CYBA基因C242T基因多态性的荟萃分析：亚洲人群急性冠脉综合征风险降低而高加索人群没有

Meta-analysis of C242T polymorphism in CYBA genes: risk of acute coronary syndrome is lower in Asians but not in Caucasians CYBA基因C242T基因多态性的荟萃分析：亚洲人群急性冠脉综合征风险降低而高加索人群没有 1 2 first-author †E-mail:hu999po@126.comwja@zju.edu.cn †E-mail:hu999po@126.comwja@zju.edu.cn hu999po@126.com 1 1 2 1 2 1 2 1 2 1 2 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:hu999po@126.comwja@zju.edu.cn †E-mail:hu999po@126.comwja@zju.edu.cn hu999po@126.com Key Laboratory for Diagnosis and Treatment of Cardiovascular Disease of Zhejiang Province, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Key Laboratory for Diagnosis and Treatment of Cardiovascular Disease of Zhejiang Province, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China Background: 2 A lot of studies have demonstrated that C242T polymorphism in CYBA genes may play an important role in the pathological process of acute coronary syndrome (ACS). However, the results are not consistent. To further evaluate this debate, we performed a meta-analysis to determine the relationship between C242T polymorphism and ACS. Methods and results: 2 We screened PubMed/MEDLINE, EBSCIO, and EMBASE research reports until Mar. 2014 and extracted data from 10 studies involving 6102 ACS patients and 8669 controls. Subgroup analysis by ethnicity documented a significant decreased risk of ACS for C242T polymorphism in the Asian population under allelic comparison (odd ratio (OR) 0.73; 95% confidence intervals (CI) 0.64–0.83), dominant model (OR 0.71; 95% CI 0.62–0.82), and homozygote comparison (OR 0.57; 95% CI 0.35–0.92). However, in the overall population and especially with Caucasians, no significant association was uncovered. Further meta-regression analysis revealed that the heterogeneity among studies was largely attributed to ethnicity. No publication bias was detected through a funnel plot and an Egger’s linear regression test. Conclusions: 2 Taken together, our results suggest that the C242T polymorphism might be a protective factor against developing ACS in the Asian population. Further researches will be needed to identify the confounding factors which modified the protective effect of T allele among Caucasians. 目的 2 探讨 CYBA 基因 C242T 基因多态性与急性冠脉综合征的关系。 创新点 2 提出了 C242T 基因多态性对急性冠脉综合征的影响存在种族差异。 方法 2 荟萃分析了 C242T 基因多态性与急性冠脉综合征的关系。 结论 2 对于亚洲人群而言， C242T 基因多态性为急性冠脉综合征的保护因素。 CYBA C242T polymorphism Acute coronary syndrome CYBA C242T 基因多态性 急性冠脉综合征 Introduction 1 With the extensive development of medication and interventional therapy, the mortality of coronary artery disease (CAD) in many countries has declined during the past decades (Nabel and Braunwald, 2012 2012 ). However, a substantial number of patients still suffer from acute coronary syndrome (ACS) (Falk et al., 2013 2013 ). In the USA, approximately 1.2 million patients are hospitalized for ACS each year (Roger et al., 2012 2012 ). Rupture or erosion of an unstable atherosclerotic plaque and subsequent thrombosis are the chief pathological characteristics of ACS (Falk et al., 2013 2013 ; Thompson et al., 2013 2013 ). Reactive oxygen species (ROS), including nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite, play an important role in vascular pathophysiology and platelet aggregation (Griendling and Fitzgerald, 2003 2003 ), which are also involved in the pathological process of ACS by activating matrix metalloproteinases (MMPs) (Galis et al., 1995 1995 ), increasing smooth muscle cells apoptosis and thus leading to a plaque rupture (Bennett, 1999 1999 ; Deshpande et al., 2002 2002 ). NAD(P)H oxidase is the predominant cellular source of ROS in the atherosclerotic lesions (Mueller et al., 2005 2005 ), which can be activated by p22phox (Sumimoto et al., 1996 1996 ). p22-phox is encoded by the CYBA gene, which is located in the human chromosome 16q24. The