Plasma proteomic biomarkers of aplastic anemia: a study based on genome-wide association studies data

Abstract

This study aims to explore the association between 4907 plasma proteins and genetic susceptibility to aplastic anemia (AA). Genetic associations with levels of 4907 plasma proteins were extracted from a large-scale protein quantitative trait loci study involving 35,559 Icelanders, with data sourced from deCODE GENETICS. Additionally, an aplastic anemia-related genome-wide association study (GWAS) dataset (ebi-a-GCST90018794) was obtained from the IEU OpenGWAS project, which conducted a GWAS on 473,500 European individuals analyzing approximately 24,192,378 SNPs following quality control and imputation. Inverse variance weighting and MR Egger methods, implemented via R packages, were primarily used to assess the causal associations between 4907 plasma proteins and aplastic anemia. The Mendelian randomization (MR) analysis revealed 12 types of plasma proteins associated with decreased genetic susceptibility to AA. The inverse variance weighting (IVW) results indicated significant associations for several proteins, including CCL25 (odds ratio (OR), 0.868; 95% confidence interval (CI), 0.790–0.954; p=0.003), DSG2 (OR, 0.882; 95% CI, 0.795–0.979; p=0.018), EPHA4 (OR, 0.896; 95% CI, 0.824–0.975; p=0.011), EPHB4 (OR, 0.876; 95% CI, 0.782–0.981; p=0.022), IL3RA (OR, 0.860; 95% CI, 0.788–0.938; p <0.001), MDGA2 (OR, 0.906; 95% CI, 0.832–0.986; p=0.022), MET (OR, 0.871; 95% CI, 0.777–0.976; p=0.017), PEAR1 (OR, 0.868; 95%CI, 0.766–0.985; p=0.028), PLXND1 (OR, 0.914; 95% CI, 0.849–0.985; p=0.018), SELE (OR, 0.889; 95% CI, 0.821–0.963; p=0.004), and TLL1 (OR, 0.844; 95% CI, 0.725–0.982; p =0.028), all showing a reduced genetic susceptibility to AA. Conversely, MMP7 was associated with an increased genetic susceptibility to AA (OR, 1.211; 95% CI, 1.011–1.452). The pathway analysis showed that 12 plasma proteins were enriched in Cytokine-cytokine receptor interaction and PI3K-Akt signaling pathway. In summary, our MR study systematically evaluated the causal relationships between plasma protein biomarkers and AA, identifying 12 plasma proteins that have a causal influence on AA.