A polymorphism in the VKORC 1-regulator calumenin predicts higher warfarin doses in African-Americans

Corresponding author: Brian F. Gage, MD, MSc, telephone (314) 454-8369, fax (314) 454-5554, bgage@im.wustl. edu, Division of General Medical Sciences, Washington University School of Medicine Campus Box 8005, 660 S. Euclid Ave., St. Louis, MO, 63110. *deceased Authorship and conflicts of interest Voora D: responsible for study design, analytical approach, analysis and interpretation of data, and drafting manuscript; no conflict of interest Koboldt DC: responsible for study design, interpretation of sequence analysis, and critical revision of manuscript; no conflict of interest King CR: responsible for study design, interpretation and performing genotype analysis, and critical revision of manuscript; no conflict of interest Lenzini P: responsible for study design, interpretation and performing statistical analysis, and critical revision of manuscript; no conflict of interest Eby C: responsible for study design, performing genotype and sequence analyses, and critical revision of manuscript; no conflict of interest Porche-Sorbet R: responsible for performing genotype analysis, and critical revision of manuscript; no conflict of interest Deych E: responsible for study design, interpretation and performing statistical analysis, and critical revision of manuscript; no conflict of interest Crankshaw M: responsible for interpretation and performing sequence analysis and critical revision of manuscript; no conflict of interest Milligan PE: responsible for participant recruitment and warfarin dose management, and critical revision of manuscript; no conflict of interest McLeod HL: responsible for study design and critical revision of manuscript; no conflict of interest Patel SR: responsible for genotyping and genotype analysis for replication cohort #2 and critical revision of the manuscript; no conflict of interest Cavallari LH: responsible for participant recruitment and data analysis for replication cohort #2 and critical revision of the manuscript; no conflict of interest Ridker P: responsible for providing PREVENT study samples and critical revision of manuscript; no conflict of interest Grice GR: responsible for participant recruitment and, warfarin dose management, and critical revision of manuscript; no conflict of interest Miller RD: responsible for study design, interpretation of sequence analysis, and critical revision of manuscript; no conflict of interest Gage BF: responsible for study design, analytical approach, analysis and interpretation of data, obtaining funding, and critical revision of manuscript; no conflict of interest Washington University in St. Louis may file for a patent for CALU rs339097. NIH Public Access Author Manuscript Clin Pharmacol Ther. Author manuscript; available in PMC 2011 April 1. Published in final edited form as: Clin Pharmacol Ther. 2010 April ; 87(4): 445–451. doi:10.1038/clpt.2009. 291. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript Background—Warfarin demonstrates wide interindividual variability that is partly mediated by variants in CYP2C9 and VKORC1. Whether variants in CALU (vitamin K reductase regulator) influence warfarin dose is unknown. Methods and Results—We resequenced CALU regions in a discovery cohort of dose-outliers: patients with high(>90th percentile, n=55) or low(<10th percentile, n=53) dose requirements(after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high-doses(p=0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: 1)496 patients of mixed ethnicity, 2)194 African-American patients. The G allele of rs339097(African-American and Caucasian allele frequency 0.14 and 0.002, respectively), was associated with a 14.5%(SD±7%) greater therapeutic dose(p=0.03) in the first replication cohort and a higher than predicted dose in the second replication cohort(allele frequency=0.14, one-sided p=0.03). Conclusions—CALU rs339097 A>G is associated with higher warfarin dose requirements independent of known genetic and nongenetic predictors of warfarin dose in African-Americans.