C242T polymorphism of the CYBA gene leads to a decreased production of ROS in the vasculature (Whitehead and Fitzgerald, 2001 2001 ), indicating a protective role of C242T polymorphism in ACS. A lot of studies have been carried out to investigate the relationship between the C242T polymorphisms and ACS. However, the results are not consistent. Hence, we conducted this meta-analysis to evaluate the association between the C242T polymorphism and ACS. Materials and methods 1 Literature search strategy 2 An extensive literature searching of PubMed/MEDLINE, EBSCIO, and EMBASE reports was performed for relevant articles without restricting the language until Mar. 2014, using the combinations of the keywords “C242T”, “p22phox”, “CYBA”, “NAD(P)H oxidase”, “nicotinamide adenine dinucleotide phosphate oxidase”, “rs4673”, “polymorphism”, “mut*”, “varia*”, “coronary”, “myocardial infarction”, “atherosclerosis”, “acute coronary syndrome”, and “unstable angina pectoris”. Additional studies were identified by scanning the references of reviews and retrieved studies. We conducted the meta-analysis according to the guidelines of the 2009 Preferred Reporting Items for the Systematic Reviews and Meta-Analysis (PRISMA) statement (Checklist S1) (Moher et al., 2009 2009 ). Inclusion criteria 2 Identified studies were screened according to the following inclusion criteria: (1) Case-control or cohort study assessing the association between C242T polymorphism and ACS risk as an original study. (2) Studies providing adequate information for calculating the genotypic odd ratio (OR) with 95% confidence interval (CI). (3) Published literatures of human genetics without ethnicity restriction. (4) If multiple articles originated from the same population, only the largest scale study was included. (5) The genotype frequencies amongst case and control must conform to the Hardy-Weinberg equilibrium (HWE). (6) ACS was defined as an acute myocardial infarction (MI) and unstable angina (Falk et al., 2013 2013 ). Data extraction and quality assessment 2 All the data were extracted independently by two investigators following the inclusion criteria described above. The following was gathered from the eligible articles: name of the first author, publication year, ethnicity, endpoint, mean ages, sample sizes for case and control groups, genotype distributions and conformity to genotype frequencies with HWE, the proportion of male, hypertension, diabetes mellitus, and smoking. Two investigators used the Newcastle-Ottawa Scale (NOS) to assess the methodological quality of all eligible studies. Studies that were awarded 5 stars or more can be regarded to be of medium to high quality. Statistical analysis 2 The HWE for the distributions of genotypes was assessed by the Pearson’s chi-square test. The pooled effect for the relationship between the C242T polymorphism and ACS risk was calculated under different models, containing allele comparison, dominant genetic model, recessive genetic model and homozygote comparison. The Cochran’s Q test and I 2 statistic were used to evaluate the between-study heterogeneity. The heterogeneity was qualified by I 2 : I 2 =0%–25%, low between-study heterogeneity; I 2 =25%–50%, moderate heterogeneity; I 2 =50%–100%, notable heterogeneity (Higgins et al., 2003 2003 ). The random effect model (REM) was adopted in the presence of notable heterogeneity ( I 2 > 50%); otherwise, the fixed-effect model (FEM) was applied. A meta-regression was run to explore the origin of the genetic heterogeneity and then stratified analysis by subgroup was adopted. Sensitivity analysis was applied to identify the influence of each study, with successive omission of individual studies (Patsopoulos et al., 2008 2008 ). The Funnel plot and Egger’s test were applied to evaluate the probability of publication bias. All