Meir J. Stampfer

Identification of prediagnostic proteomic biomarkers for colon and rectal cancer in 3 prospective cohorts

BACKGROUND: Large-scale proteomics may reveal circulating biomarkers of colorectal cancer (CRC) years before diagnosis, yet cross-cohort reproducibility and anatomic site-specificity remain unclear. METHODS: We conducted nested case-control studies in three prospective cohorts with banked blood and cancer follow-up (median 7 years), totaling 851 incident CRC cases matched 1:1 to controls, with 1,801 pre-diagnostic plasma proteins from Olink panels. RESULTS: Twelve proteins showed significant paired differences between CRC cases and controls (FDR <0.1), with modest effect sizes. These included previously implicated CRC-biomarkers (e.g., higher GDF15 and TFF2) as well as less established associations (e.g., lower LEPR and BCAN). Paired protein differences are significantly distinct in colon vs. rectal cancer pairs (P = 0.005), driven by genes enriched in leukocyte activation, cell activation, and extracellular components. In stratified analysis, for colon cancer, 11 out of 12 proteins were lower in cases (FDR <0.1), including BCAN with 0.83 (0.74-0.94) odds ratio (OR, with 95% CI) per 1-unit increase in quantile-normalized NPX level, with cross-cohort consistency (I2 <0.01). For rectal cancer, 25 out of 28 proteins were higher in cases, including HDGF (OR 1.75 [1.15-2.66], I2 <0.01). HDGF could partially mediate BMI-rectal cancer risk (25.0%, FDR=0.044). Overall, we found that pre-diagnostic plasma proteomics identified proteins and pathways with modest effect sizes and clear differences between future risk of colon and rectal cancer. CONCLUSION: These findings provide insight for future mechanistic validation of pre-diagnostic plasma proteins as CRC biomarkers and motivate site-specific biomarker discovery that distinguishes colon from rectal cancer.

Gut microbiome maturation in early childhood interacts with host genetics to predict type 1 diabetes risk

Prospective evidence linking early-life microbiome development and host genetics with type 1 diabetes (T1D) risk is limited. Here, we describe how gut microbiome maturation and host genetics influence T1D risk in the TEDDY study. We analysed 12,151 longitudinal metagenomes and host genetic data from 887 children at high genetic risk for T1D followed for up to 6 years. We identify three microbiome maturational patterns: Early Matured, Late Matured and Early Plateaued, driven primarily by non-linear changes in species from the Bifidobacterium and Ruminococcus genera. The Early Matured pattern is enriched in galactose metabolism and exhibits higher production of aromatic amino acids and B-group vitamins at early follow-ups, whereas the Early Plateaued pattern has increased microbial production of branched-chain amino acids. Notably, the Early Plateaued pattern is associated with a threefold elevated risk of T1D, whereas other patterns are not associated with T1D risk. Furthermore, we find that host genetic variants related to antimicrobial and antiviral immune responses modify the association between the Late Matured pattern and T1D risk. These findings highlight the role of early microbial exposures and host genetics in T1D susceptibility.

Processed meat, unprocessed red meat, poultry, seafood, and egg intake and stomach cancer risk: a pooled analysis of 20 cohorts

BACKGROUND: Processed meat is classified as a carcinogen and unprocessed red meat a probable carcinogen, but their associations with stomach cancer are not established. We evaluated intakes of these food groups and poultry, seafood, and eggs in relation to stomach cancer risk. METHODS: Individual-level data for 1 100 370 females and 891 919 males from 20 cohorts were analysed. Diet was assessed at baseline by using food-frequency questionnaires or diet histories generally covering the past year and harmonized across studies. We used Cox regression to estimate multivariable-adjusted study- and sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with each food group and combined study-specific estimates by using random-effects meta-analysis. We repeated analyses using an aggregated dataset combining all studies. RESULTS: During follow-up (mean = 8-23 years across studies), 8561 invasive gastric adenocarcinomas were diagnosed. Processed meat intake showed weak evidence of an overall association with stomach cancer risk (HR, 1.15 for ≥45 vs <3 g/day; 95% CI, 1.00-1.32 and HR, 1.03 per 25-g/day increment; 95% CI, 0.99-1.07). This association was limited to current smokers (Pinteraction = .01) and differed by geographic region, with evidence for an association in Australian and European studies and no association observed in Asian studies (Pinteraction = .02). Positive associations with stomach cancer were observed for egg intake; no association was found for unprocessed red meat, poultry, or seafood. CONCLUSION: Higher processed meat intake was associated with a modestly increased risk of stomach cancer among current smokers, although residual confounding by smoking dose remains possible. Findings for eggs warrant further investigation.

