Dr. Perera's long-term career goal is to implement clinical pharmacogenetic testing as an indispensable part of clinical care. With the explosion of pharmacogenetic research, the opportunity to advance the use of pharmacogenetics into clinical care has become apparent. Warfarin has been a long-standing target of research because of its narrow therapeutic index and serious side effect profile. Currently, algorithms using genetic variants in CYP2C9 and VKORC1 have been developed to predict maintenance dose of warfarin in Caucasians and Asians. However, the extent of variation that affects dose in African Americans and an algorithm to guide dosing have yet to be investigated. In pursuit of this goal, Dr. Perera will first determine the genetic haplotype structure of CYP2C9 and VKORC1 in African Americans. By using comparative genomics and software that identifies putative functional regions, resequencing can be narrowed to areas most likely to yield informative SNPs. Next, haplotype-tagging SNPs along with non-genetic factors will be used to develop a predictive algorithm for maintenance dose in this population. Dr. Perera, along with collaborating physicians, will recruit African American anticoagulation patients and collect genotype data and non-genetic information. Regression analysis will be used to derive a dosing algorithm to predict maintenance dose. A second cohort of patients will be recruited to test the predictive power of this algorithm. Patient will be dosed empirically, as is standard of care;however, the correlation between predicted and observed maintenance dose will be determined. Lastly, she will evaluate the clinical outcomes through a pilot study in African American orthopedic patients. This study will be conducted to determine aspects of feasibility. Outcomes such as time to therapeutic INR and adverse events will be determined to assist in the development of a well-power clinical trial. Additional cost-effective analysis will be conducted to determine the utility of this algorithm in clinical care. The proposed research is both timely and necessary to fill gaps in the current knowledge and to affect real translation of pharmacogenetics into clinical practice. Such studies have the potential to change the way medicine is practiced.

Public Health Relevance

The accurate dosing of warfarin is critical to both clinicians and institutions. Therefore the development of an algorithm that would predict warfarin dose in African Americans, a currently under-studied population, would greatly improve clinical practice in numerous medical fields. Such research will help lead the way to the translation of pharmacogenetic findings into clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL089808-05
Application #
8463589
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F1))
Program Officer
Scott, Jane
Project Start
2009-07-15
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$120,339
Indirect Cost
$8,914
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Perera, M A; Cavallari, L H; Johnson, J A (2014) Warfarin pharmacogenetics: an illustration of the importance of studies in minority populations. Clin Pharmacol Ther 95:242-4
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
Perera, Minoli A; Cavallari, Larisa H; Limdi, Nita A et al. (2013) Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet 382:790-6
Shahin, Mohamed Hossam A; Cavallari, Larisa H; Perera, Minoli A et al. (2013) VKORC1 Asp36Tyr geographic distribution and its impact on warfarin dose requirements in Egyptians. Thromb Haemost 109:1045-50
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
Cavallari, Larisa H; Vaynshteyn, David; Freeman, Kimberly M et al. (2013) CYP2C9 promoter region single-nucleotide polymorphisms linked to the R150H polymorphism are functional suggesting their role in CYP2C9*8-mediated effects. Pharmacogenet Genomics 23:228-31
Cavallari, Larisa H; Perera, Minoli; Wadelius, Mia et al. (2012) Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans. Pharmacogenet Genomics 22:152-8
Gamazon, Eric R; Skol, Andrew D; Perera, Minoli A (2012) The limits of genome-wide methods for pharmacogenomic testing. Pharmacogenet Genomics 22:261-72
Cavallari, Larisa H; Shin, Jaekyu; Perera, Minoli A (2011) Role of pharmacogenomics in the management of traditional and novel oral anticoagulants. Pharmacotherapy 31:1192-207
Perera, M A; Thirumaran, R K; Cox, N J et al. (2009) Prediction of CYP3A4 enzyme activity using haplotype tag SNPs in African Americans. Pharmacogenomics J 9:49-60