statistical analyses were carried out with Stata Version 12.0 (Stata Co., College Station, TX, USA) and Review Manager Version 5.2 (RevMan, Cochrane Collaboration, Oxford, England). P < 0.05 was considered statistically significant. Results 1 Characteristics of the studies 2 The flow chart for the literature search is shown in Fig. 1 1 . A total of 271 relevant references were included, with 257 publications excluded. One study (Katakami et al., 2009 2009 ) was excluded since it was overlapped by another study with a larger scale (Katakami et al., 2010 2010 ). Three publications did not meet the requirements of HWE ( P HWE < 0.05) (Mata-Balaguer et al., 2004 2004 ; Morgan et al., 2007 2007 ; Hashad et al., 2014 2014 ). Finally, a total of 10 case-control studies were retrieved on ACS and the CYBA C242T polymorphism (Gardemann et al., 1999 1999 ; Stanger et al., 2001 2001 ; Yamada et al., 2002 2002 ; Murase et al., 2004 2004 ; Vasiliadou et al., 2006 2006 ; Macías-Reyes et al., 2008 2008 ; Katakami et al., 2010 2010 ; de Caterina et al., 2011 2011 ; Goliasch et al., 2011 2011 ; Narne et al., 2012 2012 ). The basic characteristics and genotype frequencies of the included studies are listed in Tables 1 1 and 2 2 . All the included studies were conducted from 1999 to 2012, with 6102 ACS patients and 8669 controls. MI was employed as the primary endpoint in five studies (Yamada et al., 2002 2002 ; Vasiliadou et al., 2006 2006 ; Katakami et al., 2010 2010 ; de Caterina et al., 2011 2011 ; Goliasch et al., 2011 2011 ), while MI and unstable angina were taken as the endpoint in two studies (Murase et al., 2004 2004 ; Macías-Reyes et al., 2008 2008 ). The endpoint of three studies was CAD, and MI was taken as the endpoint in subgroup analysis (Gardemann et al., 1999 1999 ; Stanger et al., 2001 2001 ; Narne et al., 2012 2012 ). There were six studies based on the Caucasian population, and four studies conducted on the Asian population. The genotype distributions among patients and controls conformed to HWE. All the 10 studies were assessed according to the NOS scale and most studies (80%) scored 5 stars or more, suggesting a moderate to good quality (Table 3 3 ). Data are expressed as values for case/control. MI: myocardial infarction; UA: unstable angina; HTN: hypertension; DM: diabetes mellitus Subgroup analysis Fisrt author Year Ethnicity End point Mean age (year) Male (%) Sample size Smoking (%) HTN (%) DM (%) Gardemann 1999 Caucasian MI * * 62.2/61.4 100/100 1031/499 62.0/54.0 19.0/11.0 Stanger 2001 Caucasian MI * * 52.9/54.2 100/100 71/45 Yamada 2002 Asian MI 62.1/62.0 100/100 1784/1074 57.8/55.2 47.0/57.3 34.7/16.2 Murase 2004 Asian UA/MI 58.0/61.0 100/100 453/762 84.3/51.8 64.2/63.9 15.0/18.9 Vasiliadou 2006 Caucasian MI 46.9/ 197/204 Macías-Reyes 2008 Caucasian UA/MI 56.0/54.5 78/74 304/315 50.0/27.3 33.9/12.1 Katakami 2010 Asian MI 62.2/59.5 64/61 226/3593 45.1/43.2 82.3/72.9 100/100 de Caterina 2011 Caucasian MI 39.6/39.6 89/89 1864/1864 87.2/48.9 27.42/9.18 7.6/0.8 Goliasch 2011 Caucasian MI 37.3/34.7 87/90 99/192 78.0/43.1 42.0/17.5 30.0/12.5 Narne 2012 Asian MI * * 73/121 100/100 HWE: Hardy-Weinberg equilibrium 2 First author 2 Genotype (TT/TC/CC) 2 Allele (C/T) (%) 2 P HWE Case Control Case Control Control Case  Gardemann 127/457/447 65/208/226 65.5/34.5 66.1/33.9 0.12 0.54  Stanger 11/30/30 6/24/15 63.4/36.6 60.0/40.0 0.46 0.45  Yamada 25/319/1440 16/242/816 89.7/10.3 87.2/12.8 0.69 0.13  Murase 2/67/384 5/170/587 92.2/7.8 88.2/11.8 0.61 0.61  Vasiliadou 34/98/65 21/95/88 57.9/42.1 66.4/33.6 0.53 0.78  Macías-Reyes 48/137/119 47/145/123 61.7/38.3 62.1/37.9 0.69 0.42  Katakami 0/36/190 33/618/2942 92.0/8.0 90.5/9.5 0.93 0.19  de Caterina 322/888/654 296/889/679 58.9/41.2 60.3/39.7 0.86 0.49  Goliasch 11/47/41 31/79/82 65.2/34.8 63.3/36.7 0.11 0.65  Narne 5/27/41 22/54/45 74.7/25.3 