Oral Health and Risk of Liver Cancer: Evidence from Pooled and Meta-Analyses

Association of long-term physical activity levels with dementia risk and cognitive function in US adults: a prospective cohort study

BACKGROUND: Previous cohort studies of physical activity and cognitive health have often been limited by small sample sizes, short follow-up durations, absence of long-term assessments of physical activity, and potential reverse causation. We aimed to prospectively examine the associations between long-term physical activity and multiple cognitive outcomes. METHODS: In this study, we used data from two ongoing US prospective cohorts: the Nurses' Health Study (established in 1976, comprising 121 700 female registered nurses aged 30-55 years at enrolment) and the Health Professionals Follow-Up Study (HPFS; established in 1986, comprising 51 492 male health professionals aged 40-75 years at enrolment). Discretionary physical activity was assessed approximately every 2-4 years using self-report questionnaires, beginning in 1986 for both cohorts. Total physical activity, walking, and vigorous aerobic exercise were each expressed as the summed metabolic equivalent of task hours per week. We ascertained incident dementia cases (a composite endpoint of self-reported physician-diagnosed dementia and deaths due to dementia) in eligible Nurses' Health Study participants (1990-2023) and HPFS participants (1990-2023); deaths due to dementia were confirmed using medical records, death certificates, and autopsy reports. Objective cognitive function was assessed in Nurses' Health Study participants only (1995-2008) using the Telephone Interview for Cognitive Status (TICS). Subjective cognitive decline was self-reported by Nurses' Health Study participants (followed up in 2012 and 2014) and HPFS participants (followed up in 2008, 2012, 2016, 2018, and 2020) via questionnaires with binary questions that assessed subjective cognitive concerns across multiple domains. Participants were excluded from the analysis if they had dementia, stroke, cancer, were missing total physical activity or walking data, or reported difficulties with walking at baseline. Outcomes were analysed using multivariable-adjusted regression models. We used a 4-year lag approach in our main analyses to minimise the potential for reverse causation. FINDINGS: Our final samples comprised 63 596 Nurses' Health Study participants and 43 440 HPFS participants for the dementia endpoints, 13 647 Nurses' Health Study participants for assessing objective cognitive function, and 29 801 Nurses' Health Study participants and 17 162 HPFS participants for assessing subjective cognitive decline. Compared with participants in the lowest quartile for total physical activity, those in the highest quartile had a lower risk of dementia (hazard ratio [HR] 0·72, 95% CI 0·68-0·76; p<0·0001 for trend) and subjective cognitive decline (relative risk [RR] 0·77, 95% CI 0·73-0·80; p<0·0001 for trend). Being in the highest versus the lowest tertile for walking or vigorous aerobic exercise was also associated with lower risk for dementia (HR 0·76, 95% CI 0·72-0·80 for walking and 0·89, 0·85-0·93 for vigorous aerobic exercise; p<0·0001 for trend for both activities) and subjective cognitive decline (RR 0·82, 95% CI 0·79-0·86 for walking and 0·89, 0·86-0·93 for vigorous aerobic exercise; p<0·0001 for trend for both activities). Additionally, being in the highest quartile of total physical activity versus the lowest quartile was associated with fewer years of age-related cognitive differences in global cognition (mean difference -1·15, 95% CI -1·69 to -0·60; p<0·0001 for trend), verbal memory (-1·27, -1·86 to -0·68; p<0·0001 for trend), and TICS score (-0·79, -1·36 to -0·23; p=0·016 for trend). Similar decreases were observed for vigorous aerobic exercise but not for walking. INTERPRETATION: Higher levels of physical activity were associated with a lower risk of dementia and better cognitive performance. These findings support physical activity as a potential strategy to promote long-term cognitive health.

Estimated preventable fraction of chronic disease attributed to long-term physical activity and diet quality, independent of body weight: a prospective cohort study of three US cohorts

Background: Body mass index (BMI) is often treated as a proxy for lifestyle, but this may discourage people with higher BMI from adopting risk-reducing behaviors and lead those with lower BMI-including individuals achieving weight reduction through pharmacotherapy-to overlook the value of lifestyle. We aimed to estimate incidence of chronic disease preventable through physical activity and diet quality, independent of BMI. Methods: We followed 142,041 adults (80% [113,727] female, mean baseline age 50 years, 96% [136,998] non-Hispanic White) from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study. Physical activity was assessed as metabolic equivalent of task (MET) hours per week, and diet quality as modified Alternative Healthy Eating Index. Chronic disease included type 2 diabetes, major atherosclerotic cardiovascular disease, and cancer. Regression models adjusted for BMI at multiple life stages allowed estimation of effects for sustained adulthood habits and midlife changes, independent of prior BMI and lifestyle. Findings: Participants in the highest deciles of physical activity and diet quality had 46% (95% confidence interval [CI], 40-52%) lower risk of chronic disease for sustained habits and 34% (95% CI, 26-41%) for midlife changes. Results were similar among women (44% lower risk [95% CI, 35-51%] sustained habits, 32% [95% CI, 20-41%] midlife changes) and men (54% lower risk [95% CI, 41-64%] sustained habits, 48% [95% CI, 33-60%] midlife changes). The proportion of cases potentially preventable was 34% (95% CI, 27-41%), or 1.1 million cases annually (95% CI, 906,000-1,376,000), for sustained habits and 26% (95% CI, 18-34%), or 873,000 cases annually (95% CI, 604,000-1,141,000), for midlife changes. Interpretation: Higher physical activity and diet quality were associated with substantially reduced chronic disease risk regardless of BMI. These findings support public health strategies that promote healthy behaviors independent of body weight.

Higher olive oil intake is linked to ~19% lower all-cause mortality compared to rare consumption.

GazianoJournal of the American College of Cardiology

Light-to-moderate alcohol intake is linked to up to ~26% lower all-cause mortality.

Higher alcohol intake linked to ~52% lower CHD risk in men with type 2 diabetes.

Multi-fluid, multi-omics signatures of insulin resistance and incident type 2 diabetes among Puerto Rican adults

Serum Galectin-9 and Decorin in relation to brain aging and the green-Mediterranean diet: A secondary analysis of the DIRECT PLUS randomized trial

BACKGROUND AND AIMS: We explored whether changes in serum proteomic profiles differed between participants with distinct brain aging trajectories, and whether these changes were influenced by dietary intervention. METHODS: In this secondary analysis of the 18-month DIRECT PLUS trial, 294 participants were randomized to one of three arms: 1) Healthy dietary guidelines (HDG); 2) Mediterranean (MED) diet (+440 mg/day polyphenols from walnuts); or 3) low red/processed meat green-MED diet (+1240 mg/day polyphenols from walnuts, Mankai plant, and green tea). We measured 87 serum proteins (Olink-CVDII). We used Magnetic-Resonance-Imaging (MRI)-assessed 3D-T1-weighted brain scans for brain age calculation (by convolutional neural network) to identify protein markers reflecting the brain age gap (BAG; deviation of MRI-assessed brain age from chronological age). RESULTS: At baseline, lower weight, waist circumference, diastolic blood pressure, and HbA1c parameters were associated with a younger brain age than expected. Specifically, higher levels of two proteins, Galectin-9 (Gal-9) and Decorin (DCN), were associated with accelerated brain aging (larger BAG). A proteomics principal component analysis (PCA) revealed a difference in PC1 between the two time-points for participants with accelerated brain aging. Between baseline and 18 months, Gal-9 significantly decreased among individuals who completed the intervention with attenuated brain aging, while DCN significantly increased among those who completed the trial with accelerated brain aging. A significant interaction was observed between the green-MED diet and proteomics PCA, resulting in a beneficial change compared to the HDG. Participants in the green-MED diet significantly decreased Gal-9 compared to the HDG diet and from baseline. CONCLUSIONS: Higher serum levels of Gal-9 and DCN may indicate an acceleration of brain aging and could be reduced by a green-MED/high-polyphenol (green tea and Mankai) and low-red/processed meat diet. TRIAL REGISTRATION NUMBER: NCT03020186.

