Cytochrome P450 2C9 gene polymorphism and warfarin ...download.xuebalib.com/xuebalib.com.10993.pdf · Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in

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This article has been accepted for publication and undergone full peer review but has not

been through the copyediting, typesetting, pagination and proofreading process, which may

lead to differences between this version and the Version of Record. Please cite this article as

doi: 10.1111/1755-5922.12230

This article is protected by copyright. All rights reserved.

Received Date : 29-Jun-2016

Revised Date : 02-Sep-2016

Accepted Date : 19-Sep-2016

Article type : Original Research Article

Cytochrome P450 2C9 gene polymorphism and warfarin maintenance dosage in

pediatric patients: A systematic review and meta-analysis

running title: CYP2C9 gene and warfarin maintenance dosage

Jinhua Zhang 1,1

, Lihong Tian1,2

,Jinlong Huang 2, 3

, Sihan Huang 3, 3

,Tingting Chai4,3

,Jianzhen

Shen*, 3

1Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou 350001, PR

China

2Department of Hematology/ Rheumatology, the Second Hospital of Xiamen, Xiamen361021, PR

China.

3Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian

Medical University Union Hospital, Fuzhou 350001, PR China

1 Lihong Tian and Jinhua Zhang contributed equally to this work.

*Correspondence to:

Dr.Jianzhen Shen;Department of Hematology, Fujian Medical University Union Hospital,

Xinquan Road #29, Fuzhou, China, 350001. Tel.: +86 591 83357896-8301; Email:

[email protected]

mailto:[email protected]

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Abstract

Aim: To assess the effect of Cytochrome P450 2C9 (CYP2C9) gene polymorphism on

pediatric warfarin maintenance dosage requirement.

Methods：A previously developed search strategy was conducted in PubMed, EMBASE,

and the Cochrane Library. Eligible studies published prior to January 27, 2016, were

identified and compared against strict inclusion/exclusion criteria. Required data were

extracted, and researchers were consulted for additional data if needed. Review Manager

Version 5.2.3 software was used to analyze the relationship between CYP2C9 polymorphisms

and warfarin maintenance doses in pediatric patients. Eight articles with a combined total of

507 pediatric patients were included in the meta-analysis.

Results：Maintenance warfarin doses in patients with CYP2C9 *1/*2 genotype, CYP2C9

*1/*3 genotype, and CYP2C9 variant carriers which contain at least one variant allele (*2 or

*3) were from 15% to 41% lower than doses in patients with the wild type allele (CYP2C9

*1/*1): all differences were significant with P-values <0.05. The Fontan procedure as a

medical indication for anticoagulation was also associated with a lower warfarin maintenance

dose; however, target INR range was not.

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Conclusions: We found that CYP2C9 gene polymorphism(referring to the presence of *1/*2,

*1/*3, and variant genotypes in the population in addition to the wild type) was significantly

associated with decreased warfarin maintenance dose requirements. Additionally, a specific

indication for warfarin, the Fontan procedure, was associated with a lower daily warfarin

dose. However, the results of our study require confirmation from more research with larger

numbers of pediatric patients.

Keywords: Warfarin, Pediatric patients, CYP2C9, Gene polymorphisms, Systematic review,

Meta-analysis

Introduction

Warfarin, a vitamin K antagonist used as an oral anticoagulant, is widely prescribed for

preventing the thrombosis. However, proper dosing can be clinically challenging due to its

narrow therapeutic range as well as an almost twenty-fold difference in the dosages required

for adequate anticoagulation. The prothrombin time (PT) and international normalized ratio

(INR) should be monitored to ensure the desired antithrombotic effect while minimizing the

risk of bleeding.

Over the past decade, researchers have proven that two genes, CYP2C9 and VKORC1,

explain up to 40% of the variability seen in maintenance warfarin dosing requirements of

adults.[1-3]CYP2C9is highly polymorphic, which can lead to a significant influence on the

metabolism of drugs.[4]In 1999,Aithal et al. have demonstrated that there is a strong association

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between CYP2C9 variant alleles and warfarin dose requirement[5]. After that, many studies have

certified the significant effect of CYP2C9on warfarin doses in adult patients[6-11].Moreover, a

dosing algorithm for adult patients has been established by the US Food and Drug

Administration and International Warfarin Pharmacogenetics Consortium[1,2]. However, due

to several factors，the pharmacogenetic model for adults cannot be directly used for pediatric

patients, and need for pediatric-focused pharmacogenomic studies[12,13].One is that the

maturation of metabolic enzymes, which is age-related, has a significant effect on warfarin

dose requirements [14].In addition, there are dietary differences in vitamin K intake among

pediatric patients (e.g., breast milk vs. formula diets in infants), which affect warfarin

activity[15].Furthermore, clinical characteristics, such as indication for warfarin and the target

INR range, cause great variability in the dose requirement for warfarin in children.

CYP2C9 is located on human chromosome 10q24.2 and is approximately 55kb in length.

In adults, CYP2C9mutant types require a 19.6 to 78.1% lower warfarin dose for proper

anticoagulation[6]. There have also been studies that focused on CYP2C9 polymorphism and

warfarin dosing in pediatric patients [16-23].Questions about the effects of CYP2C9

polymorphism on pediatric warfarin dosing and about the possible development of a

pharmacogenetic model for children remain unanswered. For this reason, it has been

proposed that a meta-analysis be performed [4].Therefore, we conducted a systematic review

to analyze the relationship between warfarin maintenance dosage and gene polymorphism in

pediatric patients.

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Methods and Materials

Search strategy

A comprehensive search was conducted in PubMed, EMBASE, and the Cochrane

library for relevant English-language research articles published prior to January 27, 2016

(the date the search was completed). The search field strategy used was (CYP2C9 OR

cytochromes OR Cytochrome-p-450 OR Cytochrome p-450 OR “Cytochrome P450”) OR

(warfarin AND [gene OR genotype OR genetics OR alleles OR polymorphisms OR

pharmacogenetics] AND (neonate OR infant OR child OR adolescents OR pediatrics OR

pediatric). The included literature references were examined and the authors were consulted

for any additional information.

Study inclusion criteria

A strict set of inclusion criteria was used to find eligible studies: (1) the focus was on the

relationship between CYP2C9 polymorphism and warfarin maintenance dosing; (2) the

sample size and mean warfarin maintenance dose and standard deviation [SD] for each

CYP2C9 genotype group was provided; (3) data was given for patients in the pediatric age

group (ages <19 years); (4) the mean age of subjects and information about their ethnicities

were given. No restrictions were set for other clinical characteristics, such as possible

interacting drugs, clinical indications for warfarin, or the sex ratio of patients.

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Study exclusion criteria

Studies were excluded from the meta-analysis if (1) data were not provided, or could not

be obtained, on the mean warfarin dose and SD, patient sample size, patient age, or patient

ethnicity; (2) data were not provided specifically for a population of pediatric patients; (3) the

data were already reported in a previous article; and (4) the publication type was an abstract,

conference proceeding, review article, letter, or case report.

Data extraction

All required data were extracted independently by two researchers. To avoid potential

data extraction errors, cross-checking was performed. If there was a question about any

extracted data, there was discussion to reach a consensus regarding the data’s inclusion.

Additional required data was obtained by consulting researchers when necessary. Information

extracted included names of the first authors, publication years, target INR ranges,

predominant patient ethnicities, mean ages, sex ratios, indications for warfarin use, sample

sizes, allele frequencies, and warfarin maintenance doses (means with SDs) for single

nucleotide polymorphism (SNP) genotypes.

Quality assessment

The criteria predefined by Lindh JD et al.[24]were used to conduct a Quality Score

Assessment. The quality criteria were (1) analytical validity of genotyping (including sample

types, time of sample collection, genotyping method, and quality control measures); (2)

selection of study subjects (including geographic area(s), recruitment period, methods,

exclusion criteria for cases and controls, sample size, mean age with SD or age range of study

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subjects, and sex ratio); (3) population stratification (including identified potential correlates

of the genotype and potential correlates taken into consideration for design or analysis); (4)

statistical issues (including the number of subjects included in the analysis, analysis method,

software used to perform the analysis, and confidence intervals [CIs]). Studies were graded as

“++”, “+”or “-”, respectively, depending on whether most criteria, some criteria, or no

criteria were fulfilled.