59.5/40.5 0.42 0.85 2 First author 2 Year 3 Quality indicators Selection Comparability Exposure  Gardemann 1999 ** * **  Stanger 2001 ** ** *  Yamada 2002 **** * *  Murase 2004 *** **  Vasiliadou 2007 **  Macías-Reyes 2008 **** ** **  Katakami 2010 ** * *  de Caterina 2011 *** * *  Goliasch 2011 *** ** *  Narne 2012 *** ** Quantitative synthesis 2 The combined results of the C242T polymorphisms with ACS are summarized in Table 4 4 . There was no significant association observed under any of the four genetic models (allele comparison: P =0.18, OR=0.91, 95% CI 0.78–1.05; dominant model: P =0.22, OR=0.90, 95% CI 0.75–1.07; recessive model: P =0.58, OR=1.04, 95% CI 0.91–1.18; homozygote comparison: P =0.51, OR=1.05, 95% CI 0.91–1.21) (Figs. 2 2 – 5 5 ). We also found notable heterogeneity in the allele comparison ( I 2 =74) and dominant model ( I 2 =71). OR: odds ratio; 95% CI: 95% confidence interval; REM: random-effects model; FEM: fix-effects model Genotype contrast Population Study number (case/control) Model for analysis OR (95% CI) P heterogeneity I 2 (%) P -value 3 Allele comparison (T vs. C) Total 10 (6102/8669) REM 0.91 (0.78, 1.05) <0.001 74 0.18 Asian 4 (2536/5550) FEM 0.73 (0.64, 0.83) 0.18 39 <0.001 Caucasian 6 (3566/3119) FEM 1.06 (0.99, 1.14) 0.33 13 0.11 3 Dominant model (TT+CT vs. CC) Total 10 (6102/8669) REM 0.90 (0.75, 1.07) <0.001 71 0.22 Asian 4 (2536/5550) FEM 0.71 (0.62, 0.82) 0.21 34 <0.001 Caucasian 6 (3566/3119) FEM 1.07 (0.97, 1.19) 0.47 0 0.16 3 Recessive model (TT vs. CT+CC) Total 10 (6102/8669) FEM 1.04 (0.91, 1.18) 0.19 27 0.58 Asian 4 (2536/5550) FEM 0.63 (0.39, 1.02) 0.31 16 0.06 Caucasian 6 (3566/3119) FEM 1.08 (0.94, 1.24) 0.33 13 0.26 3 Homozygote comparison (TT vs. CC) Total 10 (6102/8669) FEM 1.05 (0.91, 1.21) 0.07 43 0.51 Asian 4 (2536/5550) FEM 0.57 (0.35, 0.92) 0.20 35 0.02 Caucasian 6 (3566/3119) FEM 1.11 (0.96, 1.29) 0.27 21 0.16 Sensitivity analysis 2 A sensitivity analysis was run to look for studies making the largest contributions to the notable heterogeneity in allele comparisons and dominant models. The results showed that no single study dramatically affected the heterogeneity, ORs and 95% CIs (Table 5 5 ). Study omitted OR (95% CI) I 2 (%) Allele comparison  Gardemann 0.88 (0.74, 1.05) 77  Stanger 0.91 (0.78, 1.06) 77  Yamada 0.92 (0.79, 1.08) 72  Murase 0.95 (0.82, 1.09) 70  Vasiliadou 0.87 (0.75, 1.00) 71  Macías-Reyes 0.89 (0.75, 1.05) 77  Katakami 0.91 (0.78, 1.07) 77  de Caterina 0.88 (0.74, 1.04) 72  Goliasch 0.90 (0.77, 1.06) 77  Narne 0.94 (0.82, 1.08) 70 Dominant  Gardemann 0.87 (0.71, 1.06) 72  Stanger 0.91 (0.76, 1.09) 73  Yamada 0.92 (0.76, 1.11) 67  Murase 0.95 (0.80, 1.12) 64  Vasiliadou 0.85 (0.72, 1.01) 68  Macías-Reyes 0.88 (0.73, 1.07) 74  Katakami 0.90 (0.74, 1.09) 74  de Caterina 0.87 (0.71, 1.07) 68  Goliasch 0.88 (0.73, 1.07) 74  Narne 0.93 (0.79, 1.11) 68 Meta-regression analysis and subgroup analysis 2 In view of a notable heterogeneity, we performed a series of univariate meta-regression analysis under the allelic model and the dominant model by adding single covariates including publication year, age, ethnicity, the proportion of male, hypertension, diabetes mellitus, and smoking status. In the univariate analysis, a large proportion of the between-study heterogeneity was significantly attributed to ethnicity (Table 6 6 ). Hence, we undertook subgroup analyses on ethnicity and the heterogeneity significantly decreased both in the allelic model and the dominant model. The risk of ACS decreased in the Asian population (allelic comparison: P < 0.01, OR=0.73, 95% CI 0.64–0.83; dominant model: P < 0.01, OR=0.71, 95% CI 0.62–0.82; homozygote comparison: P =0.02, OR=0.57, 95% CI 0.35–0.92). Variable Coefficient P -value tau 2 - value R 2 (%) Allelic model  Ethnicity −0.4427 0.035 0.0506 45.68  Year 0.0006 0.981 