A Population-Based Study of Genes Previously Implicated in Breast Cancer.

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).

Association between Inflammatory Dietary Pattern and Mammographic Features.

BACKGROUND: The empirical dietary inflammation pattern score (EDIP), which measures the ability of the diet to regulate chronic inflammation, is associated with both higher adiposity and breast cancer (BC) risk. Mammographic density (MD) is an important risk factor for BC. OBJECTIVE: We examined the associations between EDIP and mammographic features overall and stratified by menopausal status, and assessed the extent to which these associations are mediated by adiposity. METHODS: We included 4145 participants without BC in the Nurses' Health Study (NHS) and NHSII. Cumulative average EDIP was assessed by food frequency questionnaires every 4-6 y. We assessed MD parameters (percent MD, dense area, and nondense area) and V (measure of grayscale variation). MD parameters were square-root transformed. Multivariable-adjusted linear regression models were used to analyze the associations between EDIP score and MD parameters. Baron and Kenny's regression method was used to assess the extent to which the associations of EDIP and mammographic traits were mediated by BMI. RESULTS: In multivariable-adjusted models, EDIP was significantly inversely associated with percent MD [top compared with bottom quartile, ß = -0.57; 95% confidence interval (CI): -0.78, -0.36]. Additional adjustment for BMI attenuated the association (ß = -0.15; 95% CI: -0.34, 0.03), with 68% (ß = 0.68, 20; 95% CI: 0.54, 0.86) mediation via BMI. In addition, EDIP was positively associated with nondense area after adjusting for BMI and other covariates. No associations were observed for dense area and V measure. Results were similar when stratified by menopausal status. CONCLUSIONS: EDIP score was inversely associated with percent MD and positively associated with nondense area, and these associations were largely mediated by BMI.

Religion/Spirituality and Prevalent Hypertension among Ethnic Cohorts in the Study on Stress, Spirituality, and Health.

BACKGROUND: Hypertension is a significant public health issue, particularly for Blacks, Hispanics/Latinos, and South Asians who are at greater risk than whites. Religion and spirituality (R/S) have been shown to be protective, but this has been identified primarily in whites with limited R/S measures examined (i.e., religious service attendance). PURPOSE: To assess hypertension prevalence (HP) in four racial/ethnic groups while incorporating an array of R/S variables, including individual prayer, group prayer, nontheistic daily spiritual experiences, yoga, gratitude, positive religious coping, and negative religious coping. METHODS: Data were drawn from the Study on Stress, Spirituality, and Health, a consortium of ethnically diverse U.S. cohorts. The sample included 994 Black women, 838 Hispanic/Latino men and women, 879 South Asian men and women, and 3681 white women. Using a cross-sectional design, prevalence ratios for R/S and hypertension were reported for each cohort, in addition to pooled analyses. Given differences in R/S among men and women, all models were stratified by gender. RESULTS: Different patterns of associations were found between women and men. Among women: 1) religious attendance was associated with lower HP among Black and white women; 2) gratitude was linked to lower HP among Hispanic/Latino, South Asian, and white women; 3) individual prayer was associated with higher HP among Hispanic/Latino and white women; 4) yoga was associated with higher HP among South Asian women, and 5) negative religious coping was linked to higher HP among Black women. Among men: significant results were only found among Hispanic/Latino men. Religious attendance and individual prayer were associated with higher HP, while group prayer and negative religious coping were associated with lower HP. CONCLUSION: Religion/spirituality is a multifaceted construct that manifests differently by race/ethnicity and gender. Medical practitioners should avoid a one-size-fits-all approach to this topic when evaluating prevalent hypertension in diverse communities.

Hypertension is a serious public health issue that affects many Americans, though non-whites are at greater risk than whites. In this study, we examine Black, Hispanic/Latino, and South Asian samples, comparing their hypertension rates to whites. We ask whether one or more aspects of religion and spirituality (R/S) might be associated with prevalent hypertension (i.e., prevalence of hypertension at a single point in time). Religious service attendance is the primary R/S variable examined in relation to hypertension, but we expand this to include individual prayer, prayer in groups, daily spiritual experiences, yoga practice, feelings of gratitude, using God to help cope with problems (positive religious coping), and experiencing doubt or fear about God in the face of challenges (negative religious coping). The results were mixed across racial/ethnic group and gender. Among women, higher religious attendance and gratitude were associated with lower hypertension prevalence, but individual prayer was associated with higher prevalence. Few associations were noted between R/S and hypertension among men. Given these findings, along with extant research, it is important for medical practitioners serving diverse communities to recognize R/S may operate differently for men and women in varied religious and ethnic groups, with differing implications for prevalent hypertension.