Lifestyle interventions improve cardiometabolic markers in weight-loss-resistant patients, boosting HDLc ~1% per kg lost.

Leisure-time physical activity after diagnosis and survival by cancer type: a pooled analysis

BACKGROUND: Evidence for potential mortality benefits of leisure-time moderate-to-vigorous intensity physical activity (MVPA) for survivors of cancer types beyond breast and colorectal is limited. The aim of this study was to evaluate relationships between postdiagnosis MVPA and all-cause mortality in participants with a history of 11 cancer types. METHODS: Data were pooled from 6 United States-based cohort studies. Cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of MVPA assessed ≥1 year after a cancer diagnosis and all-cause mortality were calculated using multivariable Cox proportional hazards models and then pooled using random effects meta-analysis. Models were adjusted for age, sex, race/ethnicity, smoking status, alcohol use, and cancer treatment and stage. The sample included 90 844 cancer survivors (mean [standard deviation] age at diagnosis = 67 [10] years, 55% women), among whom 45 477 died during 10.9 [7.0] years of follow-up. RESULTS: Compared with no MVPA, engaging in recommended amounts of MVPA (7.5 to <15 MET-hr/wk) was related to better overall survival in participants with a history of 1 of 10 cancer types: oral (HR = 0.44, 95% CI = 0.27 to 0.73), endometrial (0.50, 95% CI = 0.34 to 0.76), lung (0.51, 95% CI = 0.38 to 0.68), rectal (0.51, 95% CI = 0.36 to 0.71), respiratory (0.51, 95% CI = 0.29 to 0.72), bladder (0.53, 95% CI = 0.40 to 0.72), kidney (0.53, 95% CI = 0.37 to 0.77), prostate (0.60,95% CI = 0.49 to 0.74), colon (0.61, 95% CI = 0.50 to 0.76), and breast (0.67, 95% CI = 0.55 to 0.81). Eight of the 10 observed inverse associations remained similar when excluding participants who died within 2 years of follow-up. CONCLUSION: Engaging in leisure-time MVPA after a cancer diagnosis appears to improve survival for people with a history of several cancer types, including bladder, breast, colon, endometrial, kidney, lung, oral, prostate, rectal, and respiratory cancer.

Long-Term Intake of Red Meat in Relation to Dementia Risk and Cognitive Function in US Adults

Higher intake of red meat, particularly processed red meat, was associated with a higher risk of developing dementia and worse cognition. Reducing red meat consumption could be included in dietary guidelines to promote cognitive health. Further research is needed to assess the generalizability of these findings to populations with diverse ethnic backgrounds.

