Genome-wide interaction analysis of folate for colorectal cancer risk.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.

Flavonoid intake and survival after diagnosis of colorectal cancer: a prospective study in 2 US cohorts.

BACKGROUND: Although experimental evidence supports anticancer effects of flavonoids, the influence of flavonoid intake on colorectal cancer (CRC) survival remains unknown. OBJECTIVES: This study aimed to assess the association of postdiagnostic flavonoid intake with mortality. METHODS: We prospectively assessed the association of postdiagnostic flavonoid intake with CRC-specific and all-cause mortality in 2552 patients diagnosed with stage I-III CRC in 2 cohort studies-the Nurses' Health Study and the Health Professionals Follow-up Study. We assessed the intake of total flavonoids and their subclasses using validated food frequency questionnaires. We used the inverse probability-weighted multivariable Cox proportional hazards regression model to calculate the hazard ratio (HR) of mortality after adjusting for prediagnostic flavonoid intake and other potential confounders. We performed spline analysis to evaluate dose-response relationships. RESULTS: The mean [standard deviation (SD)] age of patients at diagnosis was 68.7 (9.4) y. During 31,026 person-y of follow-up, we documented 1689 deaths, of which 327 were due to CRC. The total flavonoid intake was not associated with mortality, but a higher intake of flavan-3-ols was suggestively associated with lower CRC-specific and all-cause mortality, with multivariable HR (95% CI) per 1-SD increases of 0.83 (0.69-0.99; P = 0.04) and 0.91 (0.84-0.99; P = 0.02), respectively. The spline analysis showed a linear relationship between postdiagnostic flavan-3-ol intake and CRC-specific mortality (P = 0.01 for linearity). As the major contributor to flavan-3-ol intake, tea showed an inverse association with CRC-specific and all-cause mortality, with multivariable HRs per 1 cup/d of tea of 0.86 (0.75-0.99; P = 0.03) and 0.90 (0.85-0.95; P < 0.001), respectively. No beneficial associations were found for other flavonoid subclasses. CONCLUSIONS: Higher intake of flavan-3-ol after CRC diagnosis was associated with lower CRC-specific mortality. Small, readily achievable increases in the intake of flavan-3-ol-rich foods, such as tea, may help improve survival in patients with CRC.

Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk.

Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.

Associations between predicted vitamin D status, vitamin D intake, and risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) severity.

BACKGROUND: Vitamin D may have a role in immune responses to viral infections. However, data on the association between vitamin D and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) severity have been limited and inconsistent. OBJECTIVE: We examined the associations of predicted vitamin D status and intake with risk of SARS-CoV-2 infection and COVID-19 severity. METHODS: We used data from periodic surveys (May 2020 to March 2021) within the Nurses' Health Study II. Among 39,315 participants, 1768 reported a positive test for SARS-CoV-2 infection. Usual vitamin D intake from foods and supplements were measured using a semiquantitative, pre-pandemic food-frequency questionnaire in 2015. Predicted 25-hydroxyvitamin D [25(OH)D] concentration were calculated based on a previously validated model including dietary and supplementary vitamin D intake, UV-B, and other behavioral predictors of vitamin D status. RESULTS: Higher predicted 25(OH)D concentrations, but not vitamin D intake, were associated with a lower risk of SARS-CoV-2 infection. Comparing participants in the highest quintile of predicted 25(OH)D concentrations with the lowest, the multivariable-adjusted OR was 0.76 (95% CI: 0.58, 0.99; P-trend = 0.04). Participants in the highest quartile of UV-B (OR: 0.76; 95% CI: 0.66, 0.87; P-trend = 0.002) and UV-A (OR: 0.76; 95% CI: 0.66, 0.88; P-trend < 0.001) also had a lower risk of SARS-CoV-2 infection compared with the lowest. High intake of vitamin D from supplements (≥400 IU/d) was associated with a lower risk of hospitalization (OR: 0.51; 95% CI: 0.29, 0.91; P-trend = 0.04). CONCLUSIONS: Our study provides suggestive evidence on the association between higher predicted circulating 25(OH)D concentrations and a lower risk of SARS-CoV-2 infection. Greater intake of vitamin D supplements was associated with a lower risk of hospitalization. Our data also support an association between exposure to UV-B or UV-A, independently of vitamin D and SARS-CoV-2 infection, so results for predicted 25(OH)D need to be interpreted cautiously.