Influence of analytic methods, data sources, and repeated measurements on the population attributable fraction of lifestyle risk factors.

Population attributable risk (PAR%) reflects the preventable fraction of disease. However, PAR% estimates of cancer have shown large variation across populations, methods, data sources, and timing of measurements. Three statistical methods to estimate PAR% were identified from a systematic literature review: the Levin's formula, the comparative incidence rate method, and the comparative risk assessment method. We compared the variations in PAR% of postmenopausal breast cancer in the Nurses' Health Study to evaluate the influence by method choice, source of prevalence data, use of single vs repeated exposure measurements, and potential joint effects of obesity, alcohol, physical activity, fruit and vegetable intake. Across models of the three methods, the estimated PAR% using repeated measurements were higher than that using baseline measurement; overall PAR% for the baseline, simple update, and cumulative average models were 13.8%, 21.1%, 18.6% by Levin's formula; 13.7%, 28.0%, 31.2% by comparative risk assessment; and 17.4%, 25.2%, 29.3% by comparative incidence rate method. The estimated PAR% of the combination of multiple risk factors was higher than the product of the individual PAR%: 18.9% when assuming independence and 31.2% when considering the risk factors jointly. The three methods provided similar PAR% based on the same data source, timing of measurements, and target populations. However, sizable increases in the PAR% were observed for repeated measures over a single measure and for calculations based on achieving all recommendations jointly rather than individually.

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.

Dietary lignans, plasma enterolactone levels, and metabolic risk in men: exploring the role of the gut microbiome.

BACKGROUND: The conversion of plant lignans to bioactive enterolignans in the gastrointestinal tract is mediated through microbial processing. The goal of this study was to examine the relationships between lignan intake, plasma enterolactone concentrations, gut microbiome composition, and metabolic risk in free-living male adults. RESULTS: In 303 men participating in the Men's Lifestyle Validation Study (MLVS), lignan intake was assessed using two sets of 7-day diet records, and gut microbiome was profiled through shotgun sequencing of up to 2 pairs of fecal samples (n = 911). A score was calculated to summarize the abundance of bacteria species that were significantly associated with plasma enterolactone levels. Of the 138 filtered species, plasma enterolactone levels were significantly associated with the relative abundances of 18 species at FDR < 0.05 level. Per SD increment of lignan intake was associated with 20.7 nM (SEM: 2.3 nM) higher enterolactone concentrations among participants with a higher species score, whereas the corresponding estimate was 4.0 nM (SEM: 1.7 nM) among participants with a lower species score (P for interaction < 0.001). A total of 12 plasma metabolites were also significantly associated with these enterolactone-predicting species. Of the association between lignan intake and metabolic risk, 19.8% (95%CI: 7.3%-43.6%) was explained by the species score alone, 54.5% (95%CI: 21.8%-83.7%) by both species score and enterolactone levels, and 79.8% (95%CI: 17.7%-98.6%) by further considering the 12 plasma metabolites. CONCLUSION: We identified multiple gut bacteria species that were enriched or depleted at higher plasma levels of enterolactone in men. These species jointly modified the associations of lignan intake with plasma enterolactone levels and explained the majority of association between lignan intake and metabolic risk along with enterolactone levels and certain plasma metabolites.

Personalized Nutrition in Disrupting Cancer - Proceedings From the 2017 American College of Nutrition Annual Meeting.

Cancer is a major public health problem and is the second leading cause of death in the United States and worldwide; nearly one in six deaths are attributable to cancer. Approximately 20% of all cancers diagnosed in the United States are attributable to unhealthy diet, excessive alcohol consumption, physical inactivity, and body fatness. Individual cancers are distinct disease states that are multifactorial in their causation, making them exceedingly cumbersome to study from a nutrition standpoint. Genetic influences are a major piece of the puzzle and personalized nutrition is likely to be most effective in disrupting cancer during all stages. Increasing evidence shows that after a cancer diagnosis, continuing standard dietary recommendations may not be appropriate. This is because powerful dietary interventions such as short-term fasting and carbohydrate restriction can disrupt tumor metabolism, synergizing with standard therapies such as radiation and drug therapy to improve efficacy and ultimately, cancer survival. The importance of identifying dietary interventions cannot be overstated, and the American College of Nutrition's commitment to advancing knowledge and research is evidenced by dedication of the 2017 ACN Annual Meeting to "Disrupting Cancer: The Role of Personalized Nutrition" and this resulting proceedings manuscript, which summarizes the meeting's findings.

Interactions of alcohol and postmenopausal hormone use in regards to mammographic breast density.

PURPOSE: We investigated the association of alcohol intake with mammographic breast density in postmenopausal women by their hormone therapy (HT) status. METHODS: This study included 2,100 cancer-free postmenopausal women within the Nurses' Health Study and Nurses' Health Study II cohorts. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were measured from digitized film mammograms using a computer-assisted thresholding technique; all measures were square root transformed. Alcohol consumption was assessed with a food frequency questionnaire (0, < 5, and ≥ 5 g/day). Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to examine associations between alcohol and breast density measures in women with no HT history, current, and past HT users. RESULTS: In multivariable analyses, we found no associations of alcohol consumption with PD (p trend = 0.32) and DA (p trend = 0.53) and an inverse association with NDA (ß = - 0.41, 95% CI - 0.73, - 0.09 for ≥ 5 g/day, p trend < 0.01). In the stratified analysis by HT status, alcohol was not associated with PD in any of the strata. We found a significant inverse association of alcohol with NDA among past HT users (ß = - 0.79, 95% CI - 1.51, - 0.07 for ≥ 5 g/day, p trend = 0.02). There were no significant interactions between alcohol and HT in relation to PD, DA, and NDA (p interaction = 0.19, 0.42, and 0.43, respectively). CONCLUSIONS: Our findings suggest that associations of alcohol with breast density do not vary by HT status.

Plasma C-peptide mammographic features and risk of breast cancer.

Our study in the Nurses' Health Study (NHS) and NHS2, a nested case-control study with 1260 cases and 2221 controls, investigated the association between C-peptide levels, mammographic density (MD) parameters, V (a measure of gray scale variation), and breast cancer (BC) risk. We also examined how C-peptide and BC risk vary across quartiles of mammographic features. Linear and logistic regressions were used to study the associations between C-peptide and MD parameters, and breast cancer. C-peptide was inversely associated with percent MD and positively with non-dense area, but no associations were found with dense area and V measure. C-peptide was associated with an increased risk of invasive BC risk (top vs. bottom quartile, odds ratio = 1.46, 95% CI: 1.12-1.91). No multiplicative interactions were found between C-peptide, MD parameters, and BC risk. Our results suggest a positive association between C-peptide and BC risk, and MD parameters do not seem to modify this association.

Timing and duration of dog walking and dog owner's chronotype in relation to incident depression risk among middle to older-aged female nurses.

BACKGROUND: We examined associations between dog ownership, morning dog walking and its timing and duration, and depression risk in female nurses, exploring effect modification by chronotype. We hypothesized that dog ownership and morning walking with the dog are associated with lower odds of depression, and that the latter is particularly beneficial for evening chronotypes by helping them to synchronize their biological clock with the solar system. METHODS: 26,169 depression-free US women aged 53-72 from the Nurses' Health Study 2 (NHS2) were prospectively followed from 2017-2019. We used age- and multivariable-adjusted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for depression according to dog ownership, and morning dog walking, duration, and timing. RESULTS: Overall, there was no association between owning a dog (ORvs_no_pets = 1.12, 95%CI = 0.91-1.37), morning dog walking (ORvs_not = 0.87, 95%CI = 0.64-1.18), or the duration (OR>30min vs. ≤15mins = 0.68, 95%CI = 0.35-1.29) or timing of morning dog walks (ORafter9am vs. before7am = 1.06, 95%CI = 0.54-2.05) and depression. Chronotype of dog owners appeared to modify these associations. Compared to women of the same chronotype but without pets, dog owners with evening chronotypes had a significantly increased odds of depression (OR = 1.60, 95%CI = 1.12-2.29), whereas morning chronotypes did not (OR = 0.94, 95%CI = 0.71-1.23). Further, our data suggested that evening chronotypes benefited more from walking their dog themselves in the morning (OR = 0.75, 95%CI = 0.46-1.23, Pintx = 0.064;) than morning chronotypes. CONCLUSIONS: Overall, dog ownership was not associated with depression risk though it was increased among evening chronotypes. Walking their dog in the morning might help evening chronotypes to lower their odds of depression, though more data are needed to confirm this finding.

