Background and Aims : Interventions in preventive cardiology traditionally focus on four standard modifiable cardiovascular risk factors (SMuRFs): hypertension, dyslipidaemia, diabetes mellitus, and smoking. Yet, a substantial proportion of incident cardiovascular events accrues for individuals with none of these factors, particularly among women for whom cardiovascular disease remains under-detected and under-treated. The utility of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) was evaluated to detect cardiovascular risk in SMuRF-less women participating in the prospective NIH-funded Women's Health Study. Methods : High-sensitivity C-reactive protein was measured at baseline among 12 530 initially healthy American women with no standard modifiable risk factors who were followed over 30 years for first major adverse cardiovascular events (myocardial infarction, coronary revascularization, ischaemic stroke, or cardiovascular death). Hazard ratios (HRs) and 95% confidence intervals (95% CI) for incident coronary heart disease (CHD), ischaemic stroke, and total cardiovascular events were calculated across quintiles of hsCRP, along with 30-year cumulative incidence curves. Hazard ratios were also computed according to common clinical thresholds of hsCRP, according to standard deviation change in hsCRP, and as a continuous variable in penalized spline regression models. Results : During 30-year follow-up, 973 first major cardiovascular events accrued. Median baseline hsCRP was significantly higher among SMuRF-less women who subsequently suffered a cardiovascular event when compared with those who did not (median hsCRP 2.22 vs 1.50 mg/L, P < .0001). In age-adjusted analyses, the HRs for the primary endpoint of incident CHD from lowest (referent) to highest levels of hsCRP at study entry were 1.0 (referent), 1.24, 1.41, 1.57, and 2.23 (P-trend < .0001) such that CHD risk over 30 years increased 21% for each increasing quintile of hsCRP (age-adjusted HR 1.21, 95% CI 1.13-1.29, P < .0001). Corresponding HRs for the top vs bottom quintile of hsCRP were 1.69 (95% CI 1.16-2.47) for ischaemic stroke and 1.74 (95% CI 1.42-2.14) for total cardiovascular disease events. Using common clinical hsCRP thresholds, SMuRF-less women with hsCRP > 3 mg/L had a 77% higher risk of CHD events, a 39% higher risk of ischaemic stroke events, and a 52% higher risk of total cardiovascular disease events when compared with those with hsCRP < 1 mg/L. Spline analyses demonstrated linear association with risk across the spectrum of hsCRP values. Hazards were moderately attenuated after additional adjustment for body mass index and estimated glomerular filtration rate [covariate-adjusted CHD HR 1.86 (95% CI 1.35-2.58, P = .0002) for comparison of the top vs bottom quintile of hsCRP and 1.52 (95% CI 1.20-1.92, P = .0006) for comparison of those with hsCRP > 3 mg/L to those < 1 mg/L]. Conclusions : Over a 30-year horizon, cardiovascular events commonly occur among 'SMuRF-less but inflamed' women who are otherwise missed by current screening algorithms, a clinically important observation given recent trial data demonstrating that statin therapy reduces risk by 38% among such individuals.

BACKGROUND:Underlying metabolic perturbations may offer insight into etiological factors related to liver cancer development. The objective of this study was to explore associations between pre-diagnostic metabolites and risk of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS:We conducted a nested case-control study within 12 prospective U.S. cohort studies, including 727 HCC cases and 126 ICC cases with matched controls. Metabolomic profiling was performed on pre-diagnostic blood samples using the Metabolon platform. Multivariable conditional logistic regression estimated adjusted odds ratios and 95% confidence intervals for associations between metabolites (per doubling in levels) and liver cancer risk. Elastic net regression selected metabolites predictive of HCC and ICC, with predictive performance assessed by area under the curve (AUC). RESULTS:Median time from blood collection to diagnosis was 11.6 years. Of 1,485 pre-diagnostic metabolites, 600 were associated with HCC risk after false discovery rate correction (366 positively, 234 negatively); no metabolites were significantly associated with ICC. Enriched pathways among HCC cases included methylhistidine metabolism, amino acid metabolism, and bile acid biosynthesis; ICC showed enrichment in valine, leucine, and isoleucine pathways. Elastic net models for HCC selected 38 metabolites with strong predictive performance (AUC = 0.87; 95% CI: 0.83 to 0.91), while eight metabolites were selected for ICC with modest discrimination (AUC = 0.64; 95% CI: 0.49 to 0.80). CONCLUSIONS:Numerous pre-diagnostic metabolites were associated with HCC risk, potentially reflecting underlying liver dysfunction. Enrichment patterns suggest distinct metabolic perturbations between HCC and ICC. Larger studies are needed to characterize metabolic risk factors for ICC and evaluate metabolites as predictors of HCC risk.

