Identification of Novel Proteins Mediating Causal Association Between Smoking and Essential Hypertension: A Mendelian Randomization Study

Background Smoking is a factor for hypertension. We aim to reveal novel plasma proteins mediating the relationship of smoking with hypertension and identify potential drug targets for hypertension on the basis of Mendelian randomization design. Methods and Results Data for smoking were selected from the largest genome‐wide association study meta‐analysis performed by the Genome‐Wide Association Study and Sequencing Consortium of Alcohol and Nicotine Use. Data for plasma proteins were selected from the deCODE Health study and the UK Biobank Pharma Proteomics Project. Data for hypertension were extracted from the FinnGen Study. Moreover, proteome‐wide Mendelian randomization and colocalization analyses, 2‐step Mendelian randomization, and gene function and network prediction, as well as druggability assessment were performed. We finally identified 8 proteins (ANXA4 [annexin A4], DLK1 [protein delta homolog 1], KLB [β‐klotho], MMP8 [matrix metallopeptidase 8], PLAT [tissue‐type plasminogen activator], POSTN [periostin], SAT2 [thialysine N‐ε‐acetyltransferase], and IFNLR1 [interferon λ receptor 1]) mediating association of smoking with hypertension. PLAT and IFNLR1 were identified to be involved in the complement and coagulation cascades and the Janus kinase/signal transducer and activator of transcription signaling pathway. ANXA4, KLB, MMP8, PLAT, and IFNLR1 had druggability. Moreover, IFNLR1 had strong evidence of genetic colocalization, because the posterior probability for H4 of IFNLR1 was 91.3%. Conclusions This study identified the 8 proteins that mediate causal association between smoking and essential hypertension. Interferon λ receptor agonist targeting IFNLR1 may open a new avenue for treating hypertension. Our discoveries provide new insights into protein pathogenesis of hypertension and to better guide hypertension prevention and treatment among smokers.