Cresci Sharon, Depta Jeremiah P, Lenzini Petra A, Li Allie Y, Lanfear David E, Province Michael A, Spertus John A, Bach Richard G
From the Department of Medicine, Cardiovascular Division (S.C., J.P.D., A.Y.L., R.G.B.), Department of Genetics (S.C.), Department of Genetics, Statistical Genomics Division (P.A.L., M.A.P.), Washington University School of Medicine, St. Louis, MO; Heart and Vascular Institute, Department of Medicine, Henry Ford Hospital, Detroit, MI (D.E.L.); Saint Luke's Mid America Heart Institute & the Department of Medicine, University of Missouri-Kansas City (J.A.S.).
Circ Cardiovasc Genet. 2014 Jun;7(3):277-86. doi: 10.1161/CIRCGENETICS.113.000303. Epub 2014 Apr 24.
Clopidogrel is recommended after acute myocardial infarction but has variable efficacy and safety, in part related to the effect of cytochrome P450 (CYP) polymorphisms on its metabolism. The effect of CYP polymorphisms on cardiovascular events among clopidogrel-treated patients after acute myocardial infarction remains controversial, and no studies to date have investigated the association of CYP variants with outcomes in black patients.
Subjects (2732: 2062 whites; 670 blacks) hospitalized with acute myocardial infarction enrolled in the prospective, multicenter TRIUMPH study were genotyped for CYP polymorphisms. The majority of whites (79%) and blacks (64.4%) were discharged on clopidogrel. Among whites, carriers of the loss-of-function CYP2C192 allele had significantly increased 1-year mortality (adjusted hazards ratio [HR]: 1.70; confidence interval [CI]: 1.01-2.86; P=0.046) and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI: 0.95-4.63; P=0.066). Among blacks, increased 1-year mortality was associated with the gain-of-function CYP2C1917 allele (adjusted HR for *1/*17 versus *1/*1: 2.02; CI: 0.92-4.44; *17/*17 versus *1/1: 8.97; CI: 3.34-24.10; P<0.0001) and the CYP1A21C allele (adjusted HR for *1/*1C versus *1/*1: 1.89; CI: 0.85-4.22; *1C/*1C versus 1/1: 4.96; CI: 1.69-14.56; P=0.014). Bleeding events were significantly more common among black carriers of CYP2C1917 or CYP1A21C.
Both loss-of-function and gain-of-function CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel-treated patients after acute myocardial infarction; the specific polymorphism and the putative mechanism vary according to race.
急性心肌梗死后推荐使用氯吡格雷，但它的疗效和安全性存在差异，部分与细胞色素P450（CYP）基因多态性对其代谢的影响有关。CYP基因多态性对急性心肌梗死后接受氯吡格雷治疗患者心血管事件的影响仍存在争议，迄今为止尚无研究调查CYP变异与黑人患者预后的关联。
纳入前瞻性多中心TRIUMPH研究的急性心肌梗死住院患者（共2732例，其中白人2062例，黑人670例）进行了CYP基因多态性基因分型。大多数白人（79%）和黑人（64.4%）出院时使用氯吡格雷。在白人中，功能缺失型CYP2C192等位基因携带者1年死亡率显著增加（校正风险比[HR]：1.70；置信区间[CI]：1.01 - 2.86；P = 0.046），复发性心肌梗死发生率有增加趋势（校正HR：2.10；CI：0.95 - 4.63；P = 0.066）。在黑人中，功能获得型CYP2C1917等位基因（*1/17与1/*1相比校正HR：2.02；CI：0.92 - 4.44；*17/17与1/1相比：8.97；CI：3.34 - 24.10；P < 0.0001）和CYP1A21C等位基因（*1/1C与1/*1相比校正HR：1.89；CI：0.85 - 4.22；1C/1C与1/1相比：4.96；CI：1.69 - 14.56；P = 0.014）与1年死亡率增加相关。CYP2C1917或CYP1A21C的黑人携带者出血事件明显更常见。
影响氯吡格雷代谢的功能缺失型和功能获得型CYP基因多态性均与急性心肌梗死后接受氯吡格雷治疗患者的死亡率增加有关；具体的基因多态性和推测机制因种族而异。
