N. Nwanze,1 W. Hernandez,1 M. Tuck,2 T. O'Brien,3 R. Kittles,4 J. Duarte,5 S. Bourgeois,6 L. Cavallari,7 M. Perera1; 1The University of Chicago, Chicago, IL, 2Veterans Affairs Medical Center, District of Columbia, DC, 3The George Washington University Medical Center, District of Columbia, DC, 4University of Arizona, Tucson, AZ, 5University of Illinois, Chicago, IL, 6Queen Mary University of London, London, United Kingdom, 7University of Florida, Gainesville, FL
BACKGROUND: Warfarin is the most widely prescribed oral anticoagulant but can have serious adverse effects, including hemorrhagic complications, which occur at a rate of up to 39% per year. Few associations between hemorrhagic risk and genetic variants have been implicated, including the well-established CYP2C9 *2 *3 and VKORC1 variants. However, these associations are observed in the initial stages of dosing yet hemorrhage may occur while a patient is on a stable warfarin dose.
METHODS: We present preliminary findings from the first genome-wide association study (GWAS) and risk of hemorrhage in African American (AA) patients (N=455). Cases (n=54) were on stable warfarin dose and had an ICD9 code indicating warfarin-related bleeding requiring hospitalization. Patients’ electronic medical records were searched to confirm status and bleed location.
RESULTS: Most bleeds occurred within or below the therapeutic INR range (30% and 52%, respectively). Although our results did not reach genome-wide significance due to our sample size, we found variants in ADAM30 (rs7547168) and SOX5 (rs10743490) and three intergenic variants (rs7503127, rs9276835, and rs9492507) associated with an increased risk of hemorrhage (ORs=2.8-3.7; P=10-6). ADAM30 functions as a blood coagulation inhibitor supporting our association for rs7547168 where the minor allele increases the risk of bleeding.
CONCLUSION: We are collaborating with institutions to increase our sample size to 570 and will validate our findings in an independent cohort of AAs on warfarin. Our study may help identify genetic variants that increase the risk of bleeding for AA patients while on therapeutic warfarin doses, and may help prioritize the use of new oral anticoagulants to reduce the risk for this dangerous adverse effect.