Identification of potential drug targets for varicose veins: a Mendelian randomization analysis

Jianfeng Lin; Jiawei Zhou; Zhili Liu; Rong Zeng; Lei Wang; Fangda Li; Liqiang Cui; Yuehong Zheng

doi:10.3389/fcvm.2023.1126208

Identification of potential drug targets for varicose veins: a Mendelian randomization analysis

Front Cardiovasc Med. 2023 Jun 19:10:1126208. doi: 10.3389/fcvm.2023.1126208. eCollection 2023.

Authors

Jianfeng Lin^#¹, Jiawei Zhou^#², Zhili Liu², Rong Zeng², Lei Wang², Fangda Li², Liqiang Cui², Yuehong Zheng²

Affiliations

¹ Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Vascular Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

^# Contributed equally.

Abstract

Introduction: Varicose veins are a common chronic disease that creates a significant economic burden on the healthcare system. Current treatment options, including pharmacological treatments, are not always effective, and there is a need for more targeted therapies. A Mendelian randomization (MR) method uses genetic variants as instrumental variables to estimate the causal effect of an exposure on an outcome, and it has been successful in identifying therapeutic targets in other diseases. However, few studies have used MR to explore potential protein drug targets for varicose veins.

Methods: To identify potential drug targets for varicose veins of lower extremities, we undertook a comprehensive screen of plasma protein with a two-sample MR method. We used recently reported cis-variants as genetic instruments of 2,004 plasma proteins, then applied MR to a recent meta-analysis of genome-wide association study on varicose veins (22,037 cases and 437,665 controls). Furthermore, pleiotropy detection, reverse causality testing, colocalization analysis, and external replication were utilized to strengthen the causal effects of prioritized proteins. Phenome-wide MR (PheW-MR) of the prioritized proteins for the risk of 525 diseases was conducted to screen potential side effects.

Results: We identified eight plasma proteins that are significantly associated with the risk of varicose veins after Bonferroni correction (P < 2.495 × 10^-5), with five being protective (LUM, POSTN, RPN1, RSPO3, and VAT1) and three harmful (COLEC11, IRF3, and SARS2). Most identified proteins showed no pleiotropic effects except for COLLEC11. Bidirectional MR and MR Steiger testing excluded reverse causal relationship between varicose veins and prioritized proteins. The colocalization analysis indicated that COLEC11, IRF3, LUM, POSTN, RSPO3, and SARS2 shared the same causal variant with varicose veins. Finally, seven identified proteins replicated with alternative instruments except for VAT1. Furthermore, PheW-MR revealed that only IRF3 had potential harmful adverse side effects.

Conclusions: We identified eight potential causal proteins for varicose veins with MR. A comprehensive analysis indicated that IRF3, LUM, POSTN, RSPO3, and SARS2 might be potential drug targets for varicose veins.

Keywords: Mendelian randomization; drug targets; genetics; proteomics; varicose veins.

Grants and funding

This work was supported by the Major Research Program of Natural Science Foundation of China (51890894), Natural Science Foundation of China (82100519 and 82070492), and the Chinese Academy of Medical Sciences, Innovation Fund for Medical Sciences (CIFMS2021-I2M-1-016). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.