BACKGROUND:Effects of ω-3 fatty acids (FAs) supplementation on cardiovascular outcomes have been investigated in several randomized controlled trials (RCTs). The VITamin D and OmegA-3 TriaL (VITAL) is the largest trial that tested the effect of ω-3 FA supplementation (840 mg/d of eicosapentaenoic acid and docosahexaenoic acid in 1.2:1) in a primary prevention population in the United States, with nonsignificant results (P > 0.05) for major cardiovascular disease (CVD) events. OBJECTIVES:To reanalyze VITAL using Bayesian methods accounting for prior evidence. METHODS:The VITAL randomly assigned 25,871 older United States adults with a median follow-up of 5.3 y. On the basis of prior evidence from RCTs, we used Weibull proportional hazards models adopting the Hamiltonian Monte Carlo sampling method to estimate posterior hazard ratio (HR) for total CAD, myocardial infarction (MI), composite major CVD events (CAD/stroke/CVD death), CVD death, all-cause death, and stroke. Several distinct informative priors were formulated based on Bayesian hierarchical models of previous trials similar to VITAL. RESULTS:Bayesian analyses with the use of noninformative prior yielded essentially the same results as the corresponding frequentist analyses. The effects of ω-3 FA supplementation on CAD and MI were robust across the priors, with the posterior HR estimates varying from 0.88 to 0.93 and 0.82 to 0.90, respectively. Without skepticism into the priors, posterior HRs were 0.95-0.96 in CVD, 0.91-0.92 in cardiovascular death, and 0.95-0.96 in all-cause death risks, respectively. Stroke risk was unchanged by the intervention. According to primary informed priors, probabilities of ω-3 FA being effective were 99.7% for CAD, 99.6% for total MI, 98.4% for CVD, 98.8% for all-cause death, 99.8% for cardiovascular death, and 33.7% for stroke, respectively. CONCLUSIONS:Bayesian analyses of VITAL incorporating previous RCT evidence suggest that daily ω-3 FA supplementation robustly lowers risk of coronary events but not stroke, providing enhanced support for the primary prevention use of ω-3 FA supplementation for coronary events. TRIAL REGISTRATION NUMBER:This study was registered at VITAL clinicaltrials.gov identifier as NCT01169259.

Supplementary Table S5 shows results of univariate analysis for 77 chronically elevated serum alanine aminotransferase (cALT)-defined nonalcoholic fatty liver disease in the Pancreatic Cancer Case-Control Consortium (PanC4) data

