The causal association between 91 inflammatory Circulating proteins and intracerebral hemorrhage: A bidirectional two-sample Mendelian randomization study

Abstract

Background: Intracerebral hemorrhage (ICH), a subtype of stroke, is associated with high incidence and disability rates. The link between inflammatory circulating proteins and ICH is still not definitively established. Our research sets out to delve into this mystery by examining the potential causal connection between 91 such proteins and ICH, employing a sophisticated two-sample Mendelian randomization approach to get to the bottom of it.

Methods: We obtained 91 SNPs associated with inflammatory circulating proteins from a genome-wide association study (GWAS). Two-sample and multivariable Mendelian randomization analyses were conducted, with inverse variance weighted (IVW) serving as the primary method to assess the relationship between exposure and outcome. To enhance the reliability of the findings, additional methods such as MR-Egger, weighted median, simple mode, and weighted mode were employed. Cochran's Q test was used to assess the heterogeneity of the SNPs, while MR-Egger regression and MR-PRESSO were applied to evaluate the directional pleiotropy of the instrumental variables.

Results: Univariate Mendelian randomization analysis identified a significant causal relationship between four inflammatory circulating proteins, Axin1 (odds ratio (OR): 0.77, 95% confidence intervals (CI): 0.61-0.96, P-value = 0.0239), CXCL1 (OR: 0.81, 95% CI: 0.68-0.96, P-value = 0.0190), CXCL9 (OR: 0.85, 95% CI: 0.74-0.98, P-value = 0.0256), and MCP4 (OR: 0.79, 95% CI: 0.69-0.90, P = 0.0007), and the risk of ICH. After adjusting for confounding factors such as body weight and alcohol consumption, multivariable Mendelian randomization analysis still demonstrated a significant causal relationship between these four proteins and ICH. Furthermore, after excluding hypertension as a confounder, MCP4 expression remained significantly associated with ICH. When adjusting for type 2 diabetes, both CXCL9 and MCP4 exhibited a significant causal relationship with ICH. Reverse Mendelian randomization analysis revealed a negative correlation between ICH (as the exposure) and the expression of seven inflammatory circulating proteins.

Conclusion: In summary, our two-sample Mendelian randomization analysis, which operates in both directions, has revealed a likely causal link between four inflammatory proteins present in circulation and the risk of ICH. Keeping track of the expression levels of these inflammatory proteins may prove beneficial for both the prevention and management of ICH.

Highlight: There is a significant bidirectional causal relationship between inflammatory circulating proteins and the risk of intracerebral hemorrhage (ICH) onset. The expression levels of Axin1, CXCL1, CXCL9, and MCP4 are negatively correlated with the risk of ICH onset, suggesting that they may serve as potential important molecular targets for ICH.

Keywords: Bidirectional analysis; GWAS; Inflammatory circulating proteins; Intracerebral hemorrhage; Mendelian randomization; Neurovascular biomarkers.