0.1079 −15.92  Age −0.0064 0.608 0.0925 −12.55  Male (%) −0.7707 0.391 0.0736 1.56  DM (%) −0.4094 0.273 0.0875 5.48  Hypertension (%) −0.3943 0.211 0.0065 38.22  Smoking (%) −0.1693 0.238 0.0853 18.15 Dominant model  Ethnicity −0.3109 0.015 0 100  Year 0.0178 0.372 0.0407 −11.90  Age −0.0125 0.177 0.0303 20.22  Male (%) −0.3030 0.632 0.0218 −16.66  DM (%) 0.0149 0.953 0.0236 −25.00  Hypertension (%) −0.4886 0.294 0.0213 11.73  Smoking (%) 0.0892 0.922 0.0286 −42.73 However, no significant association was observed in the Caucasian population (allelic comparison: P =0.11, OR=1.06, 95% CI 0.99–1.14; dominant model: P =0.16, OR=1.07, 95% CI 0.97–1.19; recessive model: P =0.26, OR=1.08, 95% CI 0.94–1.24; homozygote comparison: P =0.16, OR=1.11, 95% CI 0.96–1.29) (Table 4 4 ). Publication bias 2 The Funnel plot (Fig. 6 6 ) and Egger’s regression were applied to evaluate the probability of publication bias. No significant publication bias was found in the overall estimates ( t =−0.88, P =0.40 for allele comparison). Discussion 1 Due to the conflicting results about the relationship between C242T polymorphisms and ACS, we conducted this meta-analysis. A total of 10 articles with 6102 ACS patients and 8669 controls were included in our study. Finally, in our meta-analysis, no significant association was observed under different genetic models with notable heterogeneity. This unexpected result may be due to the presence of notable heterogeneity, which confounded the possible effect. Further meta-regression identified that a large proportion of between-study heterogeneity was explained by ethnicity. Subgroup analysis by ethnicity documented a significant decreased risk of ACS under allelic comparison, dominant model, and homozygote comparison in the Asian population, while no significant association was observed among Caucasians. ROS were involved in plaque rupture and platelet aggregation (Galis et al., 1995 1995 ; Bennett, 1999 1999 ; Deshpande et al., 2002 2002 ; Griendling and Fitzgerald, 2003 2003 ), suggesting the important role of ROS in the pathological process of ACS. NAD(P)H oxidase is the predominant cellular source of ROS in the context of atherosclerosis (Mueller et al., 2005 2005 ), which can be activated by p22phox (Sumimoto et al., 1996 1996 ). The C242T polymorphism results in a substitution of Tyr for His at residue 72 of p22phox, and significantly reduced vascular NAD(P)H oxidase activity (Guzik et al., 2000 2000 ). This might be expected to reduce the generation of ROS, indicating a protective role of T allele in ACS, which is consistent with the results for the Asian population as suggested by our meta-analysis. It is really puzzling to us that no significant association was observed among Caucasians. The ethnicity-related discrepancy in the effect of the C242T polymorphism could be attributed to multiple cardiovascular risk factors, which confound the possible effects. Fan et al. ( 2007 2007 ) reported that body adiposity may modify the genetic effect of C242T polymorphism. The prevalence of adult obesity in the United States (2011–2012) is 34.9% (Ogden et al., 2014 2014 ), while it is only 12.9% in China (2010) (Li et al., 2012 2012 ). Obesity may be one of the confounding factors, which modified the effect of T allele among Caucasians, which is in accordance with the suggestion of previous meta-analysis studies (Wu et al., 2013 2013 ). Recently, some investigators reported that increased body mass index (BMI) in adults is associated with increased methylation at the HIF3A (Dick et al., 2014 2014 ). Hence, we forward the hypothesis that obesity regulated the methylation level of the CYBA gene, and then modified the protective effect of C242T polymorphism among Caucasians. Further researches will be needed to confirm our hypothesis, and the important effects of other confounding factors should also be studied. It has been reported that physical activity could modify this genetic effect of the CYBA gene (Zhu et al., 2012 2012 ). The c.