Cross omics risk scores of inflammation markers are associated with all-cause mortality: The Canadian Longitudinal Study on Aging

Inflammation is a critical component of chronic diseases, aging progression, and lifespan. Omics signatures may characterize inflammation status beyond blood biomarkers. We leveraged genetics (Polygenic-Risk-Score; PRS), metabolomics (Metabolomic-Risk-Score; MRS), and epigenetics (Epigenetic-Risk-Score; ERS) to build multi-omics-multi-marker risk scores for inflammation status represented by the level of circulating C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor alpha (TNFa). We found that multi-omics risk-scores generally outperformed single-omics risk scores in prediction of all-cause mortality in the Canadian Longitudinal Study on Aging. Compared with circulating inflammation biomarkers, some multi-omics risk scores had a higher HR for all cause-mortality when including both score and circulating IL6 in the same model (1-SD IL6 MRS-ERS: HR=1.77 [1.15-2.72] vs. 1-SD circulating IL6 HR=1.11 [0.75,1.66]; 1-SD IL6 PRS-MRS: HR=1.32 [1.21,1.45] vs. 1-SD circulating IL6 HR=1.31 [1.12, 1.53]; 1-SD PRS-MRS-ERS: HR=1.62 [1.04, 2.53] vs. 1-SD circulating IL6: HR=1.16 [0.77, 1.74]). In the Nurses’ Health Study (NHS), NHS II, and Health Professional Follow-up Study with available omics, 1-SD of IL6 PRS and 1-SD IL6 PRS-MRS had HR=1.13 [1.00,1.27] and HR=1.13 [1.01,1.27], among individuals >65years without mutual adjustment of the score and circulating IL6. Our study demonstrated that some multi-omics scores for inflammation markers may characterize important inflammation burden for an individual beyond those represented by blood biomarkers and improve our prediction capability for aging process and lifespan.

Data from Sex-specific associations between adiponectin and leptin signaling and pancreatic cancer survival

Abstract Background: Circulating adiponectin and leptin have been associated with risk of pancreatic cancer. However, the relationship between long-term exposure to these adipokines in the prediagnostic period with patient survival has not been investigated. Methods: Adipokine levels were measured in prospectively collected samples from 472 pancreatic cancer patients. Due to sex-specific differences in adipokine levels, associations were evaluated separately for men and women. In a subset of 415 patients, we genotyped 23 nucleotide polymorphisms (SNPs) in adiponectin receptor genes (ADIPOR1, ADIPOR2) and 30 SNPs in the leptin receptor gene (LEPR). Results: Adiponectin levels were inversely associated with survival in women (HR=1.47, 95% CI: 1.03-2.11, comparing top to bottom quartile) but not in men (HR=0.93, 95% CI: 0.54-1.59). The SNPs rs10753929 and rs1418445 in ADIPOR1 were associated with survival in the combined population (per minor allele HR=0.66, 95% CI: 0.51-0.84, and HR=1.33, 95% CI: 1.12-1.58, respectively). Among SNPs in LEPR, rs12025906, rs3790431, and rs17127601 were associated with survival in the combined population [HRs (95% CI) of 1.54 (1.25-1.90), 0.72 (0.59-0.88), and 0.70 (0.56-0.89), respectively], while rs11585329 was associated with survival in men only (HR=0.39, 95% CI: 0.23-0.66) (P-interaction=0.0002). Conclusions: High levels of adiponectin in the prediagnostic period were associated with shorter survival among women, but not among men with pancreatic cancer. Several polymorphisms in ADIPOR1 and LEPR are associated with patient survival. Impact: Our findings reveal the association between adipokine signaling and pancreatic cancer survival and demonstrate the importance of examining obesity-associated pathways in relation to pancreatic cancer in a sex-specific manner.

Supplementary Figure S2 from Sex-specific associations between adiponectin and leptin signaling and pancreatic cancer survival

Association between adiponectin levels and pancreatic cancer mortality using spline regression.

Supplementary Figure S1 from Sex-specific associations between adiponectin and leptin signaling and pancreatic cancer survival

Association between leptin levels and pancreatic cancer mortality using spline regression.

Supplementary Figure S2 from Sex-specific associations between adiponectin and leptin signaling and pancreatic cancer survival

Association between adiponectin levels and pancreatic cancer mortality using spline regression.

Supplementary Figure S1 from Sex-specific associations between adiponectin and leptin signaling and pancreatic cancer survival

Association between leptin levels and pancreatic cancer mortality using spline regression.