Using Mendelian randomization provides genetic insights into potential targets for sepsis treatment

Abstract

Sepsis is recognized as a major contributor to the global disease burden, but there is a lack of specific and effective therapeutic agents. Utilizing Mendelian randomization (MR) methods alongside evidence of causal genetics presents a chance to discover novel targets for therapeutic intervention. MR approach was employed to investigate potential drug targets for sepsis. Pooled statistics from IEU-B-4980 comprising 11,643 cases and 474,841 controls were initially utilized, and the findings were subsequently replicated in the IEU-B-69 (10,154 cases and 454,764 controls). Causal associations were then validated through colocalization. Furthermore, a range of sensitivity analyses, including MR-Egger intercept tests and Cochran's Q tests, were conducted to evaluate the outcomes of the MR analyses. Three drug targets (PSMA4, IFNAR2, and LY9) exhibited noteworthy MR outcomes in two separate datasets. Notably, PSMA4 demonstrated not only an elevated susceptibility to sepsis (OR 1.32, 95% CI 1.20-1.45, p = 1.66E-08) but also exhibited a robust colocalization with sepsis (PPH4 = 0.74). According to the present MR analysis, PSMA4 emerges as a highly encouraging pharmaceutical target for addressing sepsis. Suppression of PSMA4 could potentially decrease the likelihood of sepsis.

Keywords: Drug target prediction; Mendelian randomization; Sepsis.

Figure 1

Overview of the study design in our Mendelian randomization study.

Figure 2

Regional Manhattan plot of associations of SNPs with PSMA4 locus. (a) In the IEU-B-4980 dataset rs9788721 was used to represent serum PSMA4 expression. (b) In the IEU-B-4980 dataset rs28669908 and its flanking 400 kb region to either side in sepsis. (c) In the IEU-B-69 dataset rs9788721 was used to proxy serum PSMA4 expression. (d) In the IEU-B-69 dataset rs55781567 and its flanking 400 kb region to either side in aortic aneurysm.