Total Vitamin D Intake and Risks of Early-Onset Colorectal Cancer and Precursors.

BACKGROUND & AIMS: Vitamin D has been implicated in colorectal cancer (CRC) pathogenesis, but it remains unknown whether total vitamin D intake is associated with early-onset CRC and precursors diagnosed before age 50. METHODS: We prospectively examined the association between total vitamin D intake and risks of early-onset CRC and precursors among women enrolled in the Nurses' Health Study II. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset CRC were estimated with Cox proportional hazards model. Multivariable-adjusted odds ratios (ORs) and 95% CIs for early-onset conventional adenoma and serrated polyp were estimated with logistic regression model. RESULTS: We documented 111 incident cases of early-onset CRC during 1,250,560 person-years of follow-up (1991 to 2015). Higher total vitamin D intake was significantly associated with a reduced risk of early-onset CRC (HR for ≥450 IU/day vs <300 IU/day, 0.49; 95% CI, 0.26-0.93; P for trend = .01). The HR per 400 IU/day increase was 0.46 (95% CI, 0.26-0.83). The inverse association was significant and appeared more evident for dietary sources of vitamin D (HR per 400 IU/day increase, 0.34; 95% CI, 0.15-0.79) than supplemental vitamin D (HR per 400 IU/day increase, 0.77; 95% CI, 0.37-1.62). For CRC precursors, the ORs per 400 IU/day increase were 0.76 (95% CI, 0.65-0.88) for conventional adenoma (n = 1,439) and 0.85 (95% CI, 0.75-0.97) for serrated polyp (n = 1,878). CONCLUSIONS: In a cohort of younger women, higher total vitamin D intake was associated with decreased risks of early-onset CRC and precursors.

Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app.

OBJECTIVES: Dietary supplements may ameliorate SARS-CoV-2 infection, although scientific evidence to support such a role is lacking. We investigated whether users of the COVID-19 Symptom Study app who regularly took dietary supplements were less likely to test positive for SARS-CoV-2 infection. DESIGN: App-based community survey. SETTING: 445 850 subscribers of an app that was launched to enable self-reported information related to SARS-CoV-2 infection for use in the general population in the UK (n=372 720), the USA (n=45 757) and Sweden (n=27 373). MAIN EXPOSURE: Self-reported regular dietary supplement usage (constant use during previous 3 months) in the first waves of the pandemic up to 31 July 2020. MAIN OUTCOME MEASURES: SARS-CoV-2 infection confirmed by viral RNA reverse transcriptase PCR test or serology test before 31 July 2020. RESULTS: In 372 720 UK participants (175 652 supplement users and 197 068 non-users), those taking probiotics, omega-3 fatty acids, multivitamins or vitamin D had a lower risk of SARS-CoV-2 infection by 14% (95% CI (8% to 19%)), 12% (95% CI (8% to 16%)), 13% (95% CI (10% to 16%)) and 9% (95% CI (6% to 12%)), respectively, after adjusting for potential confounders. No effect was observed for those taking vitamin C, zinc or garlic supplements. On stratification by sex, age and body mass index (BMI), the protective associations in individuals taking probiotics, omega-3 fatty acids, multivitamins and vitamin D were observed in females across all ages and BMI groups, but were not seen in men. The same overall pattern of association was observed in both the US and Swedish cohorts. CONCLUSION: In women, we observed a modest but significant association between use of probiotics, omega-3 fatty acid, multivitamin or vitamin D supplements and lower risk of testing positive for SARS-CoV-2. We found no clear benefits for men nor any effect of vitamin C, garlic or zinc. Randomised controlled trials are required to confirm these observational findings before any therapeutic recommendations can be made.

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (ß-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of ß-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk. CONCLUSIONS: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.

No Association Between Vitamin D Supplementation and Risk of Colorectal Adenomas or Serrated Polyps in a Randomized Trial.

