Journal of the Neurological Sciences 336 (2014) 93–98

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Three polymorphisms of ALOX5AP and risk of ischemic stroke in Chinese: Evidence from a meta-analysis Fei Ye ⁎, Nan-Nuan Liu, Yong-Qiang Zheng, Wen-Jun Zhang, Chen-Mou Wang, Yue Xu, Xiao-Ling Den, Jian Wang Department of Neurology of Ren Min Hospital, Hubei University of Medicine, Hubei Province, PR China

a r t i c l e

i n f o

Article history: Received 4 August 2013 Received in revised form 6 October 2013 Accepted 7 October 2013 Available online 16 October 2013 Keywords: 5-Lipoxygenase activating protein Gene Polymorphism Ischemic stroke Etiology Meta-analysis

a b s t r a c t The impacts of three polymorphisms (SG13S114A/T, SG13S89A/G and SG13S32A/C) of 5-lipoxygenase activating protein (ALOX5AP) on the risk of ischemic stroke (IS) have been extensively studied for Chinese people, while conflicting results have been reported. The aim of meta-analysis was to further explore the associations to get a more robust conclusion. We researched the databases of Medline, Embase and Wangfang with latest update of August 1st, 2013. Odds ratio and corresponding 95% confidence interval (OR and 95%CI) were used to present the strength of the associations. Eleven case–control studies with 11,037 Chinese peoples (5361 IS cases and 5676 controls) were included. Overall, combined analysis indicated that AA genotype of ALOX5AP SG13S114A/T was significantly associated with increased risk of IS incidence compared with TT genotype [OR and 95%CI: 1.47 (1.13–1.91), P=0.005]. In addition, when subgroup analysis was conducted by subtypes of IS (atherothromboticor small artery disease-IS, AHS- or SAD-IS), A allele of SG13S114A/T was found to be associated with increased risk of AHS-IS compared with T allele [OR and 95%CI: 1.51 (1.28–1.79), P b 0.01 for AA vs. TT, and 1.12 (1.03– 1.22), P = 0.010 for A carriers v. T carriers]. However, SG13S89A/G and SG13S32A/C were not overall associated with IS incidence. Due to limited number of included studies, subgroup analyses were not conducted for SG13S89A/G and SG13S32A/C polymorphisms. Sensitivity analyses indicated the robustness of all combined analyses, and publication bias was not found. In conclusion, ALOX5AP SG13S114A/T, rather SG13S89A/G and SG13S32A/C, was significantly associated with risk of IS development for Chinese. More studies were required to warrant the findings of this study. Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved.

1. Introduction Stroke is one of the most common diseases in the world, and notably causes high mortality and disability. For instance, stroke is the third leading cause of death in the United States. More than 700,000 new cases of IS are diagnosed per year, and there are more than 4.4 million stroke survivors [1]. In addition, about 2.5 million new cases of stroke are diagnosed per year in China, and there are more than 7.5 million stroke survivors [2]. Ischemic stroke (IS) as the main subtype of stroke accounts for over 50% of all stroke cases. The incidence of IS is a complex process with multiple factors involved, including environmental and genetic factors. It has been confirmed that smoking and drinking are important risk factors for IS incidence [3,4]. On the other hand, numerous genetic polymorphisms have been found to be contributors of IS incidence, including 5-lipoxygenase activating protein (ALOX5AP) gene. It has been reported that 5-lipoxygenase (5-LO) regulated by membrane protein 5-lipoxygenase-activating protein (FLAP) is a key enzyme for metabolizing the oxidation of arachidonic acid (AA) to ⁎ Corresponding author. E-mail address: [email protected] (F. Ye).

leukotriene A4 (LTA4) in the leukotriene pathway [5], which is significantly associated with atherosclerotic vascular pathological diseases like IS and myocardial infarction. Three single-nucleotide polymorphisms (SG13S114A/T, SG13S89A/G and SG13S32A/C) of ALOX5AP with the relationship to IS incidence have been extensively studied in Asians and Caucasians; however, conflicting results have been reported. A case–control study conducted by Kaushal R [6] based on 357 White and Black patients of IS and 482 controls implicated that none of the three ALOX5AP single-nucleotide polymorphisms (SNPs) were associated with risk of IS development. However, another study conducted by Lohmussaar E et al. [7] based on 639 European stroke patients and 736 healthy controls found that SG13S114A/T, but not SG13S89A/G and SG13S32A/C, was associated with risk of IS incidence. Similarly, a case–control and meta-analysis including 1092 IS patients and 781 healthy controls of two different subsets from Spain and Portugal and including published case–control studies [8] also found that SG13S114A/T was a risk factor for IS development. Different ethnic peoples with the same genetic polymorphism may have different magnitudes of susceptibilities to the same diseases. Taking AGT M235T polymorphism as an example, a recent metaanalysis based on 17 case–control studies indicated that it was associated with risk of IS incidence in Asians rather than in Caucasians.

