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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: 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). Methods: Four single nucleotide polymor-phisms (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. Results: The study in-cluded 142 patients, among whom 21 experienced bleeding complications. We identified a haplo-type, H2 (TCG), carrying three SNPs of ACE (rs1800764, rs4341, and rs4353), which showed a sig-nificant 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 ad-dition, 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. Conclusion: 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.

Original languageEnglish
Article number824
Issue number8
StatePublished - Aug 2021


  • Haplotype
  • Hemorrhage
  • Machine learning
  • Polymorphism
  • Renin–angiotensin system
  • Warfarin


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