Importance: Pre-pandemic physical activity (PA) levels may be associated with a lower risk of experiencing depressive symptoms in the context of psychosocial resilience during a global crisis. Objective: To investigate the association between self-reported pre-pandemic PA levels and the risk of experiencing depressive symptoms during the beginning of the COVID-19 pandemic in older U.S. adults. Design, Setting, and Participants: We combined three large ongoing prospective cohorts of US adults who provided pre-pandemic baseline self-reports of leisure-time PA and other risk factors using the most recent questionnaire completed as of December 2019. In June 2020, participants reported in a survey whether they had experienced depressive symptoms in the last 7 days. Exposure: Pre-pandemic PA data were categorized by validated criteria into three groups by metabolic equivalent hours per week (MET-hr/wk): inactive (0-3.5), insufficiently active (>3.5 to <7.5), and sufficiently active (≥7.5). Main Outcome and Measures: Our primary outcome was depressive symptoms experienced during the beginning of the COVID-19 pandemic in 2020, assessed by the PROMIS-29 depression domain. We used multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of each of the two upper pre-pandemic PA categories versus the lowest PA category with depressive symptoms during the early pandemic. Results: In total, 35,320 older U.S. adults comprised the pooled cohort (mean [standard deviation] age, 74.9[5.9] years; 66.8% female). For PA categories, 15.8% were inactive; 10.4% insufficiently active; and 73.8%, sufficiently active. A total of 1668 participants reported experiencing depressive symptoms in June 2020. After controlling for demographics, lifestyle factors, comorbidities, medications, and pre-pandemic depression at the beginning of the COVID-19 pandemic, compared with the inactive group, those sufficiently active had significantly lower odds of experiencing depressive symptoms (OR, 0.75; 95% CI, 0.66-0.86). In subgroup analyses, the association between PA and depressive symptoms differed by ethnic group. Conclusion and Relevance: In this cohort of older U.S. adults, those who achieved at least 7.5 MET-hr/wk of pre-pandemic PA had lower odds of exhibiting depressive symptoms during the early months of the pandemic. Hence, higher pre-pandemic PA levels may be associated with lower odds of experiencing depressive symptoms during exceptional global crises, such as the COVID-19 pandemic.

Supplementary Table S3 shows results of univariate analysis for 36 biopsy-confirmed nonalcoholic fatty liver disease SNPs in the PanScan sample

SNPs in adiponectin and leptin receptor genes and their association with receptor expression

Supplementary Table S4 shows results of univariate analysis for 17 imaging and biopsy validated SNPs in the PanScan sample

BACKGROUND AND OBJECTIVES:In the United States, stroke is the third leading cause of death among women, with 1 in 5 women aged 55 to 75 years expected to experience a stroke. The Brain Care Score (BCS) is an evidence-based tool designed to motivate lifestyle changes, with higher scores associated with reduced risk of stroke, dementia, and depression. We aim to measure the association of the BCS and incident cerebrovascular events (CVEs), including stroke and transient ischemic attack (TIA), in the Women's Health Study (WHS). METHODS:The WHS comprises women health professionals aged 45 and older in the United States. Participants without history of CVE and complete data available to calculate a BCS and covariates 5 years after enrollment were included. Higher BCS reflects better risk factor control, with the minimum score being 0 and the maximum score being 20. Cox proportional hazard models examined the association between BCS and incident CVE adjusted for potential confounders. RESULTS:A total of 21,271 women were eligible with a median age of 57.9 years (interquartile range: 53.9-63.8) and median BCS of 15 (interquartile range [IQR]:13-16). There were 1,294 incident CVE cases (6.1%) during a median follow-up of 22.4 (IQR: 15.9-23.5) years. A five-point higher baseline BCS was associated with a 37% decrease in the risk of incident CVE after adjusting for age, menopausal status, use of hormonal replacement therapy, and other known cardiovascular disease risk factors (hazard ratio [HR] 0.63, 95% CI 0.56-0.71). This association remained significant after adjusting for race, educational attainment, and income (HR 0.64, 95% CI 0.57-0.72). There was a 28% decreased risk of incident CVE among those with a BCS equal to or above the median compared with those with a BCS below the median, in a fully adjusted model (HR 0.72, 95% CI 0.64-0.80). DISCUSSION:Higher baseline BCS was associated with a decreased risk of incident CVE in the WHS. Future studies are needed to study the BCS in more diverse populations and to investigate how changes in BCS across the lifespan affect risk of CVE.