0022-510X/$ – see front matter. Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.10.013

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Table 1 The basic information of included studies in this meta-analysis. Authors

Zhang Gao He Xu Gao Lee Zhao Zhang Wang Sun Li a b

Year

2006 2008 2009 2009 2010 2011 2012 2012 2012 2012 2013

Cases

1285 100 412 472 346 291 682 236 690 440 411

Controls

1713 100 368 312 425 279 598 218 767 486 411

SG13S114A/T

SG13S89A/T

SG13S32A/C

Case: MAFa

Control: MAF

HWEb

Case: MAFa

Control: MAF

HWEb

Case: MAFa

Control: MAF

HWEb

0.30 0.30 0.39 0.31 0.80 0.42 0.33 0.36 0.38 0.36 0.41

0.30 0.29 0.34 0.29 0.63 0.41 0.29 0.38 0.36 0.28 0.36

0.08 0.77 0.05 0.72 0.01 0.85 0.99 0.79 0.95 0.74 0.40

0.05 0.05 – 0.04 0.03

0.05 0.06 – 0.05 0.02

0.15 0.18 – 0.14 0.69

– – – 0.38 0.26

– – – 0.32 0.33

– – – b0.01 0.37

0.05 0.02 – – –

0.05 0.02 – – –

0.06 0.76 – – –

0.41 0.40 – 0.31 –

0.40 0.34 – 0.31 –

b0.01 0.33 – 0.72 –

MAF, minor allele frequency; for SG13S114A/T, MAF is A allele for SG13S89A/T, MAF is A allele; for SG13S32A/C, MAF is C allele. HWE, Hardy–Weinberg equilibrium.

In this meta-analysis, we explored the associations of three SNPs of ALOX5AP (SG13S114A/T, SG13S89A/G and SG13S32A/C) with the risk of IS. In order to get a more robust conclusion, we restricted the participants of this study within Chinese peoples.

SG13S89A/G and SG13S32A/C polymorphisms and risk of IS in Chinese peoples; and (2) provided the sufficient data for combined analyses. If there were more than two studies using the same or overlapped data, the study providing more information for combined analysis was prior to be selected.

2. Materials and methods 2.3. Data extraction 2.1. Literature search We electronically searched the potential eligible articles in English and Chinese published in the following databases: (i) Medline in PubMed searching engine; (2) Embase database; (3) Wangfang Chinese database, and (4) Chinese National Knowledge Infrastructure (CNKI) database. The latest date for searching literatures was August 1st, 2013. The keywords for literature searching were: ‘5-lipoxygenase activating protein’ or ‘ALOX5AP’, ‘polymorphism’ or ‘variant’ or ‘genotype’, and ‘ischemic stroke’ or ‘brain infarction’ or ‘cerebral infarction’. The searching was conducted with restriction on human subjects, and references of included studies were reviewed to find additional eligible studies for this metaanalysis. 2.2. Selection criteria All included studies must meet the following criteria: (1) case– control study explored the association between ALOX5AP SG13S114A/T,

The data in included studies were extracted by two authors (Ye F and Liu NN) independently. Disagreements were solved with all authors together to get a consensus. The following data were extracted: the name of first author, publication year, number of IS cases and controls, minor allele frequency (MAF) in case and control groups, subtype of IS and the testing result of Hardy–Weinberg equilibrium (HWE). According to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) [9], IS consists of atherothrombotic-IS (AHS), small artery disease-IS (SAD) and cardioembolic-IS subtypes. 2.4. Statistical methods The combined OR and 95%CI were calculated for the genetic comparisons to illustrate the strength of the associations between three SNPs of ALOX5AP and risk of IS, and P value of Z-test b0.05 indicated the statistical significance. Subgroup analyses for subtype of IS (AHS- or SAD-IS) were conducted for ALOX5AP SG13S114A/T

Fig. 1. Combined analysis indicated that AA genotype of ALOX5AP SG13S114A/T was significantly associated with increased risk of IS for Chinese compared with TT genotype. Because of between-study heterogeneity, random-effect model was used.