Statistical analysis

In our meta-analysis, we defined CYP2C9 *1/*1genotype (the wild type) as the

reference group, and included any genotype containing at least one variant allele (*2 or *3) in

the variant group. To reduce the existence of any heterogeneity due to pharmacodynamic

differences in warfarin sensitivity among study populations, warfarin maintenance doses

(mean ± SD) for each genotype group (including the variant group) were normalized using

the method of Lindh et al[6] ( dividing the mean maintenance dose of reference group).The

normalized mean daily warfarin dose (MDWDs) of the genotype groups were compared with

the MDWD of the reference group. However, due to the normalization procedure, results

were not expressed as absolute difference, but as relative differences (e.g., a mean difference

of 0.5 indicates a 50% increase in the MDWD.)[6].

Meta-analysis was conducted using Review Manager Software version 5.2.3. The inverse

variance method was used to weight each study, and the mean difference (MD) was

employed to determine the effect of each CYP2C9 genotype on the MDWD. The Weighted

Mean Difference (WMD) could be acquired by multiplying each MD by the relative weight

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of each study. The total WMD in each comparison was obtained by adding each WMD of the

included studies, indicating the effect of each SNP on the MDWD. The influence of genotype

polymorphism was considered statistically significant when the P-value was less than 0.05.

Heterogeneity among studies for each comparison group was tested by Cochran's Q test

(Mantel-Haenszel chi-squared test), and expressed by the PH value and I2. A PH value >0.1 or

I2

< 25% was defined as negative for heterogeneity[6].Then, a fixed effect model was used in

the absence of heterogeneity; whereas, a random effect model was used if it was present.

Sensitivity analyses were performed using a one by one study elimination process.

Publication bias was also assessed using tests from Begg[25] and Egger's test[26].

Results

Study identification and characteristics

A total of 210 articles were screened through the literature search. Use of strict

inclusion/exclusion criteria resulted in only eight articles with a total of 507 pediatric patients

remaining for meta-analysis [16-19,27-30].The flow diagram for study selection is shown in

Supplementary Figure S1. All studies are of high quality, being graded as “++”. Some studies

were excluded for insufficient data [20-22,31]. All of the included remaining studies were

published in English and primarily consisted of Caucasian patients, except for the one by

Hirai et al[29].Years of publication ranged from 2012 to 2015. Characteristics of selected

studies are shown in Table 1.

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The frequency of *1/*1 (wild type), *1/*2, *1/*3, *2/*2, and *2/*3 was calculated as

70.4%, 13.8%, 10.7%, 3.6%, and 1.6, respectively. No pediatric patients in the remaining

studies had the CYP2C9 *3/*3 genotype. Comparison of CYP2C9 genotype frequencies

between adult and pediatric patients is shown in Supplementary Table S1.

Meta-analysis

The relationship between CYP2C9 *1/*2 and warfarin maintenance dosage

There were five studies investigating the impact of the CYP2C9 *1/*2 genotype on

warfarin maintenance dosage [18,19,27,28,30]. The result of the meta-analysis is shown in

Fig. 1. Analysis revealed that the CYP2C9 *1/*2 genotype was associated with a warfarin

maintenance dose that was 15% lower than that found with CYP2C9*1/*1 (wild) genotype

(P = 0.03, WMD = -0.15, 95% CI -0.29 to -0.01). (No heterogeneity was found in the

meta-analysis [I2

= 0%, PH = 0.70], so a fixed-model was used.) The effect of CYP2C9

*1/*2on warfarin maintenance dosage in Caucasians pediatric patients was compared to adult

patients, and is shown in Supplementary Table S1.

The relationship between CYP2C9 *1/*3 and warfarin maintenance dosage

There were also five studies included for meta-analysis which gave data for the CYP2C9

*1/*3 genotype [18,19,27-29].Compared with the wild genotype, pediatric patients with

CYP2C9 *1/*3 required a 41% lower warfarin maintenance dose (P < 0.00001, WMD=

-0.41, 95% CI -0.51 to -0.31). (Again, the fixed-model was applied due to lack of

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heterogeneity [I2

< 25%, PH = 0.26]). The result is presented in Fig. 2. A comparison of the

CYP2C9 *1/*3 genotype between pediatric and adult patients in Caucasians is found in

Supplementary Table S1.