-930A > G promoter polymorphism and the 640A > G polymorphism in the CYBA gene have also been implicated in the development of cardiovascular disease (Goliasch et al., 2011 2011 ; Xu et al., 2014 2014 ). Further researches will be needed to clarify the possible correlation of the three haplotypes of the CYBA gene. Three previous meta-analyses had evaluated the effect of the C242T polymorphism on CAD risk, the results are in conformity with notable heterogeneity. Fang et al. ( 2010 2010 ) first undertook a meta-analysis suggesting that C242T polymorphism had a significant protective effect among Asians but not among Caucasians, which is consistent with the results as suggested by Xu et al. ( 2014 2014 ). However, Wu et al. ( 2013 2013 ) reported that the T allele had a marginal risk increase of CAD among Caucasians (recessive model: OR=1.21, 95% CI 1.00–1.46) and no significant association was observed in the Asian population. The typical pathology of ACS and stable angina are significantly different (Falk et al., 2013 2013 ; Thompson et al., 2013 2013 ). ROS play an important role in the pathological process of ACS rather than stable angina. The stable angina cases included in the three meta-analyses may be contributed to the notable heterogeneity. Analyzing the effect of the C242T polymorphism on ACS may be more convincing. Fang et al. ( 2010 2010 ) and Xu et al. ( 2014 2014 ) had not discussed the relationship between the C242T polymorphisms and ACS. Although Wu et al. ( 2013 2013 ) had carried out tests to investigate the relationship between the C242T polymorphisms and ACS, the subgroup analysis included only six ACS studies with notable heterogeneity, and the genotype frequencies of one study did not conform to HWE (Morgan et al., 2007 2007 ). Hence, our meta-analysis excluded patients with stable angina and conformed to HWE in both the controls and patients with ACS. A large proportion of between-study heterogeneity was explained by ethnicity in our meta-analysis. The heterogeneity of subgroup analysis by ethnicity was low or moderate. The reason for the similar results between our paper and two of the three meta-analyses may be the population source (Fang et al., 2010 2010 ; Xu et al., 2014 2014 ). A large proportion of the eligible articles, which are included in the two meta-analyses, were hospital-based, and most of the patients were hospitalized for ACS. Although we have tried our best to improve this manuscript, there are still some limitations. First, the number of eligible articles in our meta-analysis is small. Second, the data of BMI in some articles are missing, which makes it difficult to confirm our hypothesis. Third, our meta-analysis did not account for the possible synergistic effects of the three common polymorphisms in the CYBA gene. Finally, the observed association between C242T polymorphism and ACS does not necessarily imply causality. In conclusion, this meta-analysis suggests that C242T polymorphism is related to ACS risk reduction only in the Asian population. We forward the hypothesis that obesity may modify the protective effect of C242T polymorphism among Caucasians. 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Physical activity modifies the association between CYBA gene polymorphisms and small artery elasticity in a Chinese population Compliance with ethics guidelines Po HU, Ming-yuan HUANG, Xin-yang HU, Xiao-jie XIE, Mei-xiang XIANG, Xian-bao LIU, and Jian-an WANG declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1400241 2014-09-09 2015-04-09 2015-01-31 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2015 2015 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 05 16