Gene Polymorphisms of the Renin-Angiotensin System and Bleeding Complications of Warfarin: Genetic-Based Machine Learning Models.

Joo Hee Kim ,Jeong Yee,Byung‐Chul Chang ,Hye Sun Gwak

doi:10.3390/ph14080824

Abstract

This study aimed to investigate the effects of genetic variants and haplotypes in the renin–angiotensin system (RAS) on the risk of warfarin-induced bleeding complications at therapeutic international normalized ratios (INRs). Four single nucleotide polymorphisms (SNPs) of AGT, two SNPs of REN, three SNPs of ACE, four SNPs of AGTR1, and one SNP of AGTR2, in addition to VKORC1 and CYP2C9 variants, were investigated. We utilized logistic regression and several machine learning methods for bleeding prediction. The study included 142 patients, among whom 21 experienced bleeding complications. We identified a haplotype, H2 (TCG), carrying three single nucleotide polymorphisms (SNPs) of ACE (rs1800764, rs4341, and rs4353), which showed a significant relation with bleeding complications. After adjusting covariates, patients with H2/H2 experienced a 0.12-fold (95% CI 0.02–0.99) higher risk of bleeding complications than the others. In addition, G allele carriers of AGT rs5050 and A allele carriers of AGTR1 rs2640543 had 5.0- (95% CI 1.8–14.1) and 3.2-fold (95% CI 1.1–8.9) increased risk of bleeding complications compared with the TT genotype and GG genotype carriers, respectively. The AUROC values (mean, 95% CI) across 10 random iterations using five-fold cross-validated multivariate logistic regression, elastic net, random forest, support vector machine (SVM)–linear kernel, and SVM–radial kernel models were 0.732 (0.694–0.771), 0.741 (0.612–0.870), 0.723 (0.589–0.857), 0.673 (0.517–0.828), and 0.680 (0.528–0.832), respectively. The highest quartile group (≥75th percentile) of weighted risk score had approximately 12.0 times (95% CI 3.1–46.7) increased risk of bleeding, compared to the 25–75th percentile group, respectively. This study demonstrated that RAS-related polymorphisms, including the H2 haplotype of the ACE gene, could affect bleeding complications during warfarin treatment for patients with mechanical heart valves. Our results could be used to develop individually tailored intervention strategies to prevent warfarin-induced bleeding.

Highlights

Warfarin has been one of the most widely used oral anticoagulants since its approval [1]
This study demonstrated that renin– angiotensin system (RAS)-related polymorphisms, including the H2 haplotype of the angiotensin I-converting enzyme (ACE) gene, could affect bleeding complications during warfarin treatment for patients with mechanical heart valves
Of the 87 who were excluded, 28 did not reach stable international normalized ratios (INRs), 4 had bleeding complications at supratherapeutic INRs, and 55 reported minimal bleeding complications not verified by health professionals

Summary

Introduction

Warfarin has been one of the most widely used oral anticoagulants since its approval [1]. Direct oral anticoagulants have become popular for patients who need anticoagulation therapy, warfarin remains the first-line anticoagulant for patients with heart valve prostheses [2]. Warfarin has several limitations, including a narrow therapeutic range and wide inter- and intra-individual variabilities [1]. Bleeding is the most serious complication of warfarin treatment [3]. Close monitoring based on the international normalized ratio (INR) is known to be effective for evaluating the efficacy and safety of warfarin, it has been reported that patients may still experience bleeding complications within therapeutic INRs, and even at sub-therapeutic. INRs [4,5]. Hypertension, and concomitant aspirin use—in addition to high INR—

Objectives

Methods

Results