The relationship between CYP2C9 variant carriers and warfarin maintenance dosage

Two studies focused on the relationship between the CYP2C9 variant genotype and

warfarin maintenance dosage[16,17].The results of meta-analysis are shown in Fig. 3, which

indicate that pediatric patients with a variant carriers required significantly lower warfarin

maintenance dosage than those with the wild-type (P = 0.004, WMD = -0.26, 95% CI -0.44

to -0.08). (A fixed model method was used because analysis showed homogeneity

[PH = 0.12]).

The effect of clinical characteristics on warfarin maintenance dosage

Included studies provided data on the significance of only two clinical factors in pediatric

patients—namely, indication for warfarin and target INR range[18,27].For analyzing data, we

divided target INR ranges into a 2–3 INR range group and a >2.5 INR group, as we had in a

previous study[32]. Indications for warfarin were also divided into two groups, Fontan

procedure vs. “others”. Meta-analysis revealed that the Fontan procedure indication was

associated with a lower warfarin maintenance dose requirement (WMD = -1.50, 95% CI

-2.46 to -0.54), while the target INR had no effect on the dose requirement (WMD = -0.12,

95% CI -1.19 to 0.96). The random effect model was used in the two meta-analyses (I2

≥

41%). The results were similar to those of our previous study[32] and are shown in Fig.4A

and 4B

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Sensitivity analysis and Publication bias

Sensitivity analysis was conducted using the method of eliminating studies one by one.

There were no significant differences or revisal changes, which meant that the results of this

analysis were stable. Both Begg's[25] and Egger's tests[26] were applied to detect publication

bias in each analysis, and none was found. These analyses indicate that our results are stable

and reliable.

Discussion

The results of meta-analysis showed that comparing to the CYP2C9 *1/*1genotype,

the CYP2C9 *1/*2genotype required15% lower warfarin maintain doses (95% CI -0.29

to -0.01), the CYP2C9*1/*3 genotyperequired 41% lower warfarin maintain doses

(95% CI -0.51 to -0.31), and the CYP2C9 variant carriers were required 26% lower

warfarin maintain doses (95% CI -0.44 to -0.08), respectively. The indication of Fontan

procedure was also associated with a lower warfarin maintenance dose (WMD=-1.50,

95% CI -2.46 to -0.54), while the target INR range was not related to the dosage level (P >

0.05).

It is well known that gene polymorphisms affect warfarin maintenance dose

requirements for adult patients, and that warfarin dosing algorithms should be used to address

the presence of variant genotypes and other factors[2,6,11,33-35].Taskın et al. have certified

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that pediatric Patients with allelic variants (VKORC1 and CYP2C9) required lower warfarin

doses, and a 64.5% correlation could be found between their calculated ideal doses and

administered warfarin doses[36].The effect of VKORC1 −1639 SNPs on pediatric warfarin

maintenance dosage has been examined[32], and the result was consistent with a previous

study in adult patients[37].Many studies have indicated that CYP2C9 polymorphisms

significantly influence warfarin maintenance dose in pediatric patients[16,18,27].The variant

genotypes CYP2C9 *1/*2 and *1/*3 are the most common and have been found to be

important factors related to warfarin dosage in adults [6].Therefore, we chose to conduct a

meta-analysis examining these two genotypes (*1/*2 and *1/*3) and warfarin dosing in

pediatric patients, and obtained results similar to those found with adult patients[6].

In addition, we believe clinical factors should be taken into consideration in the

determination of warfarin maintenance doses. Sixteen years ago, Streif et

al.[38]demonstrated, based on data from 319 patients, that age and the clinical indication for

warfarin use was associated with the actual maintenance dose needed. Since then, more

studies have shown that various clinical factors (age, weight, indication for warfarin, and

target INR range) significantly affect the maintenance dose requirement[16,18,19,27].In this

meta-analysis, the effect of two factors (target INR range and indication of warfarin) were

analyzed and results showed that pediatric patients on warfarin for a history of Fontan

procedure needed significantly lower warfarin doses, whereas the target INR range did not

influence dosage requirements.