BACKGROUND & AIMS: The effects of vitamin D on risk of colorectal cancer precursors are not clear. We examined the influence of vitamin D supplementation on risk of colorectal adenomas and serrated polyps in a prespecified ancillary study of a large-scale prevention trial (the vitamin D and omegA-3 trial, VITAL) of individuals who were free of cancer and cardiovascular disease at enrollment. METHODS: In VITAL trial, 25,871 adults with no history of cancer or cardiovascular disease (12,786 men 50 years or older and 13,085 women 55 years or older) were randomly assigned to groups given daily dietary supplements (2000 IU vitamin D3 and 1 g marine n-3 fatty acid) or placebo. Patients were assigned to groups from November 2011 through March 2014 and the study ended on December 31, 2017. We confirmed conventional adenomas and serrated polyps by reviewing histopathology reports from participants who had reported a diagnosis of polyps and were asked by their doctors to return for a repeat colonoscopy or sigmoidoscopy in 5 years or less. We calculated the odds ratios (ORs) and 95% CIs by logistic regression, after adjusting for age, sex, n-3 treatment assignment, and history of endoscopy at time of randomization. RESULTS: During a median follow-up of 5.3 years, we documented 308 cases of conventional adenomas in 12,927 participants in the vitamin D group and 287 cases in 12,944 participants in the placebo group (OR for the association of vitamin D supplementation with adenoma, 1.08; 95% CI, 0.92-1.27). There were 172 cases of serrated polyps in the vitamin D group and 169 cases in the placebo group (OR for the association of vitamin D supplementation with serrated polyp, 1.02; 95% CI, 0.82-1.26). Supplementation was not associated with polyp size, location, multiplicity, or histologic features. We found evidence for an interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D, measured in 15,787 participants at randomization. Among individuals with serum levels of 25-hydroxyvitamin D below 30 ng/mL, the OR associated with supplementation for conventional adenoma was 0.82 (95% CI, 0.60-1.13), whereas among individuals with serum levels of 25-hydroxyvitamin D above 30 ng/mL, the OR for conventional adenoma was 1.20 (95% CI, 0.92-1.55) (P for interaction = .07). There was a significant interaction between vitamin D supplementation and serum level of 25-hydroxyvitamin D in their association with advanced adenoma (P for interaction = .04). CONCLUSIONS: Based on an ancillary study of data from the VITAL trial, daily vitamin D supplementation (2000 IU) was not associated with risk of colorectal cancer precursors in average-risk adults not selected for vitamin D insufficiency. A potential benefit for individuals with low baseline level of vitamin D requires further investigation. ClinicalTrials.gov number: NCT01169259.

Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses.

BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2). CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

Metabolomic Signatures of Long-term Coffee Consumption and Risk of Type 2 Diabetes in Women.

OBJECTIVE: Coffee may protect against multiple chronic diseases, particularly type 2 diabetes, but the mechanisms remain unclear. RESEARCH DESIGN AND METHODS: Leveraging dietary and metabolomic data in two large cohorts of women (the Nurses' Health Study [NHS] and NHSII), we identified and validated plasma metabolites associated with coffee intake in 1,595 women. We then evaluated the prospective association of coffee-related metabolites with diabetes risk and the added predictivity of these metabolites for diabetes in two nested case-control studies (n = 457 case and 1,371 control subjects). RESULTS: Of 461 metabolites, 34 were identified and validated to be associated with total coffee intake, including 13 positive associations (primarily trigonelline, polyphenol metabolites, and caffeine metabolites) and 21 inverse associations (primarily triacylglycerols [TAGs] and diacylglycerols [DAGs]). These associations were generally consistent for caffeinated and decaffeinated coffee, except for caffeine and its metabolites that were only associated with caffeinated coffee intake. The three cholesteryl esters positively associated with coffee intake showed inverse associations with diabetes risk, whereas the 12 metabolites negatively associated with coffee (5 DAGs and 7 TAGs) showed positive associations with diabetes. Adding the 15 diabetes-associated metabolites to a classical risk factor-based prediction model increased the C-statistic from 0.79 (95% CI 0.76, 0.83) to 0.83 (95% CI 0.80, 0.86) (P < 0.001). Similar improvement was observed in the validation set. CONCLUSIONS: Coffee consumption is associated with widespread metabolic changes, among which lipid metabolites may be critical for the antidiabetes benefit of coffee. Coffee-related metabolites might help improve prediction of diabetes, but further validation studies are needed.