Experimental studies have shown anti-carcinogenic properties of vitamin D, but meta-analyses of randomized trials of vitamin D supplementation show reduction in cancer mortality but not cancer incidence. This study evaluated the effects of randomized moderate-dose vitamin D3 supplementation on mammographic features associated with breast cancer, and gene expression pathways in breast tumors. As part of an ancillary study to the VITamin D and OmegA-3 TriaL (VITAL) trial, we collected digital mammograms from women ≥ 55 years old, randomized in a 2X2 factorial design to vitamin D3 supplementation (2, 000 IU/day of cholecalciferol; n = 1317) or placebo (n = 1280). Digital mammograms were collected prior to randomization, and at 1, 3, and 4 years post randomization. Formalin fixed paraffin embedded tissue tumor blocks were collected for women who reported breast cancer post-randomization. RNASeq data were obtained from 25 tumors in the vitamin D arm and 21 from the placebo arm. The primary outcomes were (a) changes in percent mammographic density (PMD), and V, a mammographic feature that captures gray-scale pixel variation, and (b) tumor gene-expression patterns. A gene expression-based vitamin D score was developed in VITAL and evaluated in 3 independent data sets (Nurses’ Health Studies, TCGA, METABRIC) to determine if it was associated with long-term survival. The mean age at randomization was 64 years of age; 27% of women self-reported their race as Black and 71% White. Both arms experienced significant declines in PMD and V from baseline to year 4. For PMD, those in the vitamin D arm had a 19.6% decline vs. 18.1% in the placebo arm (p=0.41 for difference between arms). For V, those in the vitamin D arm had a 6.5% decline compared with 4.0% in the placebo arm (p=0.02). There was a significant p-trend in the net effect of vitamin D3 over time for V (p=0.01). However, after adjustment for time-varying BMI the net effect was attenuated (p=0.11).Tumors in the vitamin D arm demonstrated down-regulation of multiple cancer related pathways (FDR ≤0.05), including proliferation and inflammation. The vitamin D gene expression score was associated with improved prognosis among stage I to III breast cancer cases in TCGA (p-trend=0.07), METABRIC (p-trend=0.005), and NHS (p-trend=0.04). Overall, randomized moderate dose vitamin D did not have a significant effect on PMD. Vitamin D had a stronger impact on V compared with placebo that appeared to be mediated through changes in BMI. Pathway analyses suggested that supplementation may have an important effect on breast cancer survival, consistent with the reduction in advanced cancers observed in VITAL. In conclusion, there was evidence that vitamin D impacted changes in breast tissue architecture on mammograms and influenced gene-expression patterns that were associated with improved breast cancer prognosis. Rulla M. Tamimi, Franco Giulianini, Cheng Peng, Nancy Cook, Yujin Heng, Vanessa Bret-Mounet, Liza Quintana, Julie Buring, JoAnn Manson, Erin Fowler, John Heine, Kathryn Rexrode. Changes in mammographic features and breast tissue gene expression associated with vitamin D supplementation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6428.

The gut-liver axis may play an important role in hepatocarcinogenesis. However, limited prospective research has explored associations with liver cancer risk. We conducted a nested case-control study based in 12 prospective cohort studies from across the United States, which included 867 cases of liver cancer and 867 matched controls. We measured bacterial translocation markers, specifically immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide and flagellin; soluble CD14 (a co-receptor for lipopolysaccharide); and lipopolysaccharide-binding protein. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) between bacterial translocation marker concentrations per doubling in concentrations and liver cancer risk. Lipopolysaccharide-binding protein concentrations were most strongly associated with higher liver cancer risk (OR per doubling in concentrations: 1.48, 95% CI: 1.23-1.79). Concentrations of anti-flagellin IgA (1.13, 1.01-1.28) and IgG (1.13, 1.01-1.28), anti-lipopolysaccharide IgG (1.20, 1.01-1.42), and soluble CD14 (1.12, 1.01-1.24) were also associated with liver cancer risk. When analyses were separated into hepatocellular carcinoma (HCC, N = 436 cases) and intrahepatic cholangiocarcinoma (ICC, N = 110 cases), no evidence of heterogeneity was observed except for lipopolysaccharide-binding protein concentrations, which were positively associated with HCC (1.77, 1.34-2.33) but not ICC (0.67, 0.37-1.22; p-heterogeneity = .003). Associations did not differ by time to liver cancer diagnosis or other subgroups. These findings support the role of gut barrier dysfunction in hepatocarcinogenesis, necessitating further research to understand the complex interplay among the mechanisms and risk factors disrupting the gut barrier, microbiota, and liver cancer.

