Associations of Dietary Cholesterol, Serum Cholesterol, and Egg Consumption With Overall and Cause-Specific Mortality, and Systematic Review and Updated Meta-Analysis

Background: Despite substantial attention underscoring the importance of exogenous dietary and endogenous serum cholesterol to human health, thorough evaluation of the associations is lacking. Our study objective was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption, and conduct an updated meta-regression analysis of cohort studies. Methods: We conducted a prospective analysis of 27,078 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Multivariable-controlled cause-specific Cox proportional hazards regression models calculated hazard ratios (HR) and 31-year absolute mortality risk differences (ARD). A systematic review and meta-analysis of cohort studies was also performed (PROSPERO: CRD42021272756). Results: Based on 482,316 person-years of follow-up, we identified 22,035 deaths, including 9,110 deaths from cardiovascular disease (CVD). Greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD mortality. HRs for each additional 300 mg cholesterol intake per day were 1.10 and 1.13 for overall and CVD mortality (respectively), and for each additional 50 g egg consumed daily HRs were 1.06 and 1.09, respectively, for overall and CVD mortality (all P-values<0.0001). After multivariable adjustment, higher serum total cholesterol concentrations were associated with increased risk of CVD mortality (HRs per 1-SD increment: 1.14; P-value<0.0001). The observed associations were generally similar across cohort subgroups. The updated meta-analysis of cohort studies based on 49 risk estimates, 3,601,401 participants, and 255,479 events) showed consumption of one additional 50 g egg daily was associated with significantly increased CVD risk: pooled RR=1.04 (95% CI: 1.00, 1.08); I 2 =80.1%). In the subgroup analysis of geographical regions (P-value-for-interaction=0.02), an increase of 50 g egg consumed daily was associated with a higher risk of CVD among US cohorts (pooled-RR=1.08, 95% CI: 1.02, 1.14), appeared related to a higher CVD risk in European cohorts with a borderline significance (pooled-RR=1.05), but was not associated with CVD risk in Asian cohorts. Conclusions: In this prospective cohort study and updated meta-analysis, greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD mortality. Our findings support restricted consumption of dietary cholesterol as a means to improve long-term health and longevity.

Nut and peanut butter consumption and risk of prostate cancer in the NIH‐AARP diet and health study

Association between serum retinol and overall and cause-specific mortality in a 30-year prospective cohort study

AbstractHow retinol as a clinical indicator of vitamin A status is related to long-term mortality is unknown. Here we report the results of a prospective analysis examining associations between serum retinol and risk of overall and cause-specific mortality. During a 30-year cohort follow-up, 23,797 deaths were identified among 29,104 men. Participants with higher serum retinol experienced significantly lower overall, CVD, heart disease, and respiratory disease mortality compared to men with the lowest retinol concentrations, reflecting 17–32% lower mortality risk (Ptrend < 0.0001). The retinol-overall mortality association is similar across subgroups of smoking intensity, alcohol consumption, body mass index, trial supplementation, serum alpha-tocopherol and beta-carotene concentrations, and follow-up time. Mediation analysis indicated that <3% of the effects of smoking duration and diabetes mellitus on mortality were mediated through retinol concentration. These findings indicate higher serum retinol is associated with lower overall mortality, including death from cardiovascular, heart, and respiratory diseases.

Association Between Plant and Animal Protein Intake and Overall and Cause-Specific Mortality

Serum Metabolomic Response to Low and High Dose Vitamin E Supplementation in Two Randomized Controlled Trials

