Just Accepted by International Journal of Neuroscience
Association between Angiotensin-Converting Enzyme Insertion/Deletion Polymorphism and Migraine: a Meta-Analysis Dongjun Wan, Chunyu Wang, Xiaofei Zhang, Wenjing Tang, Ming Chen, Zhao Dong, Shengyuan Yu doi:10.3109/00207454.2015.1025395
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Abstract Background: Many studies investigated the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and migraine, with controversial results. Thus we performed a meta-analysis to better evaluate the correlation of this polymorphism and migraine. Methods: We retrieved studies published up to September 2014 about the ACE gene polymorphism and migraine from electronic database. Pooled odds ratios (ORs) with 95% confidence interval (CI) were calculated to examine the strength of association between the ACE I/D polymorphism and migraine, using random-effects models. Results: We identified 14 separate studies, in which 7334 migraineurs and 22,990 healthy controls were eligible for the meta-analysis. The results showed no relationship between the ACE I/D polymorphism and any migraine. Stratification revealed a protective effect in the Turkish population against migraine with aura for the II genotype model (II vs. DD: pooled OR D 0.366, 95% CI D 0.137–0.980; II vs. DI C DD: pooled OR D 0.370, 95% CI D 0.145–0.945). Similar results were obtained for Turkish people with migraine without aura (II vs. DD: pooled ORD0.386; 95% CID0.166–0.900; II vs. DICDD: pooled ORD0.347; 95% CID 0.156–0.773).Conclusions: The data suggest that the ACE II genotype could exert a protective effect against migraine with aura and without aura at least in the Turkish population.
© 2015 Informa Healthcare USA, Inc. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
Publisher: Taylor & Francis
Association between Angiotensin-Converting Enzyme Insertion/Deletion
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Polymorphism and Migraine: a Meta-Analysis
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Dongjun Wana, Chunyu Wangb, Xiaofei Zhanga, Wenjing Tanga, Ming Chena, Zhao Donga,
a
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Shengyuan Yua*
Department of Neurology, Chinese PLA General Hospital, Beijing 100853, China
b
Department of Endocrine, Lanzhou General Hospital of Lanzhou Military Area Command of Chinese
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PLA, Lanzhou, 730050, China
*Corresponding author:
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DOI: http://dx.doi.org/10.3109/00207454.2015.1025395
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Journal: International Journal of Neuroscience
Shengyuan Yu
Department of Neurology, Chinese PLA General Hospital, 28 Fuxing Road, 1
Haidan District, Beijing 100853,China
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Tel: +86-10-68182255 Fax: +86-10-68182255
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Abstract
Background: Many studies investigated the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and migraine, with controversial results. Thus we
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performed a meta-analysis to better evaluate the correlation of this polymorphism and migraine. Methods:
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We retrieved studies published up to September 2014 about the ACE gene polymorphism and migraine from electronic database. Pooled odds ratios (ORs) with 95% confidence interval (CI) were calculated to examine the strength of association between the ACE I/D polymorphism and migraine, using randomeffects models. Results: We identified 14 separate studies, in which 7334 migraineurs and 22,990 healthy
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controls were eligible for the meta-analysis. The results showed no relationship between the ACE I/D polymorphism and any migraine. Stratification revealed a protective effect in the Turkish population against migraine with aura for the II genotype model (II vs. DD: pooled OR = 0.366, 95% CI = 0.137– 0.980; II vs. DI + DD: pooled OR = 0.370, 95% CI = 0.145–0.945). Similar results were obtained for
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E-mail:
[email protected] Turkish people with migraine without aura (II vs. DD: pooled OR=0.386; 95% CI=0.166–0.900; II vs. DI+DD: pooled OR=0.347; 95% CI= 0.156–0.773).Conclusions: The data suggest that the ACE II
genotype could exert a protective effect against migraine with aura and without aura at least in the Turkish population.
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Keywords: Angiotensin-converting enzyme; insertion/deletion polymorphism; migraine disorders;
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migraine with aura; migraine without aura; meta-analysis
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Introduction Migraine is a debilitating neurovascular disorder characterized by moderate to severe recurrent headache, accompanied by autonomic and neurologic symptoms, with a prevalence of 9.3% in mainland
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China[1]. Because of its heavy burden for individuals and society, migraine has been recognized as the seventh most disabling disease in the world[2]. Multiple genetic and environmental factors may
seeking susceptibility genes related to neurotransmitter pathways, inflammation, pain, and vascular
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factors[4], the molecular and genetic basis of migraine is still far from completely understood.
Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin-aldosterone system (RAS). ACE is involved in modulating vascular tone, and also has effects on homeostasis and the
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neuroendocrine and autonomic systems[5, 6]. The ACE I/D polymorphism, which results from insertion
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(I) or deletion (D) of a 287-bp sequence in intron 16, influences the expression level and activity of ACE[7, 8]. Clinical research has suggested that serum levels of ACE are higher in people with migraine than in healthy controls who are free of headache[9]. Similarly, the expression level of ACE was higher in people with the DD genotype than in people with the DI or II genotypes [7]. In addition, ACE inhibitors
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were demonstrated to have efficacy in migraine prophylaxis[10]. Many studies have investigated the association between this polymorphism and migraine including migraine with aura(MA) and/or without aura(MO); however, the results are contradictory[8, 11-23].
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contribute to the etiology of migraine [3]. Despite much effort to elucidate the underlying mechanisms by
Patterna and colleagues first reported that the ACE DD genotype was associated with migraine in MO patients[11]. Subsequently, the DD genotype was found to increase risk for MA among the Japanese population. In contrast, several studies among Caucasians and the Chinese have failed to replicated these
findings[8, 19, 23].A meta-analysis published in 2010 suggested that the ACE II genotype may reduce risk for migraine with and without aura, especially in non-Caucasian populations[24]. Because five more
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studies have since been published[8, 20-23], we performed a re-analysis to clarify the association between ACE I/D polymorphism and migraine.
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Materials and methods Study selection
We retrieved studies published up to September 2014 about the ACE gene polymorphism and
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“angiotensin converting enzyme”, “ACE”, “peptidyl-dipeptidase A”, or “rs1799752”; and
“polymorphism”, “genetic polymorphism”, or “genetic variation”; combined with “migraine”, “migraine disorders”, or “headache disorders”. In addition, a manually search was performed by reviewing the
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references of the identified papers. In order to get more eligible studies, the search had no restrictions. The inclusion criteria were all of the following: (i) case-control, cross-sectional or cohort study; (ii)
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control subjects comprised a healthy population; and (iii) study provided precise genotype and allele frequencies to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The exclusion criteria were: (i) migraine diagnosis failing to meet the criteria of the International Classification of Headache
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Disorders I or II edition; (ii) migraine together with other headache; and (iii) with overlapping cases or controls in studies, excluded others except the largest study. Data extraction
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migraine from the PubMed, Embase, and Science Citation Index online databases using the key words
Data from the retrieved studies were independently extracted by two investigators and any
controversies were resolved by a third headache expert. The information extracted was: first author’s name, title of study, journal name, year of publication, study design type, genotyping methods, migraine type (any migraine, MA or MO), sex of subjects, setting(clinic or population), numbers of cases and
controls, and frequencies of genotypes and alleles of the ACE I/D polymorphism. Ethnicity was categorized as Caucasian, Asian or Turkish. 5
Statistical analysis A pooled OR with its 95% CI was calculated to evaluate the strength of linkage between ACE I/D polymorphism and migraine, using random-effects models because they have fewer assumptions than
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fixed-effects models [24]. The data were also stratified by ethnicity and migraine subtype. The Z-test was carried out to assess pooled OR; P < 0.05 was considered significant. Hardy-Weinberg equilibrium
consistent with HWE.
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Sensitivity analysis was applied to estimate the influence of a single study on the results.
Heterogeneity was examined by the I2 test and Q-test. I2 < 25%, I2 = 25–50%, and I2 > 50% indicated low, moderate, and high heterogeneity, respectively[25]. Meta-regression was performed to evaluate whether
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ethnicity (Caucasian, Asian, Turkish) or HWE (deviation or not) was a source of heterogeneity. Potential
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publication bias was evaluated by Begg’s funnel test and Egger’s test. All statistical analyses were conducted with the STATA 20.0 software package (Stata, College Station, TX, USA).
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Results Eligible studies
A total of 111 studies from the electronic databases were screened initially; 83 were removed
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(HWE) of genotype distribution in the controls of each study was also examined with P > 0.05 as
because of duplication, irrelevancy, or inappropriate publication type (review or letter). Seven meeting
abstracts were excluded because they did not provide detailed genotype or allele frequencies. Four studies with a case-case clinical design were excluded because they did not include healthy controls [26-29]. Where there were two papers from the same project, the one with more subjects was selected [19, 30]. The selection process is shown in Figure 1. Finally, 14 studies, with 7334 migraineurs and 22,990 controls, were eligible for our meta-analysis. These included 12 studies of any migraine, nine of MO, and
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nine of MA. The main characteristics of the studies on any migraine are presented in Table 1. Among the 14 studies, five were performed in Caucasians, four in Asians, and five in the Turkish population, and
Association between ACE I/D polymorphism and migraine
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three studies [19, 20, 22] were deviated from HWE.
