# Association of Modifiable Lifestyle and Metabolic Factors With the Risk of Developing Sepsis: 2-Sample Mendelian Randomized Study

## TL;DR

This study finds that lifestyle and metabolic factors like smoking, physical activity, and waist circumference are linked to sepsis risk, suggesting potential targets for prevention.

## Contribution

The study uses Mendelian randomization to establish causal links between modifiable lifestyle and metabolic factors and sepsis risk.

## Key findings

- Genetically predicted smoking and higher cigarette consumption increase sepsis risk.
- Higher education and light physical activity are protective against sepsis.
- Waist circumference remains an independent risk factor for sepsis after adjusting for obesity.

## Abstract

Sepsis is a life-threatening condition characterized by organ dysfunction resulting from dysregulated host response to infections. Approximately 48.9 million people worldwide are diagnosed with sepsis annually, leading to 11 million deaths and representing 19.7% of all global deaths. No specific, effective treatments for sepsis, which has a poor prognosis, are available.

The study aimed to systematically explore the association between genetically predicted modifiable risk factors and sepsis.

Univariable 2-sample Mendelian randomization (MR) analysis was performed to explore the association between 30 modifiable risk factors (12 lifestyle, 3 educational and psychological, and 15 metabolic factors) and sepsis. Heterogeneity was evaluated using the Cochran Q analysis. Sensitivity analyses were conducted using the MR-Egger regression intercept tests and leave-one-out analyses. Additionally, multivariable MR analyses were performed to adjust for genetic associations between the instruments and obesity.

Genetically predicted smoking (odds ratio [OR] 1.20, 95% CI 1.06‐1.36; P=.005), a higher number of cigarettes smoked daily (OR 1.70, 95% CI 1.29‐2.23; P<.001), a higher overall health rating (OR 2.19, 95% CI 1.61‐2.98; P<.001), BMI (OR 1.50, 95% CI 1.38‐1.63; P<.001), waist circumference (OR 1.70, 95% CI 1.53‐1.89; P<.001), whole body fat mass (OR 1.50, 95% CI 1.37‐1.64; P<.001), trunk fat mass (OR 1.48, 95% CI 1.36‐1.62; P<.001), arm fat mass (OR 1.57, 95% CI 1.43‐1.71; P<.001), and leg fat mass (OR 1.69, 95% CI 1.51‐1.90; P<.001) were associated with increased sepsis risk. However, light physical activity (OR 0.26, 95% CI 0.08‐0.83; P=.03), higher education attainment (OR 0.52, 95% CI 0.40‐0.67; P<.001), and high-density lipoprotein cholesterol (OR 0.91, 95% CI 0.84‐0.98; P=.02) exhibited protective effects against sepsis. Using a multivariate analysis of obesity traits, the waist circumference (OR 2.16, 95% CI 1.18‐3.96; P=.01) was an independent risk factor of sepsis.

Our study demonstrated that genetic predictors of lifestyle (smoking and physical activity), educational level, and metabolic factors (waist circumference and high-density lipoprotein cholesterol) exhibited a causal association with sepsis risk. Future research should further investigate the underlying mechanisms of these associations to inform more effective preventive strategies against sepsis.