Research on single nucleotide polymorphism with initial anticoagulative effect and maintenance dose of Warfarin

doi:10.3969/j.issn.1673-8640.2015.07.010

Abstract

Abstract: Objective

To screen genetic factors influencing Warfarin initial anticoagulative effect and maintenance dose.

Methods

A total of 212 Chinese Han mechanical heart valve replacement patients were enrolled as initial anticoagulative effect group. △INR_4-1 [the difference between international normalized ratio (INR) at the end of observation and initial INR] was used as an index to screen genetic factors during 4 d after their operations. The obtained results were needed to be identified whether they were associated with other endpoint events like overanticoagulation (INR>3 and INR>4) and time to first therapeutic INR in 3 d. In the maintenance dose group, 266 Chinese Han outpatients who had been taking Warfarin for over 3 months were enrolled. Warfarin maintenance dose was defined as the dose that led to the patients' INR within the therapeutic range measured at least 7 d, which was used to screen genetic factors.

Results

In the initial anticoagulative effect group, CYP2C9 (rs1057910), VKORC1 (rs9923231) and VKORC1 (rs2292566) were associated with △INR_4-1(P<0.05), and CYP2C9 (rs1057910) and EPHX1(rs2292566) were associated with time to first therapeutic INR (P<0.001, P<0.05). In the maintenance dose group, CYP2C9 (rs1057910) and VKORC1 (rs9923231) were associated with daily and weekly maintenance doses (P<0.05).

Conclusions

CYP2C9 (rs1057910),VKORC1 (rs9923231) and EPHX1 (rs2292566) show strongly association with Warfarin initial anticoagulative effect. CYP2C9 (rs1057910) and VKORC1 (rs9923231) are significant factors for maintenance dose.

Key words: Warfarin, Single nucleotide polymorphism, Initial anticoagulative effect, Maintenance dose

CLC Number:

Q503

WU Jiong, LI Jun, WU Shengchao, ZHANG Chunyan, SONG Binbin, WANG Beili, GUO Wei, PAN Baishen. Research on single nucleotide polymorphism with initial anticoagulative effect and maintenance dose of Warfarin[J]. Laboratory Medicine, 2015, 30(7): 707-714.

Figures/Tables 8

References 16

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基因	SNPs位点	序列(5'→3')	产物长度(bp)
VKORC1	rs9923231	F- GGGTTCAAGTGGTTCTCGTG	250
		R- CCTCTGGGAAGTCAAGCAAG
VKORC1	rs9934438	F- GGGTGGAACCAGGTTAGGAC	188
		R- AGGGGAGGATAGGGTCAGTG
CYP2C9	rs1799853	F- CCTGGGATCTCCCTCCTAGT	318
		R- CCGCTTCACATGAGCTAACA
CYP2C9	rs1057910	F- CTCCTTTTCCATCAGTTTTACT	284
		R- GATACTATGAATTTGGGACTTC
CYP4F2	rs2108622	F- CGATAAGTTCCGTTTCACC	470
		R- AGATTGCCACATCATTGGAC
EPHX1	rs2292566	F- CGATAAGTTCCGTTTCACC	331
		R- AGATTGCCACATCATTGGAC
EPHX1	rs4653436	F- TACCTGATGTACCTGGAAA	308
		R- ATCCTAATACCCTCCTACTT
EPHX1	rs1877724	F- TACAGGTAAGGAGGGTGG	357
		R- GGTTAGGGACTGGGAGAC
GGCX	rs12714145	F- TGTCTCTAAACATTGCCAAA	366
		R- AGGCTGGTCTCAAACTCC

基因	SNPs位点	序列(5'→3')	产物长度(bp)
VKORC1	rs9923231	F- GGGTTCAAGTGGTTCTCGTG	250
		R- CCTCTGGGAAGTCAAGCAAG
VKORC1	rs9934438	F- GGGTGGAACCAGGTTAGGAC	188
		R- AGGGGAGGATAGGGTCAGTG
CYP2C9	rs1799853	F- CCTGGGATCTCCCTCCTAGT	318
		R- CCGCTTCACATGAGCTAACA
CYP2C9	rs1057910	F- CTCCTTTTCCATCAGTTTTACT	284
		R- GATACTATGAATTTGGGACTTC
CYP4F2	rs2108622	F- CGATAAGTTCCGTTTCACC	470
		R- AGATTGCCACATCATTGGAC
EPHX1	rs2292566	F- CGATAAGTTCCGTTTCACC	331
		R- AGATTGCCACATCATTGGAC
EPHX1	rs4653436	F- TACCTGATGTACCTGGAAA	308
		R- ATCCTAATACCCTCCTACTT
EPHX1	rs1877724	F- TACAGGTAAGGAGGGTGG	357
		R- GGTTAGGGACTGGGAGAC
GGCX	rs12714145	F- TGTCTCTAAACATTGCCAAA	366
		R- AGGCTGGTCTCAAACTCC

组别	例数	性别(例)		年龄 (岁)		身高 (cm)			体重 (kg)
组别	例数	男	女	年龄 (岁)		身高 (cm)			体重 (kg)
初始剂量组	212	106	106	53.39±12.73		163.24±12.20			62.85±10.96
维持剂量组	266	146	120	60.98±14.38		166.07±8.19			66.61±11.95
组别	例数	糖尿病(例)		高血压(例)		吸烟(例)		饮酒(例)			服用胺碘酮(例)
组别	例数	是	否	是	否	是	否	是		否	是		否
初始剂量组	212	24	188	45	167	14	198	10		202	78	134
维持剂量组	266	30	236	NA		12	254	6		260	20	246

组别	例数	性别(例)		年龄 (岁)		身高 (cm)			体重 (kg)
组别	例数	男	女	年龄 (岁)		身高 (cm)			体重 (kg)
初始剂量组	212	106	106	53.39±12.73		163.24±12.20			62.85±10.96
维持剂量组	266	146	120	60.98±14.38		166.07±8.19			66.61±11.95
组别	例数	糖尿病(例)		高血压(例)		吸烟(例)		饮酒(例)			服用胺碘酮(例)
组别	例数	是	否	是	否	是	否	是		否	是		否
初始剂量组	212	24	188	45	167	14	198	10		202	78	134
维持剂量组	266	30	236	NA		12	254	6		260	20	246

基因型	分组	△INR_4-1				3 d内是否入窗
基因型	分组	1	2	3	4	P值	否	是	P值
CYP2C9(rs1799853)	Ⅰ	50	58	50	54	NA	102	110	NA
	Ⅱ	0	0	0	0		0	0
CYP2C9(rs1057910)	Ⅰ	50	56	42	46	0.003	101	93	<0.001
	Ⅱ	0	1	9	8		1	17
VKORC1(rs9923231)	Ⅰ	34	44	44	52	0.022	80	94	0.183
	Ⅱ	16	10	8	4		22	16
CYP4F2(rs2108622)	Ⅰ	24	28	28	24	0.868	52	52	0.590
	Ⅱ	27	28	23	30		50	58
EPHX1(rs1877724)	Ⅰ	24	26	28	36	0.145	54	60	0.815
	Ⅱ	26	32	23	17		48	50
EPHX1(rs4653436)	Ⅰ	30	30	33	33	0.940	62	64	0.700
	Ⅱ	20	25	21	20		40	46
EPHX1(rs2292566)	Ⅰ	34	38	20	22	0.031	63	51	0.025
	Ⅱ	19	21	29	29		39	59
GGCX (rs12714145)	Ⅰ	24	26	18	22	0.669	40	50	0.358
	Ⅱ	26	30	34	32		62	60