# Examining socioeconomic differences in sepsis risk and mediation by modifiable factors: a Mendelian randomization study

## TL;DR

Higher education is linked to lower sepsis risk, and this is partly explained by modifiable factors like smoking and diabetes.

## Contribution

This is the first Mendelian randomization study using within-family genetic instruments to explore how education affects sepsis risk and how modifiable factors mediate this relationship.

## Key findings

- Each standard deviation increase in educational attainment reduces sepsis risk by 28%.
- Modifiable factors like smoking and type 2 diabetes explain 56% of the effect of education on sepsis risk.
- Results were consistent across multiple sensitivity analyses, including within-sibship comparisons.

## Abstract

Educational attainment is inversely related to sepsis risk, but the causal nature is still unclear. We therefore conducted the first Mendelian randomization (MR) study of genetically predicted educational attainment on sepsis that also uses a within-family genetic instrument for education. To further explore possible mechanistic pathways that can inform strategies to reduce sepsis risk, we examined the mediating effects of factors that are modifiable or can be prevented.

The association between genetically predicted educational attainment and sepsis was estimated using summary-level data from recent genome-wide association studies. Possible bias due to population stratification, dynastic effects, and assortative mating in the genetic instrument for education was evaluated using summary-level data from a within-sibship genome-wide association study. We used inverse variance weighted MR analysis to estimate the effect of one standard deviation increase in years of education on sepsis risk. The robustness of the findings was assessed in sensitivity analyses, applying weighted median, weighted mode, and MR Egger regression. Finally, we applied multivariable MR analyses to estimate the mediating effects of smoking initiation, alcohol consumption, body mass index, high-density lipoprotein (HDL)-cholesterol, systolic blood pressure and type 2 diabetes.

For each standard deviation increase in genetically predicted educational attainment (3.4 years), the odds ratio (OR) for sepsis was 0.72 (95% confidence interval (CI) 0.66 to 0.78). The results of the analysis using the within-sibship genetic instrument and other sensitivity analyses were in line with this finding: within-sibship OR 0.88 (95% CI 0.64 to 1.18), weighted median OR 0.70 (95% CI 0.62 to 0.80), weighted mode OR 0.70 (95% CI 0.43 to 1.13), and MR Egger OR 0.65 (95% CI 0.50 to 0.85). The mediation analysis showed that 56% of the effect of educational attainment on sepsis risk can be explained by modifiable or preventable factors.

Higher educational attainment is strongly associated with a reduced risk of sepsis, pointing to important socioeconomic differences in this disease. The results also suggest that interventions targeting modifiable or preventable factors could contribute to reducing the socioeconomic differences in sepsis risk.

The online version contains supplementary material available at 10.1186/s12879-025-11130-y.