BACKGROUND:Bile acids are produced in the liver and are important for lipid digestion. Higher-circulating bile acid levels, however, have been linked to metabolic disorders, inflammation, and gut microbiota dysbiosis, which have been implicated in liver carcinogenesis. To date, few epidemiological studies have explored the association between circulating bile acids and liver cancer risk. METHODS:We conducted a nested case-control study among 12 prospective cohort studies located in the United States. Fifteen prediagnostic circulating bile acids were measured from blood samples among 872 individuals who developed liver cancer and 872 matched control participants. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted conditional logistic regression analysis of circulating bile acid levels and liver cancer risk. RESULTS:Primary conjugated bile acid concentrations were positively associated with higher risk of liver cancer (OR per doubling in concentrations [log2] and 95% CI of glycocholic acid: 1.32, 1.24 to 1.40; glycochenodeoxycholic acid: 1.33, 1.24 to 1.43; taurocholic acid: 1.28, 1.22 to 1.35; and taurchenodeoxycholic acid: 1.32, 1.24 to 1.39). Secondary conjugated bile acids were also positively associated with liver cancer risk (doubling of concentrations OR ranged from 1.11 to 1.22). Unconjugated bile acid concentrations were generally not associated with liver cancer risk, except lithocholic acid (OR per doubling: 1.27, 1.16 to 1.39). When analyses were separated into the 2 main subtypes of liver cancer, hepatocellular carcinoma (HCC; 438 cases/438 controls) and intrahepatic cholangiocarcinoma (ICC; 111 cases/111 controls), significant heterogeneity was observed for primary conjugated bile acid concentrations (all P < .001) that showed positive significant associations with HCC but not ICC. CONCLUSIONS:These results suggest that bile acids may be important markers of HCC risk and contribute to hepatocarcinogenesis; however, further research using serial measurements is needed.

Supplementary Table S9 shows descriptive Statistics for PanScan sample

Background/Objectives: While previous study results have suggested an elevated risk of type 2 diabetes with potato consumption, limited and inconsistent results are available on the association of potato consumption with the risk of cardiovascular disease (CVD) and hypertension (HTN). We assessed the associations of (i) total potato consumption with the risk of CVD and HTN as the primary aim and (ii) fried potatoes and combined baked, boiled, and mashed potatoes with the risk of CVD and HTN as the secondary aim. Methods: We conducted a meta-analysis using data from seven cohorts for CVD (n = 110,063) and five cohorts for HTN (n = 67,146). Cox regression was used to estimate multivariable adjusted hazard ratios separately in each cohort and the cohort-specific results were meta-analyzed using an inverse-variance weighted method. Results: The mean age ranged from 25 to 72 years, 65% of the respondents were women, and the mean consumption of total potatoes ranged from 1.9 to 4.3 times per week. In the primary analysis, total potato intake was not associated with the risk of either CVD or HTN: multivariable adjusted HR (95% CI) comparing 5+ servings/week to no potato intake: 0.96 (0.89-1.04) for CVD and 1.04 (0.99-1.08) for HTN. In secondary analyses, the consumption of combined baked, boiled, and mashed potatoes was not associated with CVD or HTN; while fried potato consumption was not associated with CVD risk, there was a 10% higher risk of HTN (95% CI: 4% to 17%) comparing 1+ servings/week to no fried potato intake. Conclusions: While the consumption of total potato was not associated with the risk of CVD or HTN risk, a modest elevated risk of HTN but not CVD was observed only with fried potato consumption.