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We performed a comparison of the CYP2C9 genotype frequency and the association

between CYP2C9 genotypes and warfarin maintenance dose for adult and pediatric patients in

Caucasian. The results were similar (see Supplementary Table S1). However, due to the low

frequencies of the CYP2C9 *2/*2, CYP2C9 *2/*3, and CYP2C9 *3/*3 genotypes, and the

small number of articles and pediatric sample sizes, the impact of these genotypes on

warfarin maintenance dose requirement is uncertain.

Sensitivity analysis and other tests revealed no publication bias or heterogeneity,

showing that the results of our meta-analysis are stable and reliable.

Considering the results of this study in combination with those from our previous study

that focused on VKORC1 polymorphism and pediatric warfarin maintenance dosing[32],we

believe that gene polymorphisms do significantly affect warfarin maintenance dosage

requirements in children. Although studies in pediatric patients to date are limited in terms of

sample size and lack of ethnic diversity, considering the data from adult studies, we do feel

that the addition of genotype to current warfarin dosing algorithms for pediatric patients

would be beneficial. Genotyping should certainly be considered for all pediatric patients who

are at high risk of bleeding complications, who are warfarin-resistant, or who suffer adverse

events while receiving warfarin.

Limitations and Perspectives

Although sensitivity analysis reflected stable results without publication bias, the results

of this meta-analysis should be considered with caution, due to the limited number of studies

meeting selection criteria and overall low numbers of pediatric patients. Moreover, the effects

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of the CYP2C9 *3/*3, *2/*2, and *2/*3 genotypes on warfarin maintenance dosage are still

uncertain, because rare research mentioned them. In addition, all studies except for one study

[29] involved in primarily Caucasian patients; therefore, the effect of CYP2C9 polymorphism

on warfarin dose requirements in Asian and African pediatric patients is undefined. More

studies looking at the relationship between CYP2C9 polymorphism and warfarin are

necessary in the future. More research examining the impact of clinical factors, such as the

medical indication for anticoagulation and age, are also needed and anticipated. Finally,

future studies, which will update this meta-analysis, and pharmacogenetic dosing algorithms,

which will be developed for pediatric patients as they have been for adults, were hope.

Conclusion

This meta-analysis firstly focused on the relationship between CYP2C9 polymorphism

and warfarin maintenance dose in pediatric patients, and we found that the CYP2C9 *1/*2,

CYP2C9 *1/*3, and CYP2C9 variant genotypes required significantly lower warfarin daily

doses. It was also shown that pediatric patients needing anticoagulation after a Fontan

procedure required significantly lower warfarin maintenance doses. A larger number of

studies is required to ensure against publication bias and confirm generalizability. More data

is also needed to build pharmacogenetic dosing algorithms for pediatric patients. Ideally,

these algorithms will include both genotype data (CYP2C9 and VKORC1) and clinical factors

(such as age, indication for warfarin, weight and possibly others).

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Funding sources

This work was supported by grants from the National Natural Science Foundation of

China (81370629), National and Fujian Provincial Key Clinical Specialty Discipline

Construction Program, P.R.C, the Scientific Research Foundation for the Returned Overseas

Chinese Scholars, State Education Ministry (2015B001) and the Fujian Medical Innovation

Project (2014-CX-18).

Conflict of Interest

The authors declared no conflict of interest.

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genetic polymorphisms on warfarin dose requirements in a pediatric population.

Anatol J Cardiol 2016: 16: 000-000.

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[37] Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on

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[38] Streif W1, Andrew M, Marzinotto V, Massicotte P, Chan AK, Julian JA, et al. .

Blood. 1999;94:3007-3014.

Figure Legends

Figure 1: Forest plot showing the influence of CYP2C9 *1/*2 on warfarin maintenance

dosage, compared with individuals with the CYP2C9 *1/*1 genotype (wild type). SD:

standard deviation of normalized mean warfarin doses associated with each genotype. CI:

confidence interval. Brackets denote 95% CIs.

Figure.2: Forest plot showing the influence of CYP2C9 *1/*3 on warfarin maintenance

dosage, compared with individuals with the CYP2C9 *1/*1 genotype (wild type). SD:

standard deviation of normalized mean warfarin doses associated with each genotype. CI:

confidence interval. Brackets denote 95% CIs.

