Xiao-Yan Nie1, Jun-Lei Li1, Yong Zhang2, Yang Xu3, Xue-Li Yang4, Yu Fu1, Guang-Kai Liang1, Yun Lu5, Jian Liu2, Lu-Wen Shi1. 1. School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. 2. Department of Cardiology, Peking University People's Hospital, Beijing 100044, China. 3. School of Public Health, Peking University Health Science Center, Beijing 100191, China. 4. Department of Epidemiology, Fuwai Hospital, Beijing 100037, China. 5. Department of Pharmacy, Hennepin County Medical Center, Minneapolis, Minnesota 55415, USA.
Abstract
OBJECTIVE: To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG). METHODS: One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs (*2,*3,*17) were genotyped and possible haplotypes were analyzed. RESULTS: The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H0 to H5) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H1 showed a significantly lower incidence of HTPR than the reference haplotype (H0) in the total study population while haplotypes H1 and H2 showed significantly lower incidences of HTPR than H0 in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR. CONCLUSIONS: The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on-clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking.
OBJECTIVE: To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG). METHODS: One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs (*2,*3,*17) were genotyped and possible haplotypes were analyzed. RESULTS: The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H0 to H5) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H1 showed a significantly lower incidence of HTPR than the reference haplotype (H0) in the total study population while haplotypes H1 and H2 showed significantly lower incidences of HTPR than H0 in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR. CONCLUSIONS: The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on-clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking.
Entities:
Keywords:
P2RY12; CYP2C19; Haplotype; Single nucleotide polymorphism (SNP); Clopidogrel; Thromboelastography
Authors: Gouri Shanker; Jimmy L Kontos; Delrae M Eckman; Deborah Wesley-Farrington; David C Sane Journal: J Thromb Thrombolysis Date: 2006-12 Impact factor: 2.300
Authors: Glenn N Levine; Eric R Bates; John A Bittl; Ralph G Brindis; Stephan D Fihn; Lee A Fleisher; Christopher B Granger; Richard A Lange; Michael J Mack; Laura Mauri; Roxana Mehran; Debabrata Mukherjee; L Kristin Newby; Patrick T O'Gara; Marc S Sabatine; Peter K Smith; Sidney C Smith Journal: Circulation Date: 2016-03-29 Impact factor: 29.690
Authors: Dominick J Angiolillo; Antonio Fernandez-Ortiz; Esther Bernardo; Fernando Alfonso; Carlos Macaya; Theodore A Bass; Marco A Costa Journal: J Am Coll Cardiol Date: 2007-03-26 Impact factor: 24.094
Authors: Goran Rudez; Heleen J Bouman; Jochem W van Werkum; Frank W G Leebeek; Adrian Kruit; Hendrik J T Ruven; Jurriën M ten Berg; Moniek P M de Maat; Christian M Hackeng Journal: Circ Cardiovasc Genet Date: 2009-07-24