Effect of Supplementation With Marine ω-3 Fatty Acid on Risk of Colorectal Adenomas and Serrated Polyps in the US General Population: A Prespecified Ancillary Study of a Randomized Clinical Trial.

IMPORTANCE: Marine ω-3 fatty acid has been suggested to protect against colorectal cancer. OBJECTIVE: To assess the effect of daily marine ω-3 fatty acid supplementation on the risk of colorectal cancer precursors, including conventional adenomas and serrated polyps. DESIGN, SETTING, AND PARTICIPANTS: This study was a prespecified ancillary study of the placebo-controlled randomized clinical trial VITAL (Vitamin D and Omega-3 Trial). An intention-to-treat analysis was used to examine the effect of daily marine ω-3 supplements among 25 871 adults in the US general population (including 5106 African American persons) free of cancer and cardiovascular disease at enrollment. Randomization was from November 2011 to March 2014, and intervention ended as planned on December 31, 2017. INTERVENTIONS: Marine ω-3 fatty acid, 1 g daily (which included eicosapentaenoic acid, 460 mg, and docosahexaenoic acid, 380 mg) and vitamin D3 (2000 IU daily) supplements. MAIN OUTCOMES AND MEASURES: Risk of conventional adenomas (including tubular adenoma, tubulovillous adenoma, villous adenoma, and adenoma with high-grade dysplasia) or serrated polyps (including hyperplastic polyp, traditional serrated adenoma, and sessile serrated polyp). In a subset of participants who reported receiving a diagnosis of polyp on follow-up questionnaires, endoscopic and pathologic records were obtained to confirm the diagnosis. Odds ratios (ORs) and 95% CIs were calculated using logistic regression, after adjusting for age, sex, vitamin D treatment assignment, and use of endoscopy. Secondary analyses were performed according to polyp features and participants' characteristics. RESULTS: The demographic characteristics of participants at randomization were well balanced between the treatment and placebo groups; for example, 50.6% vs 50.5% were women, and 19.7% vs 19.8% were African American persons were included in each group. The mean (SD) age was 67.1 (7.1) years in the placebo group and 67.2 (7.1) in the ω-3 treatment group. During a median follow-up of 5.3 years (range, 3.8-6.1 years), 294 cases of conventional adenomas were documented in the ω-3 group and 301 in the control group (multivariable OR, 0.98; 95% CI, 0.83-1.15) (1:1 ratio between number of cases and number of participants). In addition, 174 cases of serrated polyps were documented in the ω-3 group and 167 in the control group (OR, 1.05; 95% CI, 0.84-1.29). Null associations were found for polyp subgroups according to size, location, multiplicity, or histology. In secondary analyses, marine ω-3 treatment appeared to be associated with lower risk of conventional adenomas among individuals with low plasma levels of ω-3 index at baseline (OR, 0.76; 95% CI, 0.57-1.02; P = .03 for interaction by ω-3 index). A beneficial association of supplementation was also noted in the African American population (OR, 0.59; 95% CI, 0.35-1.00) but not in other racial/ethnic groups (P = .11 for interaction). CONCLUSIONS AND RELEVANCE: Supplementation with marine ω-3 fatty acids, 1 g per day, was not associated with reduced risk of colorectal cancer precursors. A potential benefit of this supplementation for individuals with low baseline ω-3 levels or for African American persons requires further confirmation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01169259.

Association Between Beverage Intake and Incidence of Gastroesophageal Reflux Symptoms.

