Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population.
BACKGROUND
Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements.


METHODS
We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin.


RESULTS
The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype.


CONCLUSIONS
Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.
Lee
Soo-Chin
SC
Department of Haematology-Oncology, National University Hospital, Oncology Research Institute, National University of Singapore, Singapore.
Ng
Swee-Siang
SS
Oldenburg
Johannes
J
Chong
Pei-Yi
PY
Rost
Simone
S
Guo
Jia-Yi
JY
Yap
Hui-Ling
HL
Rankin
Sheila Clare
SC
Khor
Hui-Boon
HB
Yeo
Tiong-Cheng
TC
Ng
Kheng-Siang
KS
Soong
Richie
R
Goh
Boon-Cher
BC
D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People; D002681:China / Q000208:ethnology; D065729:Cytochrome P-450 CYP2C9; D018076:DNA, Complementary / Q000235:genetics; D005006:Ethnicity; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007194:India / Q000208:ethnology; D008296:Malaysia / Q000208:ethnology; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011446:Prospective Studies; D012846:Singapore; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000925:Anticoagulants; D018076:DNA, Complementary; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases