1. PPARGC1β is a Genetic Determinant of the Cardiovascular Risk Factor, Thromboxane A 2 – an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Sub-study Nina McCarthy 1, Ciara Vangjeli 1, Praveen Surendran 1,4, Achim Treumann 1, Cathy Rooney 1, Emily Ho 1, Peter Sever 2, Simon Thom 2, Alun Hughes 2, Patricia Munroe 3, Philip Howard 3, Toby Johnson 3, Mark Caulfield 3, Denis Shields 4, Eoin O’Brien 4, Desmond Fitzgerald 4, Alice Stanton 1. 1 Royal College of Surgeons in Ireland, Dublin 2, Ireland 2 Imperial College London, London W21LA, UK 3 Barts and The London, Queen Mary's School of Medicine and Dentistry, London EC1M 6BQ, UK 4 University College Dublin, Dublin 4, Ireland

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

3. TxA 2 Formation

4. TxA 2 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 TxB 2 (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 Proportion of TxM variation explained by the three genotypes:  All subjects: 5.2%  Subjects not on aspirin: 8.8%  Subjects on aspirin: 1.8% Minor alleles Major alleles

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 TxA 2 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. Is genotype associated with events in whole ASCOT cohort? (N=~9,000) Functional studies Validation of SNP as a pharmacogenetic marker Future work