Paraoxonase-1 activity affects the clopidogrel response in CYP2C19 loss-of-function carriers.
BACKGROUND
The impact of paraoxonase-1 (PON1) activity on the response to clopidogrel may differ in patients treated with drug-eluting stents (DES) in association with CYP2C19 loss-of-function (LOF) polymorphisms.


METHODS
This study included 112 Japanese patients receiving clopidogrel (75 mg/day) and aspirin (100mg/day) who underwent optical coherence tomography (OCT) examination 9 months after DES implantation. The CYP2C19 genotype was analyzed and LOF carriers (1/2, 1/3, 2/2, 3/3, 2/3) were identified. At the 9-month follow-up, platelet reactivity was determined by measuring the P2Y12 reactivity unit (PRU) using a VerifyNow P2Y12 assay, PON1 activity was evaluated and intra-stent thrombus was evaluated by OCT.


RESULTS
Of the 112 Japanese patients, 75 were LOF carriers (67.0%). The patients were divided into tertiles according to the PON1 activity (tertile 1; <230 U/L, tertile 2; 230-283U/L, tertile 3; >283 U/L). In the VerifyNowP2Y12 analysis, tertile 1 had a higher PRU than tertiles 2 and 3 in LOF carriers, and there was no difference among tertiles in non-carriers. The highest incidence of intra-stent thrombus was observed in tertile 1 followed by tertiles 2 and 3 in LOF carriers, whereas there was no such difference in non-carriers. Multivariate analysis revealed that LOF carriers and PON1 activity tertile 1 were independent predictors of intra-stent thrombus in all patients. In LOF carriers, tertile 1 was the only independent predictor for intra-stent thrombus.


CONCLUSIONS
Low PON1 activity is associated with a low response to clopidogrel and a high frequency of intra-stent thrombus only in LOF carriers.
Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine.
Ryo
R
Nishio
Toshiro
T
Shinke
Hiromasa
H
Otake
Masayuki
M
Nakagawa
Takumi
T
Inoue
Hirotoshi
H
Hariki
Tsuyoshi
T
Osue
Yu
Y
Taniguchi
Masamichi
M
Iwasaki
Noritoshi
N
Hiranuma
Akihide
A
Konishi
Hiroto
H
Kinutani
Masaru
M
Kuroda
Ken-Ichi
K
Hirata
D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D001241:Aspirin / Q000627:therapeutic use*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D054855:Drug-Eluting Stents / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D013927:Thrombosis / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D043303:Aryldialkylphosphatase; D013988:Ticlopidine; D001241:Aspirin
CYP; CYP2C19; DES; EES; LOF; MI; OCT; PCI; PES; PON1; PRU; Paraoxonase-1; SES; TLR; VerifyNowP2Y12; clopidogrel; cytochromeP450; drug-eluting stent; everolimus-eluting stent; intra-stent thrombus; loss-of-function; myocardial infarction; optical coherence tomography; paclitaxel-eluting stent; paraoxonase-1; percutaneous coronary intervention; platelet reactivity unit; sirolimus-eluting stent; target lesion revascularization