viernes, 7 de junio de 2013

Gene Variant in Blacks Alters Warfarin Response

Gene Variant in Blacks Alters Warfarin Response
NHLBI in the News
Medpage Today
Gene variant in Blacks alters warfarin response
The first genome-wide association study to focus on warfarin dose in African Americans found a genetic variant that explains their variable response to the blood thinner. The National Heart, Lung, and Blood Institute helped support this research.

Putting Breaking Medical News Into Practice

Gene Variant in Blacks Alters Warfarin Response

By Chris Kaiser, Cardiology Editor, MedPage Today

Published: June 05, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

The first genome-wide association study to focus on warfarin dose in African Americans found a genetic variant that explains their variable response to the blood thinner.
African Americans with one copy of the rs12777823 variant would need to reduce their warfarin dosage by 6.92 mg per week to obtain its full benefits, according to Julie Johnson, PharmD, of the Center for Pharmacogenomics at the University of Florida in Gainesville, and colleagues.
Those of African descent with two copies of this single-nucleotide polymorphism (SNP) would require a dose reduction of about 9 mg/week, a good portion of the 40 mg average weekly dose for African Americans, researchers reported online in The Lancet.
When researchers included this genetic marker to standard dosing algorithms, the predictability of warfarin dosing improved by 21%.
The effect size and the frequency of the SNPs make these findings important at a population level, researchers said.
"Use of genetic backgrounds to help to guide warfarin dosing has been advocated for several years by the FDA. However, the practical aspects -- and limitations -- have not been fully appreciated," commented Mark Alberts, MD, from UTSW Medical Center in Dallas, in a statement. Alberts was not involved in this study.
"Genetic testing has several challenges: it is not widely available in some areas, it is costly, and clinicians often can identify the correct dose before test results are available. If these problems were corrected, the actual use of such tests might increase substantially," Alberts added.
SNPs are also responsible for the one in five stenting patients in the U.S. who are poor responders to clopidogrel.
Researchers are finalizing a genotype-guided system expected to come online this fall that will administer clopidogrel alternatives, such as ticagrelor or prasugrel, when needed, said co-author Nita Limdi, of the University of Alabama Birmingham School of Medicine, in a statement.
Warfarin has been around for nearly 60 years and is prescribed as an anticoagulant in patients with atrial fibrillation, a history of previous blood clots, or after major surgery.
But dose requirements vary widely among people making it difficult to get the dose right, and warfarin contributes to a third of hospitalizations for adverse drug reactions in people older than 65 in the U.S.
The metabolization of warfarin is affected by SNPs in genes encoding CYP2C9 and VKORC1, the latter being the target enzyme for the drug.
These two genotypes account for about 30% of the variability of warfarin dose requirements in people of European and Asian descent, but just 7% to 10% in those of African ancestry.
Johnson and colleagues noted that African Americans have been absent in previous warfarin genome-wide association studies.
They therefore analyzed health information and DNA samples from 533 African-American adults on stable doses of warfarin from the International Warfarin Pharmacogenetics Consortium (IWPC) and the University of Alabama Birmingham School of Medicine.
When they found the strong association between rs12777823 and warfarin dose, they confirmed it in another independent cohort of 432 participants.
"On the basis of our data, the IWPC [dosing] algorithm could be used to estimate warfarin dose, and then the rs12777823 variant in African Americans could be accounted for with dose reductions," they concluded.
However, they cautioned that the results do not prove causation and more studies are needed to confirm these findings.
Anne E. Kwitek, PhD, associate director of the Iowa Institute of Human Genetics and not involved in the study, told MedPage Today there are inherent limitations to this type of study."A genome-wide association study assumes that the observed anomalies are common DNA variants found across different populations. But this type of genome study doesn't find every single variant that might play a role in a particular variability," she said.
"The authors of the study indicate the found variant is common. It's possible, however, that the [rs12777823] variant is not actually the causal variant, but only a variant inherited along with the actual causal variant. This is a potential limitation," she added.
UPDATE: This article, originally published June 4 at 8:14 p.m., was updated with new material (June 5, 11:26 a.m.).

Individual authors had support from NIH, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and Wellcome Trust.
Johnson reported she had no conflicts of interest. One co-author reported ties to Roche Diagnostics; another to Gentris Corporation. One co-author has a patent pending for CYP4F2 use for warfarin dosing, while another is founder, equity holder, and consultant for Personalis.

From the American Heart Association:

Primary source: The Lancet
Source reference:
Perera MA, et al "Genetic variants associated with warfarin dose in African-American individuals: A genome-wide association study" Lancet 2013; 381.