Cytochrome p450 gene variants, race, and mortality among clopidogrel-treated patients after acute myocardial infarction.
BACKGROUND
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.


RESULTS
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 CYP2C19*2 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 CYP2C19*17 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 CYP1A2*1C 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 CYP2C19*17 or CYP1A2*1C.


CONCLUSIONS
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.
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.). scresci@dom.wustl.edu.
Sharon
S
Cresci
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.).
Jeremiah P
JP
Depta
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.).
Petra A
PA
Lenzini
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.).
Allie Y
AY
Li
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.).
David E
DE
Lanfear
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.).
Michael A
MA
Province
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.).
John A
JA
Spertus
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.).
Richard G
RG
Bach
D000328:Adult; D000368:Aged; D044383:Black People / Q000235:genetics; D000077144:Clopidogrel; D015331:Cohort Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology* / Q000208:ethnology / Q000401:mortality; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D044465:White People / Q000235:genetics
D000077144:Clopidogrel; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
clopidogrel; genetic variation; mortality; myocardial infarction