BACKGROUND & AIMS: Patients are frequently advised to eliminate coffee, tea, and/or soda to reduce symptoms of gastroesophageal reflux (GER), such as heartburn or regurgitation. However, there are no data from prospective studies to support these recommendations. METHODS: We collected data from the prospective Nurses' Health Study II from 48,308 women, 42-62 years old, who were free of regular GER symptoms, without cancer, and not taking proton pump inhibitors or H2 receptor agonists. Multivariate Cox proportional hazards models were used to assess associations between beverage intake and risk for GER symptoms. RESULTS: During 262,641 person-years of follow up, we identified 7961 women who reported symptoms of GER once or more per week. After multivariable adjustment, hazard ratios (HRs) for women with the highest intake of each beverage (more than 6 servings/day) compared to women with the lowest intake (0 servings/day) were 1.34 for coffee (95% CI, 1.13-1.59; Ptrend < .0001), 1.26 for tea (95% CI, 1.03-1.55; Ptrend < .001), and 1.29 for soda (95% CI, 1.05-1.58; Ptrend < .0001). We obtained similar results when we stratified patients according to caffeine status. No association was observed between milk, water, or juice consumption and risk for GER symptoms. In a substitution analysis, replacement of 2 servings/day of coffee, tea, or soda with 2 servings of water was associated with reduced risk of GERD symptoms: coffee HR, 0.96 (95% CI, 0.92-1.00); tea HR, 0.96 (95% CI, 0.92-1.00); and soda HR, 0.92 (95% CI, 0.89- 0.96). CONCLUSIONS: In an analysis of data from the prospective Nurses' Health Study II, intake of coffee, tea, or soda was associated with an increased risk of GER symptoms. In contrast, consumption of water, juice, or milk was not associated with GER symptoms. Drinking water instead of coffee, tea, or soda reduced the risk of GER symptoms.

Type 2 Diabetes Prevention Diet and Hepatocellular Carcinoma Risk in US Men and Women.

OBJECTIVES: Adherence to a healthy diet has been associated with a reduced risk of type 2 diabetes (T2D). Hepatocellular carcinoma (HCC) may have overlapping mechanisms with T2D, such as inflammation and insulin resistance. Thus, we examined the association between a previously developed T2D prevention dietary pattern and HCC risk. METHODS: We followed 87,943 women in the Nurses' Health Study and 49,665 men in the Health Professionals Follow-up Study for up to 32 years. The dietary diabetes risk reduction score, which includes dietary glycemic index, cereal fiber, ratio of polyunsaturated to saturated fats, trans fat, sugar-sweetened beverages, nuts, coffee, and red and processed meats, was obtained using validated food frequency questionnaires and updated every 4 years. The Cox proportional hazards regression model was used to calculate multivariable hazard ratios and confidence intervals (95% CIs). RESULTS: During over 1.9 million person-years, a total of 160 incident HCC cases were identified. The dietary diabetes risk reduction score was associated with a lower risk of HCC (top vs bottom quartile; hazard ratio: 0.57, 95% CI: 0.34-0.95; Ptrend = 0.03). All the individual food and beverage items were associated with the risk of HCC in the expected direction, although the association was weaker than the overall dietary pattern. DISCUSSION: Greater adherence to the T2D prevention diet was associated with a lower risk of developing HCC among US men and women. Further studies are needed to confirm and extend our findings.

Role of Dietary Flavonoid Compounds in Driving Patterns of Microbial Community Assembly.

Flavonoids are a group of polyphenolic dietary compounds found in many different plant-based foods. There is increasing evidence that higher flavonoid intake may be causally linked to a reduced risk of cardiovascular disease and other chronic diseases. The bioactivity and bioavailability of many dietary flavonoids can be influenced by gastrointestinal microbiome metabolism. However, the role that habitual flavonoid intake plays in shaping the human gut microbiome is poorly understood. We describe an application of an ecosystem-based analytic approach to nutritional, microbiome, and questionnaire data from a cohort of more than 240 generally healthy adult males to assess the role of dietary flavonoid compounds in driving patterns of microbial community assembly. We identified six subclass-specific microbial communities (SMCs) uniquely and independently associated with intakes of the six flavonoid subclasses. Eggerthela lenta was positively associated with intakes of flavonol and flavanone, and Adlercreutzia equolifaciens was positively associated with intakes of flavonols and flavanol monomers. In contrast, for nearly all flavonoid subclasses, Flavonifractor plautii was inversely associated with subclass consumption. Consuming tea at least once per week explained 10.4% of the total variance in assembly of the 20 species comprising the flavanol monomer SMC. The novel methodology employed, necessitated by multidimensional microbiome data that consist of nonindependent features that exhibit a wide range of distributions and mean values, addresses a major challenge in our ability to understand associations of the microbiome in a wide range of clinical and epidemiologic settings.IMPORTANCE Dietary flavonoids, which have been implicated in lowering chronic disease risk and improving blood pressure, represent a diverse group of polyphenolic compounds found in many commonly consumed foods such as tea, red wine, apples, and berries. The bioactivity and bioavailability of more dietary flavonoids can be influenced by gastrointestinal microbiome metabolism. With demonstrated prebiotic and antimicrobial effects in in vitro and in animal models, it is surprising that there are not many human studies investigating the role dietary flavonoids play in shaping the gastrointestinal microbiome. Our analysis revealed patterns of community assembly that uniquely and independently characterize an individual's exposure to various flavonoid compounds. Furthermore, this study confirmed, independent from effects of other dietary and lifestyle factors included in the multivariate-adjusted model, that flavonoid intake is associated with microbial community assembly.

