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Meta-Analysis
. 2020 Jun;107(6):1420-1433.
doi: 10.1002/cpt.1755. Epub 2020 Jan 28.

Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis

Innocent G Asiimwe  1 , Eunice J Zhang  1 , Rostam Osanlou  1 , Amanda Krause  2 , Chrisly Dillon  3 , Guilherme Suarez-Kurtz  4 , Honghong Zhang  5 , Jamila A Perini  6 , Jessicca Y Renta  7 , Jorge Duconge  7 , Larisa H Cavallari  8 , Leiliane R Marcatto  9 , Mark T Beasly  3 , Minoli A Perera  5 , Nita A Limdi  3 , Paulo C J L Santos  10 , Stephen E Kimmel  11 , Steven A Lubitz  12 , Stuart A Scott  13   14 , Vivian K Kawai  15 , Andrea L Jorgensen  16 , Munir Pirmohamed  1
Affiliations
Meta-Analysis

Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis

Innocent G Asiimwe et al. Clin Pharmacol Ther. 2020 Jun.

Abstract

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.

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Conflict of interest statement

CONFLICT OF INTEREST

S.A.L. receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb / Pfizer and Bayer AG. All other authors declared no competing interests for this work.

Figures

Figure 1.
Figure 1.
Evidence search and selection
Figure 2.
Figure 2.. Forest plots for associations between CYP2C9 and stable warfarin dose.
*CYP2C9 star allele, †standard meta-analysis (fixed effects assumed with low heterogeneity (I2 <30%), else random effects), ‡article as data source (otherwise author-provided). CI = confidence intervals; CYP2C9 = cytochrome P450 family 2 subfamily C member 9; MD = mean difference; SD = standard deviation.
Figure 2.
Figure 2.. Forest plots for associations between CYP2C9 and stable warfarin dose.
*CYP2C9 star allele, †standard meta-analysis (fixed effects assumed with low heterogeneity (I2 <30%), else random effects), ‡article as data source (otherwise author-provided). CI = confidence intervals; CYP2C9 = cytochrome P450 family 2 subfamily C member 9; MD = mean difference; SD = standard deviation.
Figure 3.
Figure 3.. Forest plots for associations between VKORC1 and stable warfarin dose.
‡article as data source (otherwise author-provided), §Shrif study estimates flipped, first genotype contrast with high heterogeneity so requires cautious interpretation. CI = confidence intervals; MD = mean difference; SD = standard deviation; VKORC1 = vitamin K epoxide reductase complex subunit 1.
Figure 3.
Figure 3.. Forest plots for associations between VKORC1 and stable warfarin dose.
‡article as data source (otherwise author-provided), §Shrif study estimates flipped, first genotype contrast with high heterogeneity so requires cautious interpretation. CI = confidence intervals; MD = mean difference; SD = standard deviation; VKORC1 = vitamin K epoxide reductase complex subunit 1.
Figure 4.
Figure 4.. Forest plots for associations between other genes and stable warfarin dose.
*CYP4F2 and NQO1 star alleles, †standard meta-analysis (fixed effects assumed with low heterogeneity (I2 <30%), else random effects), ‡article as data source (otherwise author-provided). CI = confidence intervals; CYP2C = cytochrome P450 family 2 subfamily C; CYP4F2 = cytochrome P450 family 4 subfamily F member 2; MD = mean difference; NQO1 = NAD(P)H quinone dehydrogenase 1; SD = standard deviation.
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