Table 2 lists the main results of meta-analysis and heterogeneity. Overall, the results showed no
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genotype model.
When stratified by migraine subtype, analyses in MA patients revealed a slightly significant difference only in the II vs. DI genotype models (pooled OR=0.823; 95% CI=0.679–0.999; Z=1.97,
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P=0.05). However, sensitivity analysis indicated a pooled OR of 0.820 (95% CI=0.667–1.007; P=0.06) after removing one study[21]. Furthermore, stratified analyses by ethnicity showed a protective effect
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against MA for the II genotype model (II vs. DD: pooled OR=0.366, 95% CI=0.137–0.980; II vs. DI + DD: pooled OR=0.370, 95% CI=0.145–0.945) among the Turkish population, but not among Caucasians or Asians (Figures 2 and 3). Heterogeneity was high in MA studies (I2=57.5%). Meta-regression excluded
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ethnicity and HWE as sources of heterogeneity. Begg’s test and Egger’s test indicated no publication bias. Similar results were observed among Turkish MO patients in the II genetic model (II vs. DD: pooled OR = 0.386, 95% CI = 0.166–0.900; II vs. DI + DD: pooled OR = 0.347, 95% CI = 0.156–0.773). There was low heterogeneity among the MO studies (I2 = 17.4%) and there was no publication bias.
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association between ACE I/D polymorphism and any migraine, neither in the allele model nor in the
Discussion
Because of vascular involvement in the pathophysiology of migraine [31, 32], ACE gene is a
possible candidate for migraine susceptibility. A number of studies have estimated the association between ACE I/D polymorphism and migraine, but the results remain controversial; reasons may be
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related to small sample size, differences in ethnicity, heterogeneity of the disease. Therefore, we performed the current meta-analysis to better evaluate the association. Our meta-analysis did not show any positive correlation between the ACE I/D polymorphism and
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any migraine; the result is consistent with the previous meta-analysis[24], and three large- scale molecular epidemiological surveys, where genome-wide association studies of migraine did not identify a genetic
among Turkish MA and MO was significantly different from the DD or DI + DD genotypes. This
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suggests that the II genotype may decrease risk for MA and MO among the Turkish population. These findings are different from those of the previous meta-analysis[24], where the ACE II genotype has overall protective against both MA and MO in non-Caucasian population rather than in Turkish
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population. This may be because the new studies focused on non-Caucasian populations, especially the
validated.
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Turkish. However, in view of the small sample number in the Turkish subgroup, the results remain to be
The results of our meta-analysis based on genetic variation cannot fully explain the clinical relationship between ACE and migraine. The following pathophysiological mechanism may give a clue.
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First, experiments suggested that RAS is involved in neurogenic inflammation, susceptibility to oxidative stress, endothelial dysfunction, and neuromodulation of nociceptive transmission, thus potentially contributing to the pathogenesis of migraine[36]. ACE inhibitors may act on RAS to exert efficacy in migraine prophylaxis. Second, the level of ACE may be regulated via the ACE I/D genetic pathway[7,
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variant in ACE [33-35]. However, stratification by ethnicity revealed that the frequency of the II genotype
37]. On the other hand, a mechanism other than gene polymorphism would participate in modulating its level, such as epigenetic modification like altered DNA methylation of the promoter [38].This might partially explain the higher serum level of ACE in migraineurs when compared with free headache controls.
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Current studies focused on the relationship between ACE I/D genetic polymorphism and migraine susceptibility. However, a new clinically useful finding from a recent study was that patients with MA and chronic migraine carrying II genotype had a lower use of preventative treatments[23]. It suggested
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that ACE polymorphism would be associated with the therapeutic response in migraine patients. Thus future studies should also define if the ACE genotype represents a marker of cardiovascular risk or
Several limitations of this study should be considered. First, migraine is an extremely
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heterogeneous condition. Although diagnosis was made according to the criteria of the International
Classification of Headache Disorders, there could still be clinical misclassification because of the lack of biomarkers to identify and validate migraine, which may be a source of heterogeneity. Second, we did not
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stratify the data by sex. Among the 14 studies, only three with small sample sizes compared the ACE I/D polymorphism between men and women so there were insufficient data. Finally, there was not enough
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information to estimate gene-gene and gene-environment interactions in migraine susceptibility. In conclusion, our meta-analysis based on the current studies did not support that the ACE I/D polymorphism affects migraine susceptibility among the non-Turkish population, but stratification
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indicated that the ACE II genotype may have a protective effect against MA and MO at least in the Turkish population. These results further need to be confirmed. And more studies should clarify if the ACE genotype might be a marker of cardiocerebralvascular risk or predicting the therapeutic response in migraineurs.