Fish and marine fatty acids intakes, the FADS genotypes and long-term weight gain: a prospective cohort study.

OBJECTIVE: We tested whether genetic variants near fatty acid desaturases gene (FADS) cluster, which were recently identified to be signatures of adaptation to fish-rich and n-3 polyunsaturated fatty acids (PUFAs)-rich diet, interacted with these dietary factors on change in body mass index (BMI). DESIGN: Three FADS variants were examined for gene-diet interactions on long-term (~10 years) changes in BMI and body weight in four prospective cohort studies. SETTING: Population based study. PARTICIPANTS: 11 323 women from the Nurses' Health Study (NHS), 6833 men from the Health Professionals Follow-up Study (HPFS) and replicated in 6254 women from the Women's Health Initiative (WHI) and 5 264 Chinese from the Singapore Chinese Health Study (SCHS). MAIN OUTCOMES: Long-term (~10 years) changes in BMI and body weight. RESULTS: In the NHS and HPFS cohorts, food-sourced n-3 PUFAs intake showed interactions with the FADS rs174570 on changes of BMI (P for interaction=0.02 in NHS, 0.05 in HPFS and 0.007 in combined). Such interactions were replicated in two independent cohorts WHI and SCHS (P for interaction=0.04 in WHI, 0.02 in SCHS and 0.001 in combined). The genetic associations of the FADS rs174570 with changes in BMI increased across the tertiles of n-3 PUFAs in all the cohorts. Fish intake also accentuated the genetic associations of the FADS rs174570 with long-term changes in BMI (pooled P for interaction=0.006). Viewed differently, long chain n-3 PUFAs intake showed stronger association with long-term changes in BMI among the rs174570 T carriers (beta=0.79 kg/m2 per g, p=3×10-5) than the rs174570 non-T carriers (beta=0.16 kg/m2 per g, p=0.08). Similar results were observed for fish intake. CONCLUSIONS: Our hypothesis-driven analyses provide replicable evidence that long chain n-3 PUFAs and fish intakes may interact with the FADS variant on long-term weight gain. Further investigation is needed to confirm our findings in other cohorts.

Coffee consumption and plasma biomarkers of metabolic and inflammatory pathways in US health professionals.

BACKGROUND: Coffee consumption has been linked to lower risk of various health outcomes. However, the biological pathways mediating the associations remain poorly understood. OBJECTIVES: The aim of this study was to assess the association between coffee consumption and concentrations of plasma biomarkers in key metabolic and inflammatory pathways underlying common chronic diseases. METHODS: We investigated the associations of total, caffeinated, and decaffeinated coffee consumption with 14 plasma biomarkers, including C-peptide, insulin-like growth factor 1 (IGF-1), IGF binding protein (IGFBP) 1, IGFBP-3, estrone, total and free estradiol, total and free testosterone, sex hormone-binding globulin (SHBG), total adiponectin, high-molecular-weight (HMW) adiponectin, leptin, C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor receptor 2 (sTNFR-2). Data were derived from 2 cohorts of 15,551 women (Nurses' Health Study) and 7397 men (Health Professionals Follow-Up Study), who provided detailed dietary data before blood draw and were free of diabetes, cardiovascular disease, or cancer at the time of blood draw. Multivariable linear regression was used to calculate the percentage difference of biomarker concentrations comparing coffee drinkers with nondrinkers, after adjusting for a variety of demographic, clinical, and lifestyle factors. RESULTS: Compared with nondrinkers, participants who drank ≥4 cups of total coffee/d had lower concentrations of C-peptide (-8.7%), IGFBP-3 (-2.2%), estrone (-6.4%), total estradiol (-5.7%), free estradiol (-8.1%), leptin (-6.4%), CRP (-16.6%), IL-6 (-8.1%), and sTNFR-2 (-5.8%) and higher concentrations of SHBG (5.0%), total testosterone (7.3% in women and 5.3% in men), total adiponectin (9.3%), and HMW adiponectin (17.2%). The results were largely similar for caffeinated and decaffeinated coffee. CONCLUSION: Our data indicate that coffee consumption is associated with favorable profiles of numerous biomarkers in key metabolic and inflammatory pathways. This trial was registered at clinicaltrials.gov as NCT03419455.

