Dysfunctional corin i555(p568) allele is associated with impaired brain natriuretic peptide processing and adverse outcomes in blacks with systolic heart failure: results from the Genetic Risk Assessment in Heart Failure substudy.
Dysfunctional corin i555(p568) allele is associated with impaired brain natriuretic peptide processing and adverse outcomes in blacks with systolic heart failure: results from the Genetic Risk Assessment in Heart Failure substudy.
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DOI：
10.1161/circheartfailure.109.866822
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Dries DL
中科院分区：
文献类型：
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作者：
Rame JE;Tam SW;McNamara D;Worcel M;Sabolinski ML;Wu AH;Dries DL
Corin 是一种在心肌细胞中表达的跨膜丝氨酸蛋白酶，可将 proANP 和 proBNP 裂解成具有生物活性的肽激素。由 T555I 和 Q568P 突变定义的小 Corin I555(P568) 等位基因在非洲血统的人中很常见，并且与高血压和心脏同心肥大的风险增加相关。含有T555I和Q568P突变的corin基因产物显着降低了利尿钠肽的处理能力。我们假设 corin I555(P568) 等位基因与患有收缩性心力衰竭的非洲裔美国人的不良后果和 BNP 处理受损有关。这是一项针对非洲-美洲心力衰竭试验 (A-HeFT) 心力衰竭遗传风险评估 (GRAHF) 子研究中 354 名受试者的回顾性研究。在corin变异组（N=50）中，与corin非变异组（N=300）相比，BNP-32（氨基酸77-108）较低（190pg/ml vs 340pg/ml，p=0.007），但未加工的BNP 1-108/加工的BNP-32的比率显着较高（P=0.05）。由于有证据表明 corin I555(P568) 等位基因与治疗分配之间存在显着相互作用，因此进行了分层分析。在安慰剂组中，多变量分析表明，corin I555(P568) 等位基因与死亡或心力衰竭住院风险增加相关（RR 3.49；95% CI 1.45-8.39；P=0.005）；然而，在治疗组（固定剂量复方硝酸异山梨酯/肼屈嗪）中，corin I555（P568）等位基因与不良后果无关。我们已经在患有收缩性心力衰竭的非裔美国人中发现了药物基因组相互作用。 Corin I555(P568) 等位基因与接受标准神经激素阻断的患者死亡或心力衰竭住院风险增加相关，但添加固定剂量复方硝酸异山梨酯/肼屈嗪 (FDC I/H) 可以改善这种风险。这种药物基因组相互作用的一个可能机制是与非携带者相比，corin I555(P568) 等位基因携带者的 BNP 加工受损。
Corin, a transmembrane serine protease expressed in cardiomyocytes, cleaves proANP and proBNP into biologically active peptide hormones. The minor corin I555(P568) allele, defined by the T555I and Q568P mutations, is common in persons of African ancestry and associated with increased risk for hypertension and cardiac concentric hypertrophy. The corin gene product containing the T555I and Q568P mutations has significantly reduced natriuretic peptide processing capacity. We hypothesized that the corin I555(P568) allele would be associated with adverse outcomes and impaired BNP processing in African-Americans with systolic heart failure. This is a retrospective study of 354 subjects in the African-America Heart Failure Trial (A-HeFT) Genetic Risk Assessment in Heart Failure (GRAHF) sub-study. In the corin variant group (N=50) compared to corin non-variant group (N=300), BNP-32 (amino acids 77-108) was lower (190pg/ml versus 340 pg/ml, p=0.007), but the ratio of unprocessed BNP 1-108/processed BNP-32 was significantly higher (P= 0.05). Stratified analyses were conducted because of evidence of significant interaction between the corin I555(P568) allele and treatment assignment. In the placebo arm, multivariable analysis demonstrated that the corin I555(P568) allele was associated with increased risk for death or heart failure hospitalization (RR 3.49; 95% CI 1.45-8.39; P=0.005); however, in the treatment arm (fixed-dose combination isosorbide-dinitrate/hydralazine), the corin I555(P568) allele was not associated with adverse outcomes. We have identified a pharmacogenomic interaction in African-Americans with systolic heart failure. The corin I555(P568) allele is associated with an increased risk for death or heart failure hospitalization in patients receiving standard neurohormonal blockade, but the addition of fixed dose combination isosorbide-dinitrate/hydralazine (FDC I/H) ameliorates this risk. A plausible mechanism for this pharmacogenomic interaction is the impaired processing of BNP in carriers of the corin I555(P568) allele as compared to non-carriers.