Inflammation Biomarkers And Risk Of Pulmonary Hypertension: A Mendelian Randomization Study

Dysregulation of inflammatory pathways are key elements in the pathogenesis of pulmonary hypertension (PH). Circulating cytokines and growth factors, such as interleukin-2 (IL-2), macrophage colony stimulating factor (MCSF) and vascular endothelial growth factor (VEGF) were likely regulators of inflammation contributed to PH in observational studies. We aimed to evaluate the effects of IL-2 receptor antagonist (IL-2Ra), MCSF, VEGF on the risk of developing PH using Mendelian randomization (MR) study, an approach to overcome reverse causation and residual confounding. We identified single nucleotide polymorphisms (SNPs) (P<5e-8) associated with these inflammation biomarkers as genetic instruments from genome-wide association study summary data in MR-Base. The result based on Wald ratio indicated that IL-2Ra per standard deviation (SD) units increase was likely associated with a decreased risk of PH (OR 0.9999; 95%CI 0.9998~1.0000; P=0.0489). Conversely, increased PAH risk resulted causally from MCSF per SD units increase (OR:1.0003; 95%CI:1.0000~1.0005; P=0.0042). Furthermore, VEGF had significantly effect on the development of PH. We used two SNPs to proxy VEGF per unit increase inverse-variance weighted method (OR 1.0005; 95%CI 1.0002~1.0008; P=0.0023) and a single SNP to proxy VEGF per unit decrease in the Wald ratio (OR 0.9993; 95%CI:0.9988~0.9998; P=0.0053). In conclusion, this study supported the causal role of genetically determined VEGF and MCSF in the etiology of PH. There was suggestive evidence that IL-2Ra had potential therapeutic value for the clinical treatment of PH.