Genetic effects of the renin-angiotensin system on warfarin bleeding complications at therapeutic INR

Abstract

연구목표 : 본 연구는 인공 심장판막치환술을 받은 환자들에서 레닌-안지오텐신 시스템(RAS)이 항응고제인 와파린 사용기간 발생한 출혈에 미치는 유전적 영향을 연구하였다. 대상 및 방법: 연구대상자는 인공 심장판막치환술 후 와파린 치료를 받고 INR 2.0-3.0을 유지한 환자들로 구성된 EAST (Ewha-Severance Treatment) 그룹에 등록된 환자들이다. REN, ACE, AGT, AGTR1 및 AGTR2, VKORC1, CYP2C9의 유전적 다형성을 분석하였다. 분석에 포함된 SNP들은 AGT (rs7536290, rs943580, rs7079, rs2478539, rs699, rs11122576, rs5051, rs5050, and rs5049), REN (rs2368564, rs6676458, rs1917539, rs41317140, and rs12750834), ACE (rs1800764, rs4329, rs4341, rs4343, rs4351, rs4353, rs4362, and rs4363), AGTR1 (rs6792788, rs416270, rs1979703, rs275651, rs2131127, rs931490, rs2640543, rs4681443, rs5182, and rs5186), AGTR2 (rs1914714, rs5950474, and rs1403543), VKORC1 (rs9934438), 그리고 CYP2C9 (rs1057910) 이었다. 유전적 다형성과 출혈 합병증 사이의 연관성을 조사하기 위해 단변량 및 다변량 로지스틱 회귀 분석을 수행하였다. 결과: 인공 심장판막치환술을 시행 받은 후 와파린을 투여중인 142 명의 환자가 연구대상에 포함되었으며 그 중 21 명이 출혈 부작용을 경험했다. 유전형을 분석한 결과, AGT rs5050의 G 대립 유전자는 CC 유전자형보다 출혈 위험이 약 4 배 (95 % CI 1.28-12.27) 높았다. ACE rs4341과 rs4353의 대립 형질은 각각 homozygotes를 갖는 것과 비교하여 치료 INR에서 4.6- (95 % CI 1.19-18.03) 및 10.8 배 (95 % CI 1.30-89.16) 높은 출혈 부작용 발생률을 보였다. 출혈 부작용을 예측하는 모델의 AUROC (receiver operating curve) 값 아래의 면적은 약 0.8이었다. 결론: 본 연구의 결과로 VKORC1, CYP2C9 뿐 아니라 RAS pathway의AGT와 ACE 유전적 다형성과 인공 심장판막을 가진 환자의 와파린 INR 2.0-3.0 유지 치료기간 중 발생한 출혈 부작용 위험과의 상관관계를 확인할 수 있었다.;Purpose: This study aimed to analyze the genetic effects of the renin–angiotensin system (RAS) on warfarin-associated bleeding at therapeutic international normalized ratios (INRs) among Korean patients with mechanical heart valve replacements. Methods: Study patients were enrolled from the Ewha-Severance Treatment (EAST) Group of Warfarin, which consisted of patients who received warfarin therapy after mechanical heart valve replacement. Patients who maintained therapeutic INRs were eligible for the study. Thirty seven single nucleotide polymorphisms, including AGT (rs7536290, rs943580, rs7079, rs2478539, rs699, rs11122576, rs5051, rs5050, and rs5049), REN (rs2368564, rs6676458, rs1917539, rs41317140, and rs12750834), ACE (rs1800764, rs4329, rs4341, rs4343, rs4351, rs4353, rs4362, and rs4363), AGTR1 (rs6792788, rs416270, rs1979703, rs275651, rs2131127, rs931490, rs2640543, rs4681443, rs5182, and rs5186), AGTR2 (rs1914714, rs5950474, and rs1403543), VKORC1 (rs9934438), and CYP2C9 (rs1057910) were investigated. Univariate and multivariate logistic regression analyses were performed to investigate the associations between genetic polymorphisms and bleeding complications. Results: Out of 142 study patients, 21 experienced bleeding episodes. After adjusting covariates, G allele of rs5050 (T>G) was associated with 4-fold (95% CI 1.28-12.27) higher risk of bleeding than TT genotype. The G allele of rs4341 (G>C) and A allele of rs4353 (A>G) had 4.6- (95% CI 1.19-18.03) and 10.8-fold (95% CI 1.30-89.16) higher rates of bleeding complications at therapeutic INRs, compared with those having CC genotype and GG genotype, respectively. The area under the receiver operating curve (AUROC) value of the models predicting bleeding complications was approximately 0.8. Conclusion: This study demonstrated that AGT and ACE gene polymorphisms could affect bleeding complications during warfarin treatment for patients with mechanical heart valves.