Abstract Objectives Vitamin E is an essential micronutrient and critical human antioxidant that has been tested for cancer and cardiovascular preventative effects for decades with conflicting results. For example, prostate cancer incidence was reduced by a low-dose vitamin E supplement in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, but the findings were not replicated by high-dose vitamin E trials such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The present investigation examined the serum metabolomic responses to low- and high-dose vitamin E supplementation in order to gain biological insight into the divergent trial outcomes. Methods We examined baseline and on-study serum samples for 154 men randomly assigned to receive 400 IU vitamin E (as alpha-tocopheryl acetate; ATA) or placebo daily in the Vitamin E Atherosclerosis Prevention Study (VEAPS), and 100 men administered 50 IU ATA or placebo daily in the ATBC Study. Over 970 known metabolites were identified using an ultrahigh-performance LC-MS/MS platform. Linear regression models estimated the change in serum metabolites of men supplemented with vitamin E to those assigned to placebo in VEAPS compared with ATBC. Results Serum alpha-carboxyethyl hydrochroman (CEHC) sulfate, alpha-tocopherol, and beta-/gamma-tocopherol were significantly altered by supplementation with ATA in both the VEAPS and ATBC trials (all P-values ≤ 5.1 × 10−5, the Bonferroni multiple-comparisons corrected statistical threshold). Serum C22 lactone sulfate was also significantly decreased in response to the high-dose vitamin E supplement in VEAPS (β = −0.70, P-value = 8.1 × 10−6), but not altered in the low-dose ATBC trial (β = −0.17, P-value = 0.4). Additionally, changes in several androgenic steroid metabolites were strongly related to the vitamin E supplement-associated change in C22 lactone sulfate only in the high-dose VEAPS trial. Conclusions We found evidence of a dose-dependent vitamin E supplementation effect on a novel C22 lactone sulfate compound as well as several androgenic steroids that may have relevance to previous controlled trial findings for prostate cancer. Funding Sources This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, U.S. Public Health Service, Department of Health and Human Services.

Relationship Between Serum Alpha-Tocopherol and Overall and Cause-Specific Mortality

A Prospective Study of Serum Vitamin E and 28-Year Risk of Lung Cancer

Abstract Background Epidemiologic data are inconsistent regarding the vitamin E-lung cancer association, and no study to our knowledge has examined serologic changes in vitamin E status in relation to subsequent risk. Methods In a cohort of 22 781 male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, we ascertained 3184 lung cancer cases during up to 28 years of observation. Cox proportional hazards models examined whether higher serum alpha-tocopherol concentrations at baseline, 3 years, or the interval change were associated with lower lung cancer risk. All statistical tests were two-sided. Results After adjustment for age, body mass index, smoking intensity and duration, serum total cholesterol, and trial intervention group, we found lower lung cancer risk in men with high baseline alpha-tocopherol (fifth quintile [Q5] vs Q1, hazard ratio [HR] = 0.76, 95% confidence interval [CI] = 0.66 to 0.87, Ptrend &lt; .001). A similar reduction in risk was seen for serum alpha-tocopherol at 3 years (Q5 vs Q1, HR = 0.78, 95% CI = 0.67 to 0.91, Ptrend = .004). The inverse risk association appeared stronger for younger men and those who had smoked fewer years but was similar across trial intervention groups. We also found reduced risk among men not supplemented with vitamin E who had a lower serum alpha-tocopherol at baseline and greater increases in concentrations at 3 years (third tertile vs first tertile of serum alpha-tocopherol change, HR = 0.74, 95% CI = 0.59 to 0.91, P = .005). Conclusions Higher vitamin E status, as measured by serum alpha-tocopherol concentration, as well as repletion of a low vitamin E state, was related to decreased lung cancer risk during a 28-year period. Our findings provide evidence supporting the importance of adequate physiological vitamin E status for lung cancer risk reduction.

Prospective serum metabolomic profiling of lethal prostate cancer

Serum Beta Carotene and Overall and Cause-Specific Mortality

Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma

Abstract BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Variant profiling is crucial for developing personalized treatment and elucidating the etiology of this disease. METHODS Patients with PDAC undergoing surgery from 2007 to 2012 (n = 73) were followed from diagnosis until death or the end of the study. We applied an anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) method to a panel of 65 selected genes and assessed analytical performance by sequencing a quantitative multiplex DNA reference standard. In clinical PDAC samples, detection of low-level KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations was validated by allele-specific PCR and digital PCR. We compared overall survival of patients according to KRAS mutation status by log-rank test and applied logistic regression to evaluate the association between smoking and tumor variant types. RESULTS The AMP-based NGS method could detect variants with allele frequencies as low as 1% given sufficient sequencing depth (&gt;1500×). Low-frequency KRAS G12 mutations (allele frequency 1%–5%) were all confirmed by allele-specific PCR and digital PCR. The most prevalent genetic alterations were in KRAS (78% of patients), TP53 (tumor protein p53) (25%), and SMAD4 (SMAD family member 4) (8%). Overall survival in T3-stage PDAC patients differed among KRAS mutation subtypes (P = 0.019). Transversion variants were more common in ever-smokers than in never-smokers (odds ratio 5.7; 95% CI 1.2–27.8). CONCLUSIONS The AMP-based NGS method is applicable for profiling tumor variants. Using this approach, we demonstrated that in PDAC patients, KRAS mutant subtype G12V is associated with poorer survival, and that transversion variants are more common among smokers.