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


Txa 2 functions
TxA Risk Factor, Thromboxane A2 Functions

  • Platelet activator

  • Vascular smooth muscle cell constrictor and mitogen

  • Plaque growth


Txa 2 formation
TxA Risk Factor, Thromboxane A2 Formation


Txa 2 and atherothrombotic events
TxA Risk Factor, Thromboxane A2 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)


Hacvd a substudy of ascot
HACVD, a Risk Factor, Thromboxane ASubstudy of ASCOT


Methods
Methods Risk Factor, Thromboxane A

  • 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


Population Characteristics Risk Factor, Thromboxane A


Results: Manhattan Plots Risk Factor, Thromboxane A


PPARGC1 Risk Factor, Thromboxane Aβ Peak


Ppargc1 peak with imputation
PPARGC1 Risk Factor, Thromboxane Aβ Peak with Imputation


Haplotype analysis
Haplotype Analysis Risk Factor, Thromboxane A

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%


Ppargc1 function
PPARGC1 Risk Factor, Thromboxane Aβ Function

Anti-atherosclerotic

MMP-9

iNOS

COX-2

TNF-α, IL-6, IL-1β

MCP-1, VCAM, ICAM


Ppargc1 variants
PPARGC1 Risk Factor, Thromboxane Aβ Variants


Study implications
Study Implications Risk Factor, Thromboxane A

  • 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


Acknowledgements
Acknowledgements Risk Factor, Thromboxane A

  • Health Research Board Ireland

  • Pfizer

  • British Heart Foundation

  • ASCOT HACVD participants


Future work
Future work Risk Factor, Thromboxane A

  • 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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