Supplementary Table S10 shows descriptive Statistics for PanC4 sample

Association between SNPs in the leptin receptor gene and pancreatic cancer mortality by sex

BACKGROUND:Traditional cardiovascular risk assessment entails investigator-defined exposure levels and individual risk markers in multivariable analysis. We sought to determine whether an alternative unbiased learning analysis might provide further insights into vascular risk. METHODS:We conducted an unsupervised learning (k-means cluster) analysis in the Women's Health Study (N=26 443) using baseline levels of triglycerides, high-sensitivity C-reactive protein, and low-density lipoprotein cholesterol to form novel exposures. We then evaluated cluster-based risk of incident coronary, cerebrovascular, and limb events using the Kaplan-Meier method and multivariable Cox models, followed by comparison with established clinical biomarker thresholds. Finally, we illustrated clinical applicability to a nonvascular outcome (type 2 diabetes). RESULTS:Four clusters emerged and were named according to aggregate biomarker profiles: Cluster 1 ("healthy," n=12 101), cluster 2 ("hypercholesterolemic," n=7424), cluster 3 ("inflammatory," n=5056), and cluster 4 ("triglyceride-rich," n=1862). Triglyceride-rich cluster identity conferred the highest risk of future cardiovascular events (adjusted hazard ratio [HRadj], 2.24 [95% CI, 1.93-2.60]) compared with those in the healthy cluster (reference group). Risk was intermediate in the hypercholesterolemic (predominantly elevated low-density lipoprotein cholesterol) and inflammatory (predominantly elevated high-sensitivity C-reactive protein) clusters (HRadj, 1.44 [95% CI, 1.28-1.61]; and 1.54 [95% CI, 1.35-1.75], respectively). Clustering yielded stronger total cardiovascular disease risk associations than traditionally defined mixed dyslipidemia with modest improvement in reclassification statistics. Cluster identities also predicted incident type 2 diabetes, with the greatest risk among the triglyceride-rich cluster (HRadj, 3.78 [95% CI, 3.29-4.35]). CONCLUSIONS:Unsupervised learning analyses demonstrated associations that may be useful when refining cardiovascular risk and may inform atherosclerosis development in healthy individuals better than traditional classification methods. REGISTRATION:URL: https://clinicaltrials.gov; Unique identifier: NCT00000479.

BACKGROUND:It remains unclear whether supplementation with vitamin D reduces risk of acute exacerbations of chronic obstructive lung disease (COPD) or asthma, major contributors to the world-wide burden of disease. OBJECTIVES:To compare effects of vitamin D with placebo supplementation for the prespecified primary endpoints 1) acute exacerbations of COPD and 2) decline in pulmonary function measures of airflow obstruction. Prespecified secondary endpoints included asthma exacerbations and control. METHODS:Lung VITamin D and OmegA-3 TriaL (VITAL) is an ancillary study of VITAL, a United States nationwide, randomized, placebo-controlled trial with a 2-by-2 factorial design of vitamin D3 (2000 IU/d) and marine n-3 fatty acids (1 g/d) among men 50 y and women 55 y of age or older. Of 25,871 randomly divided participants, 3632 at risk for respiratory exacerbations, including 1977 with COPD by diagnosis or symptoms and 1654 with self-reported asthma diagnosis, were followed annually for 5 y by self-administered respiratory questionnaire. Spirometry was performed at baseline and 2 y after randomization by 1648 participants from 12 urban centers. Decline in forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity was measured between baseline and follow-up. RESULTS:Supplementation with vitamin D was not associated with lower risk of any primary or secondary end point. Over the 5-y follow-up, the number of COPD exacerbations was 0.27/y in the vitamin D group and 0.25/y in the placebo group (rate ratio 1.10; 95% confidence interval, 0.93, 1.29). Over the 2-y follow-up, supplementation was not associated with slower decline (mL/y) in FEV1. CONCLUSIONS:Supplementation with vitamin D, compared with placebo, did not result in a lower rate of COPD exacerbations or improved pulmonary function in community-dwelling adults not selected for vitamin D deficiency. This trial was registered at Lung VITAL clinicaltrials.gov as NCT01728571 with Protocol ID 2010-P-000622 (https://prevention.cancer.gov/clinical-trials/clinical-trials-search/nct01728571).