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Fig. 2. Subgroup analyses indicated that AA genotype of ALOX5AP SG13S114A/T was significantly associated with increased risk of atherothrombotic-IS for Chinese compared with TT genotype. Fixed-effect model was used. AHS, atherothrombotic-IS; SAD, small artery disease-IS.

polymorphism. However, for ALOX5AP SG13S89A/G and SG13S32A/C polymorphisms, participants and number of the included studies were relatively small, thus subgroup analysis was not performed. Between-study heterogeneity was explored using Q-test. If Pb 0.05 or I2 (%) N 50%, which indicated significant between-study heterogeneity, random-effect model using DerSimonian and Laird method [10] was conducted; otherwise, fixed-effect model using the Mantel–Haenszel method [11] was used. Sensitivity analysis was conducted to check the stability of the combined results by removing each study one at a time. Publication bias was explored using funnel plots and Egger's regression test (P b 0.05 indicated statistical significance). All statistical analyses in this study were conducted using STATA software package (version 12.0; Stata Corporation, College Station, TX) with two-sided P-value.

3.3. Meta-analysis for three SNPs of ALOX5AP and subgroup analysis

3. Results

For ALOX5AP SG13S114A/T polymorphism, it was significantly associated with increased risk of IS development in AA vs. TT and A carriers vs. T carriers [OR and 95%CI: 1.47 (1.13–1.91), and P = 0.005 for AA vs. TT; 1.12 (1.00–1.25), and P=0.040 for A carriers vs. T carriers] (Fig. 1). When subgroup analysis was conducted for AHS- and SAD-IS, the combined results indicated that A allele of ALOX5AP SG13S114A/T polymorphism was significantly associated with increased risk of AHS-IS, but not SAD-IS [OR and 95%CI for AA vs. TT: 1.51 (1.28–1.79), and P b 0.001 for AHS-IS; 0.96 (0.71–1.28), and P = 0.763 for SAD-IS] (Fig. 2). For ALOX5AP SG13S89A/G and SG13S32A/C polymorphisms, both of them were not associated with risk of IS occurrence [OR and 95%CI: 1.44 (0.71–2.95), and P = 0.315 for SG13S89A/G AA vs. GG; 1.15 (0.97–1.37), and P = 0.104 for SG13S32A/C CC vs. AA] (Fig. 3A and B). The results of combined analyses were shown in Table 2.

3.1. Searching results

3.4. Sensitivity analysis and publication bias

A total of 85 literatures were identified: Medline (n = 46), Embase (n = 58), Wangfang (n = 21) and CNKI (n = 19). After removing the duplications among the databases, the titles and abstracts were reviewed. Then the full texts of 16 studies were reviewed. Five studies reported the associations between other SNPs of ALOX5AP and risk of IS, and two studies used duplicated data (one of them was selected). Eventually, 11 studies with 11,037 Chinese individuals (5361 IS cases and 5676 controls) were included in this meta-analysis [12–22]. Among these studies, 11 studies were for ALOX5AP SG13S114A/T polymorphism [12–22], six studies were for ALOX5AP SG13S89A/G polymorphism [12,15,16,18,20,21], and five studies were for SG13S32A/ C polymorphism [15,16,20–22].

Sensitivity analysis for the SG13S114A/T polymorphism indicated that the combined ORs in AT vs. TT, A carriers vs. TT and A carriers vs. T carriers could be substantially influenced by single study (Supplementary Fig. 1A–D), which indicated that more well-designed studies with large sample size were required. However, the combined OR for AA vs. TT was robust, which was not influenced by single study. For SG13S89A/G and SG13S32A/C polymorphisms, the combined ORs for all genetic comparisons were robust (data not shown). Funnel plot and Egger's regression test indicated that there was no publication bias for all genetic comparisons for the three SNPs of ALOX5AP gene (Fig. 4), and the results were shown in Table 3. 4. Discussion

3.2. The characteristics of included studies The included studies were published between 2006 and 2013, and the sample sizes ranged from 200 to 2993 Chinese participants. Five studies were written in Chinese [18–22], and other studies were written in English [12–17]. The controls of all included studies were selected from healthy people. The MAF distribution and HWE testing results for three SNPs of ALOX5AP were shown in Table 1.

