Editors' ChoiceHuman Genomics

Pondering the Significance of PON1

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Science Translational Medicine  12 Jan 2011:
Vol. 3, Issue 65, pp. 65ec5
DOI: 10.1126/scitranslmed.3002105

Clopidogrel, an antiplatelet agent that is used to prevent strokes and heart attacks in high-risk patients, is the second most highly prescribed drug in the world. However, the efficiency of clopidogrel response varies among individuals. In fact, up to 25% of individuals fail to respond to clopidogrel, and these nonresponders harbor a much greater risk for a lethal clotting phenomenon known as stent thrombosis (ST). Recently, a genetic predisposition to diminished clopidogrel responsiveness has been documented. However, currently identified polymorphisms, which reside in the hepatic cytochrome system, account for a relatively modest portion of the estimated 80% genetic contribution to clopidogrel response variability.

Now, data published online by Bouman et al. reveal where this missing heritability lies. In elegant fashion, the investigators first expressed enzymes—hepatic cytochromes and plasma esterases—thought to be involved in clopidogrel metabolism in a human embryonic kidney cell line. Interestingly, they found that clopidogrel bioactivation involves two critical sequential steps: oxidation and hydrolysis by plasma esterases. Notably, the second step—hydrolysis by paraoxonases 1 and 3 (PON1 and PON3)—generated the pharmacologically active form of clopidogrel, which is a novel finding. They also found that a common coding polymorphism in PON1 (Q192R) correlated strongly with clopidogrel active metabolite levels, plasma paraoxonase activity, and the clopidogrel antiplatelet effect. Moreover, in two independent cohorts involving over 9000 coronary artery disease patients, the homozygote carriers (QQ192) of the PON1 mutation had a striking 12-fold increase in risk for ST. A significant gene dose effect was also observed, with heterozygotes (QR192) having a substantive fourfold increase in risk for ST. Multivariate adjustment for known hepatic cytochrome variants did not attenuate the PON1 genotype effect, thus indicating a robust and independent effect.

Thus, there is no further need to ponder the importance of PON1. Rather, these transformative findings advance the case for routine genotyping when selecting dual antiplatelet therapy, especially given the more potent alternatives to clopidogrel therapy that are now readily available for use.

H. J. Bouman et al., Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat. Med. 17, 110–116 (2010). [Abstract]

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