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predicting the response to therapy in migraineurs[36].
Acknowledgements: We sincerely appreciate Dr. Guangyu Li, assistant professor at East Tennessee State University, for helping us revise our manuscript. Conflict of interest The authors have no conflicts of interest to declare.
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Table 1. Main characteristics of studies on any migraine in the meta-analysis. any migraine Study design
ethni city
gende r
NS
casecontrol
Cauca sian
F/M
clinic
casecontrol
Asian
study size
controls
D D
DI
II
D
I
502
20 0
22 3
79
62 3
38 1
F/M
151
23
60
68
10 6
19 6
Palmirotta,R.(2 014)
Italy
An,XingKai(2013)
China
Sipahi,Tamma m(2013)
Turke y
NS
casecontrol
Turki sh
F
105
36
57
12
12 9
81
Ozbey,Ulku(20 10)
Turke y
NS
casecontrol
Turki sh
F/M
101
38
57
6
13 3
69
Schuerks,M.(2 009)
USA
popula tion
crosssec tional
Cauca sian
F
4577
13 31
21 44
11 02
48 06
43 48
Joshi,G.(2009)
India
clinic
casecontrol
Asian
F/M
150
18
78
54
11 4
18 6
Tronvik,E.(200 8)
Norwa y
clinic
casecontrol
Cauca sian
F/M
347
78
18 6
83
34 2
Kara,I.(2007)
Turke y
NS
casecontrol
Turki sh
F/M
180
72
95
13
Lin,JJ.(2005)
China
clinic
casecontrol
Asian
Lea,RA.(2005)
Austr alia
NS
casecontrol
Cauca sian
Kowa,H.(2005)
Japan ese
NS
casecontrol
Asian
Cakmak,EA.(2 003)
Turke y
NS
casecontrol
Turki sh
study size
323
DI
II
D
I
13 0
14 6
47
406
240
0.56 45
137
29
56
52
114
160
0.06 31
97
35
32
30
102
92
0.00 09
101
32
68
1
132
70
0.00 00
20423
59 96
93 73
50 54
213 65
194 81
0.00 00
150
12
78
60
102
198
0.05 20
35 2
403
92
20 4
10 7
388
418
0.78 16
23 9
12 1
210
81
90
39
252
168
0.12 05
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C
HWE
D D
240
40
95
10 5
17 5
30 5
200
34
85
81
153
247
0.15 60
250
77
14 2
31
29 6
20 4
244
76
12 2
46
274
214
0.81 05
F/M
176
33
86
57
15 2
20 0
248
31
11 4
10 3
176
320
0.95 01
F/M
200
77
83
40
23 7
16 3
231
88
99
44
275
187
0.09 28
F/M
AC
F/M
ST
F:female; M:male; HWE:hard-Weinberg equilibrium; NS: not specified.
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settin g
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Count ry
Author
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Table 2. Meta analysis of the association between ACE I/D polymorphism and migraine I vs D
II vs DD
II+DI vs DD
II vs DI+DD
DI vs DD
II vs DI
studies OR(95%CI)
Ph
I2
OR(95%CI)
Ph
I2
OR(95%CI)
Ph
I2
OR(95%CI)
I2
OR(95%CI)
Ph
I2
OR(95%CI)
Ph
I2
TE D
any migraine(12 )
Ph
0.959(0.741,1.241 0.03 65.1 0.880(0.520,1.489 0.04 63.0 0.896(0.598,1.341 0.13 46.6 0.961(0.711,1.299 0.11 49.6 0.891(0.654,1.215 0.43 0.974(0.770,1.233 0.35 0.0% 6.9% ) 5 % ) 4 % ) 2 % ) 4 % ) 4 ) 8
turkey(4)
0.861(0.720,1.030 0.31 14.9 0.684(0.313,1.493 0.01 71.0 0.947(0.751,1.194 0.86 0.658(0.263,1.649 0.00 82.0 1.070(0.783,1.464 0.20 35.1 0.641(0.226,1.822 0.00 84.5 0.0% ) 8 % ) 6 % ) 5 ) 1 % ) 2 % ) 0 %
