percent ratio per unit increase in PRS; q = 0.1). While larger-scale studies are needed to confirm these results, this exploratory study presents biologically plausible findings that are consistent with previously reported associations between lipids and breast cancer risk. If confirmed, these lipids could be targeted for lifestyle and pharmaceutical interventions among women at increased genetic risk of breast cancer.

Antihypertensive medications and risk of colorectal cancer in British Columbia.

Introduction: There is conflicting evidence for the association between antihypertensive medications and colorectal cancer risk, possibly reflecting methodological limitations of previously conducted studies. Here, we aimed to clarify associations between commonly prescribed antihypertensive medication classes and colorectal cancer risk in a large, retrospective, cohort study. Methods: Using linked administrative data between 1996 and 2017 from British Columbia, we identified a cohort of 1,693,297 men and women who were 50 years of age or older, initially cancer-free and nonusers of antihypertensive medications. Medication use was parameterized as ever use, cumulative duration, and cumulative dose. Cox proportional hazard models were used to estimate hazard ratios (HRs) and associated 95% confidence intervals (95% CIs) for associations of time-varying medication use [angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and diuretics] with colorectal cancer risk. Results: There were 28,460 incident cases of colorectal cancer identified over the follow-up period (mean = 12.9 years). When medication use was assessed as ever/never, diuretics were associated with increased risk of colorectal cancer (HR 1.08, 95% CI 1.04-1.12). However, no similar association was observed with cumulative duration or cumulative dose of diuretics. No significant associations between the other four classes of medications and colorectal cancer risk were observed. Conclusion: No compelling evidence of associations between antihypertensive medications and colorectal cancer were observed.

Provincial variation in colorectal cancer screening adherence in Canada; evidence from the Canadian Partnership for Tomorrow's Health.

Introduction: Although colorectal cancer (CRC) screening program is proven to reduce CRC incidence and mortality, understanding patterns and predictors of suboptimal adherence in screening program requires further investigation in Canada. Methods: We used self-reported data from five regional cohorts of the Canadian Partnership for Tomorrow's Health (CanPath), namely the BC Generations Project (BCGP), Alberta's Tomorrow Project (ATP), the Ontario Health Study (OHS), Quebec's CARTaGENE, and the Atlantic Partnership for Tomorrow's Health Study (Atlantic PATH). We stratified participants into the following four risk categories: 1) age 50-74 years, 2) family history in a first-degree relative, 3) personal history of chronic inflammatory bowel disease and/or polyps, and 4) co-existence of personal risk and family history. Multivariable logistic regression was used to identify predictors of adherence to the screening guidelines. Results: Adherence to CRC screening varied considerably between regions, ranging from 16.6% in CARTaGENE to 47.7% in OHS. Compared to the largest cohort OHS, the likelihood of non-adherence to CRC screening was significantly higher in BCGP (OR 1.15, 95% CI 1.11-1.19), the Atlantic PATH (OR 1.90, 95% CI 1.82-1.99) and CARTaGENE (OR 5.10, 95% CI 4.85-5.36). Low physical activity, current smoking, presence of personal risk, family history of CRC significantly reduced the likelihood of adherence to screening recommendations. Discussion/conclusion: Compared to the national target of ≥ 60% for participation in CRC screening, adherence to regular CRC screening was suboptimal in this cohort of Canadians and varied by region. Further efforts are needed to identify the specific barriers to screening adherence in different provinces and across risk categories.

Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years.

Diabetes medications may modify the risk of certain cancers. We systematically searched MEDLINE, Embase, Web of Science, and Cochrane CENTRAL from 2011 to March 2021 for studies evaluating associations between diabetes medications and the risk of breast, lung, colorectal, prostate, liver, and pancreatic cancers. A total of 92 studies (3 randomized controlled trials, 64 cohort studies, and 25 case-control studies) were identified in the systematic review, involving 171 million participants. Inverse relationships with colorectal (n = 18; RR = 0.85; 95% CI = 0.78-0.92) and liver cancers (n = 10; RR = 0.55; 95% CI = 0.46-0.66) were observed in biguanide users. Thiazolidinediones were associated with lower risks of breast (n = 6; RR = 0.87; 95% CI = 0.80-0.95), lung (n = 6; RR = 0.77; 95% CI = 0.61-0.96) and liver (n = 8; RR = 0.83; 95% CI = 0.72-0.95) cancers. Insulins were negatively associated with breast (n = 15; RR = 0.90; 95% CI = 0.82-0.98) and prostate cancer risks (n = 7; RR = 0.74; 95% CI = 0.56-0.98). Positive associations were found between insulin secretagogues and pancreatic cancer (n = 5; RR = 1.26; 95% CI = 1.01-1.57), and between insulins and liver (n = 7; RR = 1.74; 95% CI = 1.08-2.80) and pancreatic cancers (n = 8; RR = 2.41; 95% CI = 1.08-5.36). Overall, biguanide and thiazolidinedione use carried no risk, or potentially lower risk of some cancers, while insulin secretagogue and insulin use were associated with increased pancreatic cancer risk.

Mental health, cancer risk, and the mediating role of lifestyle factors in the CARTaGENE cohort study.

BACKGROUND: Evidence on the association between mental health disorders and cancer risk is inconclusive, despite well-established associations between mental health disorders and lifestyle factors such as smoking. This study examines the relationships between depression, anxiety and cancer risk, and the potential mediating effects of lifestyle factors. METHODS: A study of 34,571 participants aged 40-69 years in the CARTaGENE cohort was conducted. Depression was defined by questionnaire (PHQ-9), antidepressant use, and a composite of questionnaire, antidepressant use, or lifetime self-reported physician diagnosis. Anxiety was defined by questionnaire (GAD-7). Co-morbid depression and anxiety was also assessed. Cox regression models were used to investigate associations between mental health and risk of prostate, lung, and all cancers combined. Mediating effects of lifestyle factors were assessed using Baron and Kenny mediation criteria. RESULTS: There were positive associations between mental health disorders, all cancers and lung cancer risk, however with the exception of anxiety and lung cancer in women (Hazard Ratio [HR] = 1.67, 95% CI: 1.01-2.76), associations were attenuated with adjustment for sociodemographics, health status and lifestyle factors. In the mediation analysis, smoking accounted for 27%, 18%, and 26%, of the total effect between depression (PHQ-9), anxiety, and co-morbidity and lung cancer, respectively in women. In men, smoking accounted for 17% of the total effect between depression (PHQ-9, antidepressant, or lifetime self-report of physician diagnosis) and all cancers. CONCLUSIONS: Positive associations were observed between mental health disorders, all cancer and lung cancer risk, however most relationships were attenuated with adjustment for lifestyle factors. Smoking status mediated a significant proportion of the relationships between mental health disorders and cancer risk.

Dietary Intake and the Neighbourhood Environment in the BC Generations Project.

Poor diet is a major risk factor for many chronic diseases including cancer. Understanding broader contextual factors that influence dietary intake is important for making tangible progress towards improving diet at the population level. This study investigated neighbourhood social and built environment factors and fruit and vegetable intake among ~28,000 adults aged 35−69 years within the BC Generations Project. Daily fruit and vegetable intake was categorized according to guidelines (≥5 servings/day vs. <5 servings/day). Geospatial characteristics included walkability, greenness, marginalization, and material and social deprivation, reflecting access to goods and amenities and social relationships. Generalized, linear mixed-effect models adjusted for sociodemographic factors and lifestyle variables were used to estimate the odds ratios (ORs). Participants living in neighbourhoods with greater material deprivation (e.g., OR = 0.77; 95% CI: 0.70−0.86 for very high material deprivation) and very high social deprivation (OR = 0.90; 95% CI: 0.82−0.99) were less likely to meet recommendations for fruit and vegetable consumption relative to those living in areas with very low material deprivation and very low social deprivation, respectively. Relative to participants living in areas with very low greenness, participants living in neighbourhoods with high (OR = 1.10, 95% CI 1.01−1.20) to very high (OR = 1.11, 95% CI 1.01−1.21) greenness were more likely to meet recommendations for fruits and vegetables. These findings highlight the complexity of dietary intake which may be shaped by multiple neighbourhood characteristics.

Colorectal Cancer and Onset of Anxiety and Depression: A Systematic Review and Meta-Analysis.