Marine omega-3 fatty acid intake and survival of stage III colon cancer according to tumor molecular markers in NCCTG Phase III trial N0147 (Alliance).

Marine omega-3 polyunsaturated fatty acids (MO3PUFAs) have anticancer properties and may improve colon cancer survival. However, it remains unknown whether the benefit differs by tumor molecular subtype. We examined data from a phase III randomized trial of FOLFOX or FOLFOX + cetuximab among 1,735 stage III colon cancer patients who completed a dietary questionnaire at enrollment. Multivariable hazard ratios and 95% confidence intervals (CIs) were calculated for the association between MO3PUFA and disease-free survival (DFS) and overall survival according to KRAS and BRAFV600E mutations and DNA mismatch repair (MMR) status. Higher MO3PUFA intake was associated with improved 3-year DFS for KRAS wild-type tumors (77% vs. 73%; HR: 0.84; 95% CI: 0.67-1.05) but not KRAS-mutant tumors (64% vs. 70%; HR: 1.30; 95% CI: 0.97-1.73; Pinteraction = 0.02). Similar heterogeneity was found by MMR (Pinteraction = 0.14): higher MO3PUFA was associated with better 3-year DFS for tumors with deficient MMR (72% vs. 67%) but not proficient MMR (72% vs. 72%). No heterogeneity was found by BRAFV600E mutation. Similar findings were obtained for overall survival. In conclusion, we found a suggestive beneficial association between higher MO3PUFA intake and improved survival among stage III colon cancer patients with wild-type KRAS and deficient MMR. Given the relatively small number of cases with tumor molecular assessments, further studies, preferably through pooled analyses of multiples cohorts, are needed to validate our findings.

Calcium Intake and Survival after Colorectal Cancer Diagnosis.

PURPOSE: Although evidence suggests an inverse association between calcium intake and colorectal cancer incidence, the influence of calcium on survival after colorectal cancer diagnosis remains unclear.Experimental Design: We prospectively assessed the association of postdiagnostic calcium intake with colorectal cancer-specific and overall mortality among 1,660 nonmetastatic colorectal cancer patients within the Nurses' Health Study and the Health Professionals Follow-up Study. Patients completed a validated food frequency questionnaire between 6 months and 4 years after diagnosis and were followed up for death. Multivariable hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazards regression. RESULTS: Comparing the highest with the lowest quartile intake of postdiagnostic total calcium, the multivariable HRs were 0.56 (95% CI, 0.32-0.96; P trend = 0.04) for colorectal cancer-specific mortality and 0.80 (95% CI, 0.59-1.09; P trend = 0.11) for all-cause mortality. Postdiagnostic supplemental calcium intake was also inversely associated with colorectal cancer-specific mortality (HR, 0.67; 95% CI, 0.42-1.06; P trend = 0.047) and all-cause mortality (HR, 0.71; 95% CI, 0.54-0.94; P trend = 0.008), although these inverse associations were primarily observed in women. In addition, calcium from diet or dairy sources was associated with lower risk in men. CONCLUSIONS: Higher calcium intake after the diagnosis may be associated with a lower risk of death among patients with colorectal cancer. If confirmed, these findings may provide support for the nutritional recommendations of maintaining sufficient calcium intake among colorectal cancer survivors.