Dataset Information

Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos.

ABSTRACT: We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (? = -0.29, P < 2.0 × 10^-16 ; ? = -0.21, P = 4.7 × 10^-7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (? = 0.10, P = 2 × 10^-4 ; ? = 0.10, P = 0.01, respectively). Associations with VKORC1 (? = -0.14, P = 2.0 × 10^-16 ), CYP2C9 (? = -0.07, P = 5.6 × 10^-10 ), and CYP4F2 (? = 0.03, P = 3 × 10^-3 ), but not NQO1*2 (? = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil.

SUBMITTER: El Rouby N

PROVIDER: S-EPMC7877858 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos.

El Rouby Nihal N Rodrigues Marcatto Leiliane L Claudio Karla K Camargo Tavares Letícia L Steiner Heidi H Botton Marianna R MR Lubitz Steve A SA Fallon Echo N EN Yee Kevin K Kaye Justin J Scott Stuart A SA Karnes Jason J Caleb Junior de Lima Santos Paulo P Duconge Jorge J Cavallari Larisa H LH

Clinical and translational science 20200908 1

We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Bra ...[more]

PMID: 32860733

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Project description:We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p<1.5 x 10(-7)) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that approximately 30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another approximately 12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10(-78)) at SNPs clustering near VKORC1 and the second lowest p-values (p<10(-31)) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p = 8.3 x 10(-10)) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.

Dataset Information

Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos.

Publications

Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos.

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