Research suggests that colorectal cancer (CRC) is associated with mental health disorders, primarily anxiety and depression. To synthesize this evidence, we conducted a systematic review and meta-analysis of studies evaluating the onset of anxiety and depression among patients with CRC. We searched EMBASE and Medline from inception to June 2022. We included original, peer-reviewed studies that: used an epidemiologic design; included patients with CRC and a comparator group of individuals without cancer; and evaluated anxiety and depression as outcomes. We used random effects models to obtain pooled measures of associations. Quality assessment was completed using the Newcastle-Ottawa scale. Of 7326 articles identified, 8 were eligible; of which 6 assessed anxiety and depression and 2 assessed depression only. Meta-analyses showed a non-significant association between CRC and anxiety (pooled HR 1.67; 95% CI 0.88 to 3.17) and a significant association between CRC and depression (pooled HR 1.78; 95% CI 1.23 to 2.57). Predictors of anxiety and depression among patients with CRC included clinical characteristics (e.g., comorbidities, cancer stage, cancer site), cancer treatment (e.g., radiotherapy, chemotherapy, colostomy), and sociodemographic characteristics (e.g., age, sex). The impacts of anxiety and depression in patients with CRC included increased mortality and decreased quality of life. Altogether, our systematic review and meta-analysis quantified the risks and impacts of CRC on anxiety and depression, particularly an increased risk of depression after CRC diagnosis. Findings provide support for oncologic care that encompasses mental health supports for patients with CRC.

A genome-wide gene-based gene-environment interaction study of breast cancer in more than 90,000 women.

Background: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. Methods: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. Results: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE=4.44×10-6). Conclusion: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Impact: Our study suggests a limited role of gene-environment interactions in breast cancer risk.

Projected Impact of Weight Gain During the COVID-19 Pandemic on the Future Burden of Cancer in Canada.

The COVID-19 pandemic and resulting public health measures have had significant impacts on daily life, including shifts in health behaviours which contribute to weight gain and may increase subsequent risk of chronic diseases such as cancer. Using OncoSim, a web-based microsimulation tool, we estimated the future burden of cancer in Canada by incorporating data on unintentional weight gain among adults during the first year of the COVID-19 pandemic. Population impact measures were estimated until 2042, assuming a 12-year latency period. We estimated 14,194 excess cancer cases and 5,324 excess cancer deaths by 2042 due to COVID-19 related weight gain. Particularly large impacts were estimated for endometrial and breast cancer among women, with 2,983 and 2,151 excess cases by 2042. For men, 1,700 excess colorectal cases and 1,188 excess kidney cancer cases were projected by 2042. Changes in health behavior during the COVID-19 pandemic are likely to have significant and long-lasting impacts on cancer burden. These projections highlight the immediate need for investment into the development and implementation of effective cancer prevention strategies.

Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies.

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSIONS: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Relevance of the MHC region for breast cancer susceptibility in Asians.

BACKGROUND: Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry. METHODS: A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined. RESULTS: We did not observe associations between any HLA allele and breast cancer risk at P < 5e-8; the smallest p value was observed for HLA-C*12:03 (OR = 1.29, P = 1.08e-3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18). CONCLUSIONS: No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.

Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci.

BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women.

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.

Anti-hypertensive medications and risk of colorectal cancer: a systematic review and meta-analysis.

PURPOSE: Antihypertensive medications may impact colorectal cancer risk. We conducted a systematic review and meta-analysis of associations, with colorectal cancer risk, of five classes of antihypertensive medications: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and diuretics. METHODS: A systematic search was conducted in MEDLINE, Embase, Web of Science, and the Cochrane library to identify relevant studies evaluating associations of ACEIs, ARBs, BBs, CCBs, and diuretics with colorectal cancer risk. Meta-analytic risk ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were calculated using the inverse variance method. RESULTS: No overall significant associations with colorectal cancer risk were observed; ACEIs (5 studies) RR 1.05, 95% CI 0.91-1.23, ARBs (5 studies) RR 0.94, 95% CI 0.80-1.11, BBs (4 studies) RR 1.00, 95% CI 0.92-1.08, CCBs (4 studies) RR 1.02, 95% CI 0.88-1.18, and diuretics (6 studies) RR 1.02, 95% CI 0.90-1.17. There was considerable heterogeneity across studies, partly explained by differences in study design and location. When stratified by study location, there was significantly reduced colorectal cancer risk for ARB use in Asian populations (2 studies, RR 0.69, 95% CI 0.58-0.83). CONCLUSION: No significant colorectal cancer risk with ACEIs, BBs, CCBs, or diuretics was observed. ARB use may be associated with decreased risk of colorectal cancer in Asian populations, although additional studies in diverse populations are needed to confirm associations and help understand possible reasons for geographical differences.

