Domain

Blood Levels

Circulating blood markers — cholesterol, inflammation, glycaemic and omega-3 status — most of which show non-linear or debated causal relationships with mortality.

LDL cholesterolOmega-3 IndexHbA1cC-reactive protein (CRP)
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4 results

Association of low-density lipoprotein cholesterol levels with the risk of mortality and cardiovascular events: A meta-analysis of cohort studies with 1,232,694 participants

Moderate
LDL cholesterolLarge cohort (100k+)Meta-analysisObservational evidence
Meta-analysis
LDL-C ≥160 mg/dL associated with higher all-cause mortality (RR 1.34, 95% CI 1.00–1.80) and CVD death (RR 1.79, 95% CI 1.26–2.54) vs LDL-C 70–129 mg/dL, in a meta-analysis of 1,232,694 adults
Causal status: Causal support strong for CVD via Mendelian randomization and RCTs; all-cause mortality signal weaker/borderline
Reliability / bias notes: All-cause mortality CI crosses 1.0; relationship appears non-linear/U-shaped, complicated by reverse causation in low-LDL groups (illness-driven cholesterol decline)
Peng et al · Medicine · 2022 · PMID 36482567
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Erythrocyte long-chain omega-3 fatty acid levels are inversely associated with mortality and with incident cardiovascular disease: The Framingham Heart Study

Moderate
Omega-3 IndexObservational evidence
Observational study
Highest vs lowest Omega-3 Index quintile associated with 34% lower risk of death from any cause in the Framingham Offspring Cohort (n=2500, median 7.3-year follow-up)
Causal status: Associational; biologically plausible anti-inflammatory/anti-arrhythmic mechanism, but single cohort, not RCT-confirmed for mortality
Reliability / bias notes: Relatively short follow-up and single baseline measurement; modest sample size and event count (350 deaths)
Harris et al · J Clin Lipidol · 2018 · PMID 29559306
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C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis

Strong
C-reactive protein (CRP)Confounding riskMeta-analysisObservational evidence
Meta-analysis
Each 3-fold (1-SD) higher log-CRP associated with 1.55x non-vascular mortality (95% CI 1.41–1.69) and similar magnitude for vascular mortality, in an individual-participant meta-analysis of 160,309 people across 54 studies
Causal status: Causal role debated; CRP likely partly a marker of underlying inflammation/disease rather than a direct cause
Reliability / bias notes: Association attenuates but persists after adjusting for conventional risk factors and fibrinogen; residual confounding by subclinical illness possible
Emerging Risk Factors Collaboration (Kaptoge et al) · Lancet · 2010 · PMID 20031199
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Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults

Strong
HbA1cObservational evidenceReverse causation risk
Observational study
In nondiabetic adults, glycated hemoglobin showed a J-shaped association with death from any cause, remaining significant after adjustment for fasting glucose, in the ARIC cohort (n=11,092)
Causal status: Causal support strong for diabetes/CVD risk; all-cause mortality relationship J-shaped, so causal direction less clear at low HbA1c
Reliability / bias notes: J-shaped curve means very low HbA1c also carries excess mortality risk, likely reflecting reverse causation/frailty; overlaps with the separate diagnosed-diabetes question, so effects are kept modest to avoid double-counting the same underlying condition
Selvin et al · N Engl J Med · 2010 · PMID 20200384
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