Figure. 3: Forest plot showing the influence of CYP2C9 variant genotype (any genotype

containing at least one variant allele) on warfarin maintenance dosage, compared with

individuals with the CYP2C9 *1/*1 genotype (wild type). SD: standard deviation of

normalized mean warfarin doses associated with each genotype. CI: confidence interval.

Brackets denote 95% CIs.

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Figure. 4A and 4B: Forest plot showing the influence of clinical characteristics on warfarin

maintenance dosage. (A)The reduction in warfarin dose requirement associated with the

indication of Fontan procedure; (B) The influence of target INR range on warfarin

maintenance dosage. SD: standard deviation of normalized mean warfarin doses associated

with each genotype. CI: confidence interval. Brackets denote 95% CIs.

Supplementary Figure S1: Flow diagram of the literature screening process.

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STUDY INR target Indication of num

ber

male

ratio predominant mean ages Frequency (%)

range Warfarin

（%） ethnicity (years) *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 Wild Mutan

t

Tabib,

A.2015[28] 2,2.5 PHV,SVA 50 70 Caucasian 11.4 (5 - 17) 44 12 4 30 10 0 - -

Hirai,Keita2013[29] - TD 37 59.46 Asian 10.2 (1.9–16.5) 94 0 5.4 0 0 0 - -

Biss,T.T.2012[27]

2-3，

2.5-3.5

FP,PHV,CA

etc. 120 76.5 Caucasian 11（1-18） 70 14.2 14.2 0.8 0.8 0 - -

Shaw,

K.2014[18]

<2.5,2–

3,>2.5

FP,PHV,DVT,P

E 93 55.9 Caucasian 4.8(0.17-17.8) 69.9 15 12.9 2.2 0 0 - -

Lala,

M.2013[30] #

PHV,FP,KD

etc. 26 61 Caucasian 4.4 (0.33-18) 85 15 0 0 0 0 - -

Nguyen,N.2013[19] & FP, PHV 37 70.3 Caucasian 9.6(1.8–18.6 ） 73 19 8 0 0 0 - -

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Table 1: Characteristics of included studies.

Vear,S.I.2014[16]

2-3，

2.5-3.5 DVT, PHV 100 46 Caucasian 12.39(1.01-19.85) 67 16 9 0 1 0 67 26

BISS,T.T.2013[17]

2-3，

2.5-3.5

FP,PHV,CA

etc. 51 76.5 Caucasian 4（1-17） 68.6 11.8 17.6 0 2 0 68.6 31.4

PHV = Prosthetic heart valve, DVT = deep venous thrombosis, FP = Fontan procedure, CA = Coronary aneurysm, TD = thromboembolic diseases, KD=Kawasaki disease,

SVA=single ventricular approaches.

"-" means no data, "Wild" means wild type, "Mutant" means mutant type.

# means target INR range=1.5-2.5(50%)，2.0-2.5（19%），2.5-3.5（31%）,

& means target INR range=1.5–2.5（10.8%）、2–3（51.4%）、2.5–3.5（21.6%）、3–4（16.2%）.

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Table 2 Comparison of the effect of variant CYP2C9 genotypes on warfarin dose

requirements in pediatric and adult patients in Caucasians (data for adult patients from [6]).

Data on the effect of variant CYP2C9 genotypes are expressed as weighted mean difference

(WMD) [95% CI].

CYP2C9 genotypes frequency (%) impact on MDWD

Adult Pediatric Adult Pediatric

*1/*1 66.17 67.79 Reference Reference

*1/*2 19.81 14.74 19.9% (17.4, 22.4) 15% (1.0%, 29.0%)

*1/*3 10.82 12.0 35.1% (29.6, 40.7) 43% (33.0%, 53.0%)

*2/*2 1.34 3.79 36.8% (28.5, 45.1) -

*2/*3 1.43 1.68 58.0% (50.0, 66.0) -

*3/*3 0.42 0 78.1% (72.0, 84.3) -

Reference [6] - [6] -

"-" means no data； MDWD means Mean Daily Warfarin Dose.

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