Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders (TEDs) is proven, it is vastly underutilized with difficulties in management &risk of complications being the main deterrents. Recognition of genetic regulation of warfarin response has fueled efforts to quantify this influence, but the focus has been restricted to select genes and outcomes mainly in Caucasians. Our effort in understanding genetic influences on warfarin response began in 2003 with a K23 grant (NS045598): Pharmacogenetic Optimization of Anticoagulation Therapy (POAT). Although this training grant focused on evaluating the influence of a single gene;cytochrome P450 2C9 (CYP2C9) genotype on warfarin dose, frequency of International Normalized Ratio (INR) outside target range, and risk of complications, the cohort provides a valuable racially diverse resource to expand our pharmacogenetic effort. The POAT cohort is, to our knowledge the largest prospective cohort (n=578, 51% men, 273 African Americans (AA)) with a 2-year longitudinal follow-up from initiation of therapy. This proposal will further the aims of POAT using a comprehensive pharmacogenetic approach in a cohort of 1200 participants (50% AA) powered (>80%, alpha=0.001) to test three hypotheses. This proposal will incorporate 50 genes involved in the clotting cascade, vitamin K cycle, and warfarin pharmacodynamics and pharmacokinetics. Non-genetic covariates will include socio-demographics, lifestyle, diet, and medical characteristics.
Aim 1 will assess the relative effects of genetic and non-genetic covariates on warfarin dose.
Aim 2 will assess the contribution of candidate genes in determining attainment and maintenance of anticoagulation and risk of over- anticoagulation (INR >4).
Aim 3 will determine the association between candidate genes and risk of hemorrhage or thromboembolism. The study will also explore gene*gene and gene*non-genetic covariate interactions. We anticipate that the results of this study will further elucidate the genetic contributions of warfarin response, provide novel genetic associations of treatment response in a previously understudied population, namely, African Americans. This knowledge will provide an evidence base for future pre-prescription genotyping for accurate warfarin dosing and facilitate its use in qualifying patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092173-05
Application #
8281482
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Link, Rebecca P
Project Start
2008-05-20
Project End
2014-01-31
Budget Start
2012-05-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$712,940
Indirect Cost
$186,185
Name
University of Alabama Birmingham
Department
Neurology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Lin, Wan-Yu; Lou, Xiang-Yang; Gao, Guimin et al. (2014) Rare variant association testing by adaptive combination of P-values. PLoS One 9:e85728
Daneshjou, Roxana; Gamazon, Eric R; Burkley, Ben et al. (2014) Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans. Blood 124:2298-305
Yan, Qi; Tiwari, Hemant K; Yi, Nengjun et al. (2014) Kernel-machine testing coupled with a rank-truncation method for genetic pathway analysis. Genet Epidemiol 38:447-56
Shendre, Aditi; Beasley, Timothy Mark; Brown, Todd M et al. (2014) Influence of regular physical activity on warfarin dose and risk of hemorrhagic complications. Pharmacotherapy 34:545-54
Thigpen, Jonathan L; Limdi, Nita A (2013) Reversal of Oral Anticoagulation. Pharmacotherapy :
Daneshjou, Roxana; Tatonetti, Nicholas P; Karczewski, Konrad J et al. (2013) Pathway analysis of genome-wide data improves warfarin dose prediction. BMC Genomics 14 Suppl 3:S11
Limdi, Mohit A; Crowley, Michael R; Beasley, T Mark et al. (2013) Influence of kidney function on risk of hemorrhage among patients taking warfarin: a cohort study. Am J Kidney Dis 61:354-7
Kabagambe, Edmond K; Beasley, T Mark; Limdi, Nita A (2013) Vitamin K intake, body mass index and warfarin maintenance dose. Cardiology 126:214-8
Horne, Benjamin D; Lenzini, Petra A; Wadelius, Mia et al. (2012) Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost 107:232-40
Cosgun, Erdal; Limdi, Nita A; Duarte, Christine W (2011) High-dimensional pharmacogenetic prediction of a continuous trait using machine learning techniques with application to warfarin dose prediction in African Americans. Bioinformatics 27:1384-9

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