单核苷酸多态性与华法林初始抗凝疗效和维持剂量的研究

doi:10.3969/j.issn.1673-8640.2015.07.010

摘要/Abstract

摘要： 目的

筛选华法林初始抗凝治疗疗效和华法林维持剂量存在显著影响的基因因素。

方法

初始抗凝疗效组:选取进行心脏瓣膜置换的汉族患者212例,以术后4 d为观测期限,根据设立初始抗凝疗效的观测指标△INR_4-1[即观测期结束时的国际标准化比值(INR)与初始INR的差值],筛选出对于该指标存在显著影响的基因因素。同时观查上述因素与其它终点事件如INR>3、INR>4和3 d内是否入窗等是否相关。维持剂量组:选取服用华法林3个月以上的门诊患者266例,需满足相隔7 d以上、在服用相同剂量华法林的情况下,2次INR检测结果均在治疗窗内。筛选显著影响的基因因素。

结果

在初始抗凝疗效组中,CYP2C9 (rs1057910)、VKORC1 (rs9923231)和VKORC1 (rs2292566)对△INR_4-1有明显影响;CYP2C9 (rs1057910)和EPHX1(rs2292566)对3 d内INR是否进入治疗范围有明显影响(P<0.001、P<0.05)。在维持剂量组中,CYP2C9 (rs1057910)和VKORC1 (rs9923231)对每日及每周华法林剂量均有明显影响(P<0.001)。

结论

CYP2C9 (rs1057910)、VKORC1 (rs9923231)和EPHX1 (rs2292566) 对于华法林初始抗凝疗效有明显影响。CYP2C9(rs1057910)、VKORC1 (rs9923231)对华法林维持剂量有明显影响。

关键词: 华法林, 单核苷酸多态性, 初始抗凝疗效, 维持剂量

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

中图分类号:

Q503

吴炯, 李军, 邬升超, 张春燕, 宋斌斌, 王蓓丽, 郭玮, 潘柏申. 单核苷酸多态性与华法林初始抗凝疗效和维持剂量的研究[J]. 检验医学, 2015, 30(7): 707-714.

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.

图/表 8

参考文献 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	例数	BSA(m²)		体重(kg)			年龄(岁)			基础INR
CYP2C9(rs1057910)
AA型	194	1.70±0.16		62.43±10.70			53.49±12.83			1.14±0.92
AC/CC型	18	1.72±0.09		63.56±5.39			52.56±11.36			1.11±0.10
P值		0.702		0.756			0.833			0.304
VKORC1(rs1057910)
AA型	174	1.71±0.16		62.97±10.62			53.16±12.41			1.13±0.087
GA型	38	1.66±0.14		60.47±8.95			54.58±14.08			1.19±0.10
P值		0.208		0.343			0.661			0.008
EPHX1(rs2292566)
GG型	114	1.70±0.16		61.87±9.98			53.63±12.72			1.14±0.097
GA/AA型	98	1.71±0.16		63.29±10.81			53/16±12.74			1.14±0.088
P值		0.534		0.485			0.851			0.682
基因型	例数	高血压(例)		糖尿病(例)		性别(例)			△INR4-1
基因型	例数	否	是	否	是	男	女	GA/AA	△INR4-1
CYP2C9(rs1057910)
AA型	194	154	40	170	24	96	98	88	0.69(0.30~1.05)
AC/CC型	18	13	5	18	0	10	8	10	1.10(0.87~1.41)
P值		0.682		0.232		0.622			0.008
VKORC1(rs1057910)
AA型	174	139	35	154	20	90	84	80	0.81(0.45~1.25)
GA型	38	28	10	34	4	16	22	18	0.31(0.12~0.75)
P值		0.397		0.865		0.283			0.003
EPHX1(rs2292566)
GG型	114	88	26	102	12	55	59		0.63(0.27~0.97)
GA/AA型	98	78	20	86	12	51	47		0.84(0.45~1.22)
P值		0.673		0.694		0.582			0.034