Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose - PubMed
- ️Sat Jan 01 2005
. 2005 Jun 2;352(22):2285-93.
doi: 10.1056/NEJMoa044503.
Affiliations
- PMID: 15930419
- DOI: 10.1056/NEJMoa044503
Free article
Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose
Mark J Rieder et al. N Engl J Med. 2005.
Free article
Abstract
Background: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin.
Methods: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples.
Results: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination.
Conclusions: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.
Copyright 2005 Massachusetts Medical Society.
Similar articles
-
Limdi NA, Beasley TM, Crowley MR, Goldstein JA, Rieder MJ, Flockhart DA, Arnett DK, Acton RT, Liu N. Limdi NA, et al. Pharmacogenomics. 2008 Oct;9(10):1445-58. doi: 10.2217/14622416.9.10.1445. Pharmacogenomics. 2008. PMID: 18855533 Free PMC article.
-
Lee SC, Ng SS, Oldenburg J, Chong PY, Rost S, Guo JY, Yap HL, Rankin SC, Khor HB, Yeo TC, Ng KS, Soong R, Goh BC. Lee SC, et al. Clin Pharmacol Ther. 2006 Mar;79(3):197-205. doi: 10.1016/j.clpt.2005.11.006. Clin Pharmacol Ther. 2006. PMID: 16513444
-
Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MT, Chen CH, Motsinger-Reif A, Sagreiya H, Liu N, Wu AH, Gage BF, Jorgensen A, Pirmohamed M, Shin JG, Suarez-Kurtz G, Kimmel SE, Johnson JA, Klein TE, Wagner MJ; International Warfarin Pharmacogenetics Consortium. Limdi NA, et al. Blood. 2010 May 6;115(18):3827-34. doi: 10.1182/blood-2009-12-255992. Epub 2010 Mar 4. Blood. 2010. PMID: 20203262 Free PMC article.
-
Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives.
Yin T, Miyata T. Yin T, et al. Thromb Res. 2007;120(1):1-10. doi: 10.1016/j.thromres.2006.10.021. Epub 2006 Dec 11. Thromb Res. 2007. PMID: 17161452 Review.
-
Oldenburg J, Bevans CG, Fregin A, Geisen C, Müller-Reible C, Watzka M. Oldenburg J, et al. Thromb Haemost. 2007 Sep;98(3):570-8. Thromb Haemost. 2007. PMID: 17849045 Review.
Cited by
-
Patillon B, Luisi P, Blanché H, Patin E, Cann HM, Génin E, Sabbagh A. Patillon B, et al. PLoS One. 2012;7(12):e53049. doi: 10.1371/journal.pone.0053049. Epub 2012 Dec 28. PLoS One. 2012. PMID: 23285254 Free PMC article.
-
The future of warfarin pharmacogenetics in under-represented minority groups.
Cavallari LH, Perera MA. Cavallari LH, et al. Future Cardiol. 2012 Jul;8(4):563-76. doi: 10.2217/fca.12.31. Future Cardiol. 2012. PMID: 22871196 Free PMC article. Review.
-
Gene-drug interaction in stroke.
Amici S, Paciaroni M, Agnelli G, Caso V. Amici S, et al. Stroke Res Treat. 2011;2011:212485. doi: 10.4061/2011/212485. Epub 2011 Nov 10. Stroke Res Treat. 2011. PMID: 22135769 Free PMC article.
-
A review of pharmacogenetics of adverse drug reactions in elderly people.
Cardelli M, Marchegiani F, Corsonello A, Lattanzio F, Provinciali M. Cardelli M, et al. Drug Saf. 2012 Jan;35 Suppl 1:3-20. doi: 10.1007/BF03319099. Drug Saf. 2012. PMID: 23446782 Review.
-
Stroke Prevention in Atrial Fibrillation: A Scientific Statement of JACC: Asia (Part 1).
Chiang CE, Chao TF, Choi EK, Lim TW, Krittayaphong R, Li M, Chen M, Guo Y, Okumura K, Lip GYH. Chiang CE, et al. JACC Asia. 2022 Aug 16;2(4):395-411. doi: 10.1016/j.jacasi.2022.05.005. eCollection 2022 Aug. JACC Asia. 2022. PMID: 36339361 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials