Large-scale proteomics identified plasma proteins linking adverse social determinants of health to heart failure risk, with Mendelian randomization and colocalization suggesting a potentially causal effect of C1QTNF1 on heart failure.
Key Findings
Methods
An SDOH factor comprising income, education, and area deprivation index was derived and associated with plasma protein levels in both Black and white ARIC participants.
9,879 community-based participants from the Atherosclerosis Risk in Communities (ARIC) cohort study were included.
4,955 plasma proteins were measured using an aptamer-based platform (SomaLogic).
The SDOH factor incorporated income, education, and area deprivation index (ADI).
Both Black and white participants were analyzed in separate race strata.
Results
Among Black participants, 36 proteins were associated with both the SDOH factor and incident heart failure at Bonferroni significance.
Proteins associated with the SDOH factor at Bonferroni significance were tested for associations with incident HF using multivariable Cox proportional hazard models.
36 proteins were identified in Black participants as associated with both SDOH burden and incident HF.
A subset of these were among the 12 proteins shared between race strata.
Results
Among white participants, 126 proteins were associated with both the SDOH factor and incident heart failure.
126 proteins reached significance in white participants for association with both the SDOH factor and incident HF.
This was substantially more than the 36 proteins identified in Black participants.
12 proteins were shared between the Black and white race strata.
Multivariable Cox proportional hazard models were used to assess associations with incident HF.
Results
Eight proteins demonstrated significant mediation effects in causal mediation models, suggesting they partially mediate the relationship between adverse SDOH and heart failure risk.
Causal mediation models were applied to proteins associated with both SDOH and incident HF.
Eight proteins showed a significant mediation effect, meaning part of the SDOH-HF association was statistically explained through these proteins.
This analysis spans across both Black and white participant strata.
Results
Key results were replicated in the UK Biobank cohort of 49,396 participants.
The UK Biobank replication sample comprised 49,396 participants.
This replication provided external validation of the protein-SDOH and protein-HF associations identified in ARIC.
The UK Biobank represents a distinct, larger population from the ARIC cohort.
Results
Mendelian randomization and colocalization analyses suggested a potentially causal effect of C1QTNF1 on heart failure.
C1q tumor necrosis factor-related protein 1 (C1QTNF1) was identified as a key candidate through Mendelian randomization.
C1QTNF1 is described as an adiponectin paralog.
Colocalization analyses corroborated the Mendelian randomization findings, supporting a potentially causal relationship between C1QTNF1 and HF.
These genetic analyses were used to help establish potential causality beyond observational association.
Background
Adverse social determinants of health associate with greater heart failure risk, motivating the investigation of biological pathways linking SDOH to HF.
The study was designed to identify protein biomarkers that may mechanistically link social disadvantage to elevated heart failure risk.
The SDOH factor integrated income, education, and area deprivation index as measures of social disadvantage.
The study sought to move beyond epidemiological association to identify potential biological intermediaries.
What This Means
This research suggests that social and economic disadvantages — such as lower income, less education, and living in more deprived areas — are linked not only to a higher risk of heart failure, but also to measurable differences in hundreds of proteins circulating in the blood. By analyzing blood samples from nearly 10,000 Americans and then replicating findings in nearly 50,000 people in the UK, the researchers identified specific proteins that appear to sit on the biological pathway connecting social hardship to heart disease. Eight of these proteins appeared to partially 'carry' the increased risk from social disadvantage to heart failure, acting as possible biological messengers.
One protein stood out in particular: C1QTNF1, a relative of the hormone adiponectin, which is involved in metabolism and inflammation. Using a genetic technique called Mendelian randomization — which can suggest causation rather than just correlation — the researchers found evidence that this protein may actually cause higher heart failure risk, not just be associated with it. This is notable because it points to a specific biological target that could potentially be studied further in the context of both social disadvantage and heart disease.
This research matters because it begins to map out the biological 'how' behind a well-known but poorly understood problem: why do people facing social and economic hardship have worse heart health? By identifying specific proteins involved in this process, the findings could eventually help researchers develop ways to measure heart failure risk more precisely in disadvantaged populations, or identify new targets for treatment or prevention strategies aimed at reducing health inequalities.
Ramonfaur D, Zierath R, Yang Y, Lamberson V, Claggett B, Powell-Wiley T, et al.. (2026). Large-scale proteomics to identify novel biomarkers linking social determinants of health to heart failure risk.. Science advances. https://doi.org/10.1126/sciadv.aec5063