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. 2021 Aug 22;14(8):824.
doi: 10.3390/ph14080824.

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

Joo-Hee Kim  1 , Jeong Yee  2 , Byung-Chul Chang  3   4 , Hye-Sun Gwak  2
Affiliations

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

Joo-Hee Kim et al. Pharmaceuticals (Basel). .

Abstract

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 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.

Results: The study included 142 patients, among whom 21 experienced bleeding complications. We identified a haplotype, H2 (TCG), carrying three 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.

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.

Keywords: haplotype; hemorrhage; machine learning; polymorphism; renin–angiotensin system; warfarin.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Area under the receiver operating characteristic curve (AUROC) for bleeding complications at therapeutic INRs. LR_T: traditional logistic regression; LR_ML: machine learning-based logistic regression; RF: random forest; SVM_L: support vector machine–linear kernel; SVM_R: support vector machine–radial kernel.
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References

    1. Elias D.J., Topol E.J. Warfarin pharmacogenomics: A big step forward for individualized medicine: Enlightened dosing of warfarin. Eur. J. Hum. Genet. 2008;16:532–534. doi: 10.1038/sj.ejhg.5201945. - DOI - PubMed
    1. Nishimura R.A., Otto C.M., Bonow R.O., Carabello B.A., Erwin J.P., Guyton R.A., O’Gara P.T., Ruiz C.E., Skubas N.J., Sorajja P., et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:2440–2492. doi: 10.1161/CIR.0000000000000029. - DOI - PubMed
    1. Marie I., Leprince P., Menard J.F., Tharasse C., Levesque H. Risk factors of vitamin K antagonist overcoagulation. QJM Int. J. Med. 2012;105:53–62. doi: 10.1093/qjmed/hcr136. - DOI - PubMed
    1. Miura T., Nishinaka T., Terada T., Yonezawa K. Relationship between aging and dosage of warfarin: The current status of warfarin anticoagulant therapy for Japanese outpatients in a department of cardiovascular medicine. J. Cardiol. 2009;53:355–360. doi: 10.1016/j.jjcc.2008.12.003. - DOI - PubMed
    1. Moffett B.S., Ung M., Bomgaars L. Risk factors for elevated INR values during warfarin therapy in hospitalized pediatric patients. Pediatr. Blood Cancer. 2012;58:941–944. doi: 10.1002/pbc.23308. - DOI - PubMed

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