Lifestyle factors and lung cancer risk among never smokers in the Canadian Partnership for Tomorrow's Health (CanPath).

BACKGROUND: Although smoking is the primary risk factor for lung cancer, 15-25% of lung cancers occur in never smokers. Emerging evidence suggests lifestyle factors are associated with lung cancer risk, but few studies among never smokers exist. METHODS: A case-control study of never smokers within the Canadian Partnership for Tomorrow's Health was conducted. At recruitment, participants provided data on lifestyle, health history and sociodemographic factors. Incident lung cancers were identified through linkage with administrative health records. Cases (n = 190) were matched to controls (n = 760) on age, sex, and follow-up time. Logistic regression analyses, adjusted for matching factors and annual income, were used to identify associations between lifestyle factors and lung cancer risk. RESULTS: Consumption of < 5 servings of fruits and vegetables/day was associated with higher risk of lung cancer (OR 1.50, 95% CI 1.03-2.17). Short or long sleep (≤ 6 or > 9 h/night) was also associated with increased risk of lung cancer (OR 1.52, 95% CI 1.01-2.29). No associations were observed for obesity measures, alcohol consumption, or physical activity. CONCLUSION: Our findings provide evidence of a potential role between sleep, fruits and vegetable consumption, and lung cancer risk in a pan-Canadian, non-smoking population. However, the sample size is modest, and further investigation is needed.

Body Composition and Metabolomics in the Alberta Physical Activity and Breast Cancer Prevention Trial.

BACKGROUND: Obesity is correlated with many biomarkers, but the extent to which these correlate with underlying body composition is poorly understood. OBJECTIVES: Our objectives were to 1) describe/compare distinct contributions of fat/lean mass with BMI-metabolite correlations and 2) identify novel metabolite biomarkers of fat/lean mass. METHODS: The Alberta Physical Activity and Breast Cancer Prevention Trial was a 2-center randomized trial of healthy, inactive, postmenopausal women (n = 304). BMI (in kg/m2) was calculated using weight and height, whereas DXA estimated fat/lean mass. Ultra-performance liquid chromatography and mass spectrometry measured relative concentrations of serum metabolite concentrations. We estimated partial Pearson correlations between 1052 metabolites and BMI, adjusting for age, smoking, and site. Fat mass index (FMI; kg/m2) and lean mass index (LMI; kg/m2) correlations were estimated similarly, with mutual adjustment to evaluate independent effects. RESULTS: Using a Bonferroni-corrected α level <4.75 × 10-5,  we observed 53 BMI-correlated metabolites (|r| = 0.24-0.42). Of those, 21 were robustly correlated with FMI (|r| > 0.20), 25 modestly (0.10 ≤ |r| ≤ 0.20), and 7 virtually null (|r| < 0.10). Ten of 53 were more strongly correlated with LMI than with FMI. Examining non-BMI-correlated metabolites, 6 robustly correlated with FMI (|r| = 0.24-0.31) and 2 with LMI (r = 0.25-0.26). For these, correlations for fat and lean mass were in opposing directions compared with BMI-correlated metabolites, in which correlations were mostly in the same direction. CONCLUSIONS: Our results demonstrate how a thorough evaluation of the components of fat and lean mass, along with BMI, provides a more accurate assessment of the associations between body composition and metabolites than BMI alone. Such an assessment makes evident that some metabolites correlated with BMI predominantly reflect lean mass rather than fat, and some metabolites related to body composition are not correlated with BMI. Correctly characterizing these relations is important for an accurate understanding of how and why obesity is associated with disease.

Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.