The relationships between three SNPs of ALOX5AP gene (SG13S114A/T, SG13S89A/G and SG13S32A/C polymorphisms) and risk of IS incidence have been widely studied, but controversial results have been reported. Therefore we conducted this meta-analysis to further explore the associations between the LOX5AP genetic polymorphisms and IS risk for Chinese peoples to get more reliable results, as a meta-analysis can greatly enlarge the sample size and significantly enhance the statistical power. Most importantly, this study was based

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Fig. 3. Combined analyses indicated that there were no associations between ALOX5AP SG13S89A/G and SG13S32A/C polymorphisms and risk of IS. A, combined analyses for SG13S89A/G (A carriers vs. G carriers); B, combined analysis for SG13S32A/C (C carriers vs. A carriers).

on homogeneous peoples (Chinese), which, to some extent, eliminated the bias caused by heterogeneous sources of participants, which is beneficial for extrapolation of the results. This study indicated that A allele of LOX5AP SG13S114A/T polymorphism was significantly associated with increased risk of IS occurrence for Chinese people in AA vs. TT and A carriers vs. T carriers comparison models. In addition, when subgroup analyses were conducted, the SG13S114A/T polymorphism was further suggested to be associated with risk of atherothrombotic-IS, but not small artery disease-IS. The findings were different from two metaanalyses published in 2009 and 2010, respectively [8,23]. The study by Zintzaras E in 2009 [23] indicated that the three SNPs of LOX5AP, including SG13S114A/T polymorphism, were not associated with risk of IS occurrence. However, the study by Domingues-Montanari S in 2010 [8] indicated that T allele of SG13S114A/T polymorphism, but not SG13S89A/G and SG13S32A/C, was significantly associated with increased risk of IS incidence for White peoples compared with A allele. The discrepancies among our study and the published studies were mainly due to the pooled analyses that were conducted based on different ethnic populations. The published meta-analyses were mainly based on Caucasians; however, our study was restricted within Chinese people.

The mechanisms for LOX5AP to IS development have been widely studied, but not fully understood. One of the important mechanisms is that FLAP (LOX5AP protein) is a key regulator for synthesis of leukotrienes (LTs) [5], which are involved in the chronic inflammation of blood vessel (especially for artery) and the arteriosclerosis [24], and contributed to the increased risk of IS and myocardial infarction incidence. Under immune, allergic or inflammatory stimulation, polyunsaturated fatty acid arachidonic acid (AA) is transferred to 5-LO by FLAP, which enhances the synthesis of LTA4 [25]. In addition, LTA4 can be further converted to pro-inflammatory LTB4, or to the vasoconstrictive and pro-inflammatory cysteinyl leukotrienes (CysLTs), namely LTC4, LTD4 and LTE4 [25,26]. It has been reported that healthy individuals with LOX5AP SG13S114 AA genotype had 3.3-fold expression of LOX5AP compared with TT genotype; however, the LOX5AP expression was not different for IS patients with AA or TT genotype [8]. All of these implicate that LOX5AP SG13S114A/T polymorphism plays an important role in the initial process of IS. An interesting finding of this study was that LOX5AP SG13S114A/T polymorphism was significantly associated with increased risk of atherothrombotic-IS, but not small artery disease-IS. It was rational

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Table 2 Meta-analysis of the associations between ALOX5AP SG13S114A/T, SG13S89A/G and SG13S32A/C polymorphisms and risk of ischemic stroke. Polymorphism

SG13S114A/T

Comparisons

AA vs. TT

AT vs. TT

A carriers vs. TT

A carriers vs. T carriers

SG12S89A/G

SG13S32A/C

a

AA vs. GG AG vs. GG A carriers vs. GG A carriers vs. G carriers CC vs. AA AC vs. AA C carriers vs. AA C carriers vs. A carriers

Subgroupa

Total AHS SAD Total AHS SAD Total AHS SAD Total AHS SAD Total Total Total Total Total Total Total Total

No. of studies

10 6 3 10 6 3 10 6 3 10 6 3 4 6 6 6 5 5 5 5

Effect size

Heterogeneity

OR

P

P

Model

1.47 (1.13–1.91) 1.51 (1.28–1.79) 0.96 (0.71–1.28) 1.08 (0.94–1.24) 1.10 (0.99–1.22) 1.01 (0.85–1.20) 1.16 (0.99–1.35) 1.17 (1.06–1.30) 1.00 (0.85–1.18) 1.12 (1.00–1.25) 1.12 (1.03–1.22) 1.00 (0.87–1.15) 1.44 (0.71–2.95) 0.99 (0.82–1.20) 1.02 (0.85–1.22) 1.02 (0.85–1.22) 1.15 (0.97–1.37) 0.93 (0.60–1.45) 0.99 (0.70–1.40) 1.01 (0.85–1.20)

