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PPARGC1β is a Genetic Determinant of the Cardiovascular Risk Factor, Thromboxane A 2 –

PPARGC1β is a Genetic Determinant of the Cardiovascular Risk Factor, Thromboxane A 2 – an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Sub-study.

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PPARGC1β is a Genetic Determinant of the Cardiovascular Risk Factor, Thromboxane A 2 –

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  1. PPARGC1β is a Genetic Determinant of the Cardiovascular Risk Factor, Thromboxane A2 – an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Sub-study Nina McCarthy1, Ciara Vangjeli1, Praveen Surendran1,4, Achim Treumann1, Cathy Rooney1, Emily Ho1, Peter Sever2, Simon Thom2, Alun Hughes2, Patricia Munroe3, Philip Howard3, Toby Johnson3, Mark Caulfield3, Denis Shields4, Eoin O’Brien4, Desmond Fitzgerald4, Alice Stanton1. 1Royal College of Surgeons in Ireland, Dublin 2, Ireland 2Imperial College London, London W21LA, UK 3Barts and The London, Queen Mary's School of Medicine and Dentistry, London EC1M 6BQ, UK 4 University College Dublin, Dublin 4, Ireland

  2. TxA2 Functions • Platelet activator • Vascular smooth muscle cell constrictor and mitogen • Plaque growth

  3. TxA2 Formation

  4. TxA2 and Atherothrombotic Events • Target of aspirin – responsible for both therapeutic and harmful effects • Independent predictor of atherothrombotic events (OR=2 for MI, OR=3.5 for CV-related death)

  5. HACVD, a Substudy of ASCOT

  6. Methods • Phenotyping • 11-dehydro TxB2 (TxM), expressed as pg of TxM/mg creatinine. • LC-MS-MS • Genotyping • CVD50K chip; 2,000 genic regions related to cardiovascular, inflammatory, and metabolic phenotypes. • Statistical Analysis: linear regression analysis, adjusting for the covariates; • age • sex • smoking habit • diabetes • systolic blood pressure • body mass index • high density lipoprotein • low density lipoprotein • aspirin use at time of TxM measurement • randomized anti-hypertensive regimen

  7. Population Characteristics

  8. Results: Manhattan Plots

  9. PPARGC1β Peak

  10. PPARGC1β Peak with Imputation

  11. Haplotype Analysis Minor alleles Major alleles • Proportion of TxM variation explained by the three genotypes: • All subjects: 5.2% • Subjects not on aspirin: 8.8% • Subjects on aspirin: 1.8%

  12. PPARGC1β Function Anti-atherosclerotic MMP-9 iNOS COX-2 TNF-α, IL-6, IL-1β MCP-1, VCAM, ICAM

  13. PPARGC1β Variants

  14. Study Implications • Suggests PPARγ transcriptional regulation regulates TxA2 production • SNPs may be genetic markers of high-risk patients • SNPs may be pharmacogenetic markers to inform use of aspirin

  15. Acknowledgements • Health Research Board Ireland • Pfizer • British Heart Foundation • ASCOT HACVD participants

  16. Future work • Is genotype associated with events in whole ASCOT cohort? (N=~9,000) • Functional studies • Validation of SNP as a pharmacogenetic marker

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