The Coriell personalized medicine collaborative pharmacogenomics appraisal, evidence scoring and interpretation system

Gharani, Neda; Keller, Margaret A; Stack, Catharine B; Hodges, Laura M; Schmidlen, Tara J; Lynch, Daniel E; Gordon, Erynn S; Christman, Michael F

doi:10.1186/gm499

Table 6 Genotype-phenotype drug response interpretations of the Pharmacogenomics Advisory Group-approved drug-gene pairs: warfarin and CYP2C9/VKORC1/CYP4F2 ^a

From: The Coriell personalized medicine collaborative pharmacogenomics appraisal, evidence scoring and interpretation system

Common diplotypes^b	Expected population frequency, %^c			PK/PD phenotype	Clinical phenotype	FDA guidelines
Common diplotypes^b	Caucasian ancestry	African ancestry	East Asian ancestry	PK/PD phenotype	Clinical phenotype	FDA guidelines
Warfarin and CYP2C9
CYP2C91/1	67	76	88	EM: normal enzymatic function and normal drug elimination	Expected to have a normal response at standard dose of warfarin	The warfarin drug label includes a table of CYP2C19 and VKORC1 genotype-based therapeutic dosing guidelines, which provides the range of expected therapeutic doses based on genotype combinations (based on VKORC1 -1639G > A (rs9923231) and CYP2C92* and CYP2C93* variants) (see Additional file 1: Table S17)
CYP2C91/2, CYP2C91/14 and other rare diplotypes (see Additional file 1: Table S12)	20	17	4	IM: reduced enzymatic function, leading to reduced drug elimination and greater drug exposure	At increased risk of bleeding at standard dose of warfarin.^d. Takes longer to reach therapeutic INR; requires lower dose of warfarin
CYP2C91/3, CYP2C2/2, CYP2C2/3, CYP2C3/3, and other rare diplotypes (see Additional file 1: Table S12)	13	7	8	PM: greatly reduced enzymatic function, leading to reduced drug elimination and greatly increased drug exposure	At increased risk of bleeding at standard dose of warfarin.^d Takes longer to reach therapeutic INR; requires lower dose of warfarin
Warfarin and VKORC1
−1639G > A (rs9923231): GG	40	74	1	Normal mRNA expression; normal enzyme activity and efficient vitamin K cycling	Associated with a requirement for higher therapeutic warfarin dose.^d Potentially at increased risk of thrombosis at standard dose
−1639G > A (rs9923231): GA	47	24	20	Reduced mRNA expression; reduced enzyme activity and vitamin K cycling	Associated with a requirement for intermediate therapeutic warfarin dose^d
−1639G > A (rs9923231): AA	13	2	79	Greatly reduced mRNA expression level; significant reduction in enzyme activity and vitamin K cycling	Associated with a requirement for lower therapeutic warfarin dose.^d Potentially at increased risk of bleeding events
Warfarin and CYP4F2
1297G > A, CYP4F2 V433M: GG	53	83	63	Higher CYP4F 2 activity results in reduced hepatic vitamin K levels	Associated with a requirement for lower therapeutic warfarin dose.^d Potentially at increased risk of bleeding events	–
1297G > A, CYP4F2 V433M: GA	40	16	33	Intermediate CYP4F2 activity results in intermediate hepatic vitamin K levels	Associated with a requirement for intermediate therapeutic warfarin dose^d	–
1297G > A, CYP4F2 V433M: AA	7	1	4	Reduced CYP4F2 activity results in increased hepatic vitamin K levels	Associated with a requirement for higher therapeutic warfarin dose.^d Potentially at increased risk of thrombosis at standard dose	–

Abbreviations: EM Extensive metabolizer, FDA Food and Drugs Administration, IM intermediate metabolizer, INR international normalized ratio, PD pharmacodynamic, PK pharmacokinetic, PM poor metabolizer.
^aSupporting evidence may be found in Additional file 2: Section S4.0 to 4.7 and Additional file 1: Tables S11 to S17. These include summaries of the PhAESIS evaluation and referenced publications supporting the drug-gene clinical phenotypes.
^bDiplotypes with frequencies of less than0.4% in Caucasians are included above. Other rare diplotypes that fall under the same phenotype category can be found in the genotype-phenotype Punnett tables (see Additional file 1: Tables S12, S14 and S16). Diplotypes above and in the genotype-phenotype Punnett tables include clinically validated genetic results (those that include variants with evidence code 1).
cPopulation frequencies are estimated based on reported gene variant allele frequencies (see Additional file 1: Table S11, S13 and S15) and Hardy-Weinberg principles.
^dEmpiric starting doses range from 3 to 5 mg/day [36, 37]; FDA therapeutic dosing guideline table ranges: low dose (0.5 to 2 mg/day), intermediate dose (3 to 4 mg/day) and high dose (5 to 7 mg/day).

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ISSN: 1756-994X

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