0.005 b0.001 0.763 0.282 0.090 0.882 0.071 0.002 0.964 0.040 0.010 0.979 0.315 0.940 0.864 0.85 0.104 0.757 0.951 0.929

b0.01 0.07 0.06 0.01 0.24 0.62 b0.01 0.19 0.43 0.01 0.64 0.58 0.99 0.32 0.38 0.46 0.57 b0.01 b0.01 0.04

Random Fixed Fixed Random Fixed Fixed Random Fixed Fixed Random Fixed Fixed Fixed Fixed Fixed Fixed Fixed Random Random Random

AHS, atherothrombotic-IS; SAD, small artery disease-IS.

for the findings of this study as FLAP was an important regulator for LTs–inflammation–arteriosclerosis pathway. The finding was consistent with published studies conducted by Zhao et al. [16] and Sun et al. [22,24]. The study conducted by Zhao et al. [16] consisting of 1280 participants (682 cases and 598 controls) indicated that individuals with AA genotype had 1.51-fold risk of atherothrombotic-IS compared with TT genotype. Similar result was also reported by Sun et al. However, the study conducted by Lee et al. [13] suggested that there was no significant association between LOX5AP SG13S114A/T polymorphism and atherothrombotic-IS. Regarding the relationships between LOX5AP SG13S89A/G and SG13S32A/C and risk of IS, the results of the meta-analysis indicated that there were no statistical significances between them. The study conducted by Zhao et al. [16] reported that neither SG13S89A/G nor SG13S32A/C was associated with risk of IS development. However, the study by Zhang et al. [12] indicated that SG13S32 AC genotype was associated with 1.5-fold risk of IS compared with AA genotype. In contrast, SG13S89A/G polymorphism was not associated with risk of IS development. The reasons for discrepancies among the studies remained unclear, probably due to limited studies being conducted, and more studies were required to further confirm the relationships.

This meta-analysis had some limitations, which should be mentioned here. First, this meta-analysis was conducted based on retrospective case–control studies, which might encounter recall and selection bias. Second, the sensitivity analysis for LOX5AP SG13S114A/T polymorphism indicated that the combined results for three genetic comparisons (AT vs. TT, A carriers vs. TT and A carriers vs. T carriers) could be influenced by a single study; however, combined analysis for AA vs. TT, which indicated the significant association between SG13S114A/T and risk of IS, remained robust in sensitivity analysis. Therefore, more studies with large sample size were required in the future. Third, this meta-analysis, same as most genetic meta-analyses, was conducted without adjustments. It was difficult for a meta-analysis to conduct combined analysis with adjustments of confounding factors. All of these limitations indicated that the results in this meta-analysis should be explained with great caution. In summary, this meta-analysis implicated that LOX5AP SG13S114A/T, but not SG13S89A/G and SG13S32A/C, was significantly associated with risk of IS for Chinese people. In addition, LOX5AP SG13S114A/T was found to be closely associated with atherothrombotic-IS. More studies with large sample size were required to confirm the findings of this study in the future.

Table 3 Egger's regression test for examining the publication bias. Polymorphism

Comparisons

SG13S114A/T

AA vs. TT AT vs. TT A carriers vs. TT A carriers vs. T carriers AA vs. GG AG vs. GG A carriers vs. GG A carriers vs. G carriers CC vs. AA AC vs. AA C carriers vs. AA C carriers vs. A carriers

SG12S89A/G

SG13S32A/C

Fig. 4. Egger's regression test indicated that there was no publication bias for ALOX5AP SG13S114A/T AA vs. TT comparison.

Coefficient

Pegger

95%CI

2.47 1.64 2.29 1.29

t value 1.54 1.36 1.71 0.80

0.16 0.21 0.12 0.45

[−1.15, 6.09] [−1.08, 4.36] [−0.74, 5.32] [−2.36, 4.94]

−0.39 −0.28 −0.26 −0.22

−1.08 −0.27 −0.26 −0.23

0.39 0.80 0.81 0.83

[−1.92, 1.15] [−3.20, 2.63] [−3.02, 2.51] [−2.80, 2.37]

1.66 3.87 2.38 1.62

1.22 0.35 0.28 0.31

0.31 0.75 0.80 0.78

[−2.69, 6.01] [−31.71, 39.46] [−24.70, 29.47] [−15.14, 18.37]

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Three polymorphisms of ALOX5AP and risk of ischemic stroke in Chinese: evidence from a meta-analysis.

The impacts of three polymorphisms (SG13S114A/T, SG13S89A/G and SG13S32A/C) of 5-lipoxygenase activating protein (ALOX5AP) on the risk of ischemic str...
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