Association of Gene Variant Type and Location with Breast Cancer Risk in the General Population.

Importance: Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 are associated with increased breast cancer risk. However, it is unknown whether breast cancer risk differs by PV type or location in carriers ascertained from the general population. Objective: To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 . Design: Age adjusted case-control association analysis for all participants, subsets of PV carriers, and women with no breast cancer family history in population-based and clinical testing cohorts. Setting: Twelve US population-based studies within the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium, and breast cancer cases from the UK-Biobank and an Ambry Genetics clinical testing cohort. Participants: 32,247 women with and 32,544 age-matched women without a breast cancer diagnosis from CARRIERS; 237 and 1351 women with BRCA2 PVs and breast cancer from the UKBB and Ambry Genetics, respectively. Exposures: PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Main Outcomes and Measures: PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and p-values) using logistic regression. Mean ages at diagnosis were compared using linear regression. Results: Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex13-27 PTVs (OR=2.7, 95%CI 1.1-7.9) and ex1-10 PTVs (OR=1.6, 95%CI 0.8-3.5) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9; ex1-10 OR=0.5, 95%CI 0.1-1.0), and earlier age of breast cancer diagnosis (ex13-27 5.5 years, p<0.001; ex1-10 2.4 years, p=0.17). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort and the population-based UK Biobank cohort. No differences in risk or age at diagnosis by gene region were observed for PTVs in other predisposition genes. Conclusions and Relevance: Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced risk of breast cancer, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs. Key Points: Question: Does ATM , BRCA1 , BRCA2 , CHEK2 and PALB2 pathogenic variant type and location influence breast cancer risk in population-based studies? Findings: Breast cancer risk and estrogen receptor status differ based on the type and location of pathogenic variants in BRCA2 . Women carrying protein truncating variants in exon 11 have a lower breast cancer risk in the population-based cohorts, older age at diagnosis and higher rates of estrogen receptor negative breast cancer than women with exon 1-10 or exon 13-27 truncation variants in population-based and clinical testing cohorts. Meaning: Incorporating pathogenic variant type and location in cancer risk models may improve individualized risk prediction.

Genome-wide association study identifies common variants associated with circulating vitamin E levels.

In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P= 1.7 × 10(-8)) and rs11057830 on 12q24.31 (P= 2.0 × 10(-8)) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P= 2.7 × 10(-10)). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P= 7.8 × 10(-12) (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P= 1.4 × 10(-10) (rs2108622 on 19pter-p13.11 near CYP4F2) and P= 8.2 × 10(-9) (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n= 992), no SNPs were significantly associated with gamma-tocopherol concentrations after including data from the replication sample for 71 independent SNPs with P< 1 × 10(-4) identified.

Genome-wide association study of circulating retinol levels.

Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10(-17)) and rs10882272 (P =6.04× 10(-12)). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses' Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10(-5)), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10(-5)). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

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.

Central Adiposity and Subsequent Risk of Breast Cancer by Menopause Status.

BACKGROUND: Increased body mass index (BMI) is associated with higher postmenopausal breast cancer risk and lower premenopausal breast cancer risk. Less is known about the central adiposity-breast cancer risk association, particularly for tumor subtypes. METHODS: We used prospective waist (WC) and hip circumference (HC) measures in the Nurses' Health Studies. We examined associations of WC, HC, and waist-to-hip ratio (WHR) with breast cancer independent of BMI, by menopausal status. Cox proportional hazards models estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for breast cancer risk factors, with and without BMI. RESULTS: Adjusting for BMI, WC and HC were not associated, and WHR was positively associated with premenopausal breast cancer risk (WHR, quintile 5 vs 1: HRQ5vQ1, BMI-adjusted = 1.27, 95% CI = 1.04 to 1.54; Ptrend = .01), particularly for estrogen receptor-negative (ER-) and progesterone receptor-negative (PR-) and basal-like breast cancers. Premenopausal WC, HC, and WHR were not associated with postmenopausal breast cancer risk, with or without BMI adjustment. Postmenopausal WC, HC, and WHR were each positively associated with postmenopausal breast cancer (eg, WC HRQ5vsQ1 = 1.59, 95% CI = 1.36 to 1.86); after adjustment for BMI, only WC remained statistically significant (HRQ5vsQ1, BMI-adjusted = 1.38, 95% CI = 1.15 to 1.64; Ptrend = .002). In postmenopausal women, associations were stronger among never-users of hormone therapy and for ER+/PR+ breast cancers. CONCLUSIONS: Central adiposity was positively associated with pre- and postmenopausal breast cancers independent of BMI. This suggests that mechanisms other than estrogen may also play a role in the relationship between central adiposity and breast cancer. Maintaining a healthy waist circumference may decrease pre- and postmenopausal breast cancer risk.

Circulating trimethylamine N-oxide in association with diet and cardiometabolic biomarkers: an international pooled analysis.

BACKGROUND: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities. OBJECTIVES: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia. METHODS: Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (ß) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant. RESULTS: After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (ß = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (ß = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (ß = -0.126 for a 5% energy increase from plant protein and -0.123 for a 1 serving/d increase of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (ß = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (ß = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (ß = 0.131 SD increase in log-TMAO), homocysteine (ß = 0.065), insulin (ß = 0.048), glycated hemoglobin (ß = 0.048), and glucose (ß = 0.023), whereas it was inversely associated with HDL cholesterol (ß = -0.047) and blood pressure (ß = -0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses. CONCLUSIONS: In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation.

Associations of circulating choline and its related metabolites with cardiometabolic biomarkers: an international pooled analysis.

BACKGROUND: Choline is an essential nutrient; however, the associations of choline and its related metabolites with cardiometabolic risk remain unclear. OBJECTIVE: We examined the associations of circulating choline, betaine, carnitine, and dimethylglycine (DMG) with cardiometabolic biomarkers and their potential dietary and nondietary determinants. METHODS: The cross-sectional analyses included 32,853 participants from 17 studies, who were free of cancer, cardiovascular diseases, chronic kidney diseases, and inflammatory bowel disease. In each study, metabolites and biomarkers were log-transformed and standardized by means and SDs, and linear regression coefficients (ß) and 95% CIs were estimated with adjustments for potential confounders. Study-specific results were combined by random-effects meta-analyses. A false discovery rate <0.05 was considered significant. RESULTS: We observed moderate positive associations of circulating choline, carnitine, and DMG with creatinine [ß (95% CI): 0.136 (0.084, 0.188), 0.106 (0.045, 0.168), and 0.128 (0.087, 0.169), respectively, for each SD increase in biomarkers on the log scale], carnitine with triglycerides (ß = 0.076; 95% CI: 0.042, 0.109), homocysteine (ß = 0.064; 95% CI: 0.033, 0.095), and LDL cholesterol (ß = 0.055; 95% CI: 0.013, 0.096), DMG with homocysteine (ß = 0.068; 95% CI: 0.023, 0.114), insulin (ß = 0.068; 95% CI: 0.043, 0.093), and IL-6 (ß = 0.060; 95% CI: 0.027, 0.094), but moderate inverse associations of betaine with triglycerides (ß = -0.146; 95% CI: -0.188, -0.104), insulin (ß = -0.106; 95% CI: -0.130, -0.082), homocysteine (ß = -0.097; 95% CI: -0.149, -0.045), and total cholesterol (ß = -0.074; 95% CI: -0.102, -0.047). In the whole pooled population, no dietary factor was associated with circulating choline; red meat intake was associated with circulating carnitine [ß = 0.092 (0.042, 0.142) for a 1 serving/d increase], whereas plant protein was associated with circulating betaine [ß = 0.249 (0.110, 0.388) for a 5% energy increase]. Demographics, lifestyle, and metabolic disease history showed differential associations with these metabolites. CONCLUSIONS: Circulating choline, carnitine, and DMG were associated with unfavorable cardiometabolic risk profiles, whereas circulating betaine was associated with a favorable cardiometabolic risk profile. Future prospective studies are needed to examine the associations of these metabolites with incident cardiovascular events.

Polyclonal human antibodies against glycans bearing red meat-derived non-human sialic acid N-glycolylneuraminic acid are stable, reproducible, complex and vary between individuals: Total antibody levels are associated with colorectal cancer risk.

