Genetic variants in PPARGC1B and CNTN4 are associated with thromboxane A₂ formation and with cardiovascular event free survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

BACKGROUND AND AIMS:Elevated urinary 11-dehydro thromboxane B₂ (TxB₂), a measure of thromboxane A₂ formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB₂ and their associations with cardiovascular morbidity were investigated in this study. METHODS:Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB₂ were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants. RESULTS:The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB₂ formation. Haplotypes of 11-dehydro TxB₂ increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB₂, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p=0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB₂ were individually associated with greater incidences of cardiovascular events - rs10515638 (HR = 1.31, p=0.01) and rs10510230 (HR = 1.25, p=0.007); effect sizes were larger in those not taking aspirin. CONCLUSIONS:PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A₂ formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention. Copyright © 2017 Elsevier B.V. All rights reserved.

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