BACKGROUND: N-glycolylneuraminic acid (Neu5Gc) is a non-human red-meat-derived sialic acid immunogenic to humans. Neu5Gc can be metabolically incorporated into glycan chains on human endothelial and epithelial surfaces. This represents the first example of a "xeno-autoantigen", against which circulating human "xeno-autoantibodies" can react. The resulting inflammation ("xenosialitis") has been demonstrated in human-like Neu5Gc-deficient mice and contributed to carcinoma progression via antibody-mediated inflammation. Anti-Neu5Gc antibodies have potential as biomarkers for diseases associated with red meat consumption such as carcinomas, atherosclerosis, and type 2 diabetes. METHODS: ELISA assays measured antibodies against Neu5Gc or Neu5Gc-glycans in plasma or serum samples from the Nurses' Health Studies, the Health Professionals Follow-up Study, and the European Prospective Investigation into Cancer and Nutrition, including inter-assay reproducibility, stability with delayed sample processing, and within-person reproducibility over 1-3 years in archived samples. We also assessed associations between antibody levels and coronary artery disease risk (CAD) or red meat intake. A glycan microarray was used to detected antibodies against multiple Neu5Gc-glycan epitopes. A nested case-control study design assessed the association between total anti-Neu5Gc antibodies detected in the glycan array assay and the risk of colorectal cancer (CRC). RESULTS: ELISA assays showed a wide range of anti-Neu5Gc responses and good inter-assay reproducibility, stability with delayed sample processing, and within-person reproducibility over time, but these antibody levels did not correlate with CAD risk or red meat intake. Antibodies against Neu5Gc alone or against individual Neu5Gc-bearing epitopes were also not associated with colorectal cancer (CRC) risk. However, a sialoglycan microarray study demonstrated positive association with CRC risk when the total antibody responses against all Neu5Gc-glycans were combined. Individuals in the top quartile of total anti-Neu5Gc IgG antibody concentrations had nearly three times the risk compared to those in the bottom quartile (Multivariate Odds Ratio comparing top to bottom quartile: 2.98, 95% CI: 0.80, 11.1; P for trend = 0.02). CONCLUSIONS: Further work harnessing the utility of these anti-Neu5Gc antibodies as biomarkers in red meat-associated diseases must consider diversity in individual antibody profiles against different Neu5Gc-bearing glycans. Traditional ELISA assays for antibodies directed against Neu5Gc alone, or against specific Neu5Gc-glycans may not be adequate to define risk associations. Our finding of a positive association of total anti-Neu5Gc antibodies with CRC risk also warrants confirmation in larger prospective studies.

Body fatness throughout the life course and the incidence of premenopausal breast cancer.

BACKGROUND: The role of body fatness in the aetiology of breast cancer is complex. We evaluated the independent and synergistic effects of body fatness, at different stages throughout a woman's life course, on premenopausal breast cancer risk. METHODS: Premenopausal participants of the Nurses' Health Study II (NHSII) were followed from 1991 up to 2009. Body fatness factors including birthweight, somatotype (a 9-level pictogram with level 1 being the leanest) at ages 5 and 10 years and body mass index (BMI) at age 18 were collected at baseline. Current BMI was updated biennially. Multivariate Cox regression models were used to evaluate the association between each body fatness factor as well as cross-classification of all factors and the incidence of breast cancer. RESULTS: Based on 1574 incident premenopausal breast cancer cases and 1 133 893 person-years of follow-up, a lower incidence was associated with lower birthweight: hazard ratio (HR) [95% confidence interval (CI)] = 0.74 (0.58-0.95) for <2.5kg vs 3.9+kg, P for trend < 0.001; higher somatotype at age 5: HR=0.57 (95% CI 0.44-0.73) for 5-9 vs 1, P fortrend < 0.0001]; and at age 10: HR=0.61 (95% CI 0.49-0.75) for 5-9 vs 1, P for trend < 0.0001]; and BMI at age 18: HR=0.67 (95% 0.47-0.95) for ≥ 27.5 kg/m2 vs < 18.5 kg/m2, P for trend = 0.009], after adjusting for age and body fatness measures earlier in life and other risk factors, respectively. No significant interaction between body fatness measures was found. Women with the lowest birthweight, the highest somatotype at ages 5 and 10 and the highest BMI at age 18 and currently had a 72% (95% CI 54%-83%) lower incidence of invasive premenopausal breast cancer than women with the opposite extreme of each body fatness indicator. CONCLUSION: The lowest incidence of premenopausal breast cancer was associated with the lowest birthweight and the highest childhood, adolescent and early adult body fatness.