total
0.948(0.876,1.026 0.14 30.7 0.848(0.683,1.051 0.01 55.2 1.004(0.943,1.068 0.78 0.846(0.696,1.029 0.00 65.9 1.029(0.963,1.100 0.65 0.832(0.674,1.028 0.00 66.9 0.0% 0.0% ) 6 % ) 1 % ) 0 ) 1 % ) 3 ) 0 %
EP
asian(4)
MA(9)
caucasian(4 0.937(0.906,1.046 0.72 0.994(0.818,1.089 0.49 1.016(0.908,1.136 0.99 0.887(0.723,1.088 0.26 24.6 1.052(0.933,1.185 0.94 0.864(0.688,1.085 0.24 28.6 0.0% 0.0% 0.0% 0.0% ) ) 9 ) 8 ) 6 ) 3 % ) 8 ) 1 %
0.812(0.458,1.438 0.01 74.7 0.584(0.182,1.877 0.03 71.4 0.624(0.256,1.517 0.08 59.8 0.768(0.393,1.502 0.07 61.4 0.621(0.322,1.198 0.26 23.9 0.776(0.492,1.224 0.32 10.7 ) 9 % ) 0 % ) 3 % ) 5 % ) 9 % ) 6 %
turkey(2)
0.583(0.296,1.147 0.16 47.1 0.366(0.137,0.980 0.42 0.603(0.249,1.460 0.14 54.0 0.370(0.145,0.945 0.52 0.702(0.266,1.856 0.11 59.0 0.385(0.145,1.021 0.82 0.0% 0.0% 0.0% ) 9 % ) 5 ) 0 % ) 1 ) 8 % ) 7
total
0.859(0.726,1.015 0.01 58.2 0.714(0.499,1.023 0.01 57.5 0.867(0.688,1.091 0.06 45.9 0.787(0.612,1.011 0.07 44.2 0.972(0.810,1.165 0.26 19.9 0.823(0.679,0.999 0.29 17.1 ) 4 % ) 6 % ) 3 % ) 4 % ) 6 % ) 0 %
AC
C
asian(3)
MO(9)
caucasian(5 0.941(0.881,1.005 0.38 0.895(0.796,1.006 0.59 0.932(0.808,1.076 0.26 23.6 0.899(0.813,0.994 0.76 0.966(0.832,1.121 0.27 22.5 0.901(0.809,1.003 0.84 3.5% 0.0% 0.0% 0.0% ) ) 7 ) 5 ) 4 % ) 2 ) 1 % ) 1
asian(3)
0.992(0.782,1.259 0.25 27.2 0.982(0.616,1.565 0.31 12.9 1.000(0.672,1.488 0.48 0.977(0.733,1.303 0.35 1.002(0.656,1.530 0.74 0.969(0.718,1.308 0.54 0.0% 3.3% 0.0% 0.0% ) 3 % ) 7 % ) 5 ) 5 ) 7 ) 8
turkey(1)
0.771(0.548,1.085 )
total
0.937(0.877,1.001 0.39 0.863(0.734,1.013 0.34 11.3 0.955(0.876,1.042 0.56 0.876(0.759,1.011 0.28 17.4 0.993(0.905,1.088 0.60 0.883(0.772,1.010 0.35 5.1% 0.0% 0.0% 9.9% ) 3 ) 0 % ) 5 ) 7 % ) 1 ) 2
ST
0.386(0.166,0.900 )
0.964(0.600,1.548 )
0.347(0.156,0.773 )
1.214(0.740,1.993 )
Ph: p value for heterogeneity analysis; OR: odd ratio; CI: confidence interval.
JU
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 06/16/15 For personal use only.
caucasian(4 0.989(0.948,1.032 0.77 0.975(0.897,1.060 0.52 1.014(0.949,1.083 1.00 0.929(0.802,1.076 0.25 25.5 1.034(0.963,1.109 0.94 0.909(0.768,1.077 0.22 31.3 0.0% 0.0% 0.0% 0.0% ) ) 7 ) 8 ) 0 ) 9 % ) 2 ) 4 %
13
0.318(0.139,0.729 )
ST
JU EP
C
AC
TE D
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 06/16/15 For personal use only.
Figure 1. Process of study selection.
14
TE D EP C AC ST
ethnicity by random-effects models for each of the nine studies (II vs. DD).
JU
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 06/16/15 For personal use only.
Figure 2. Forest plot of the association between migraine with aura and the ACE I/D polymorphism stratified by
15
TE D EP C AC ST
ethnicity by random-effects models for each of the nine studies (II vs. DI+DD).
JU
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 06/16/15 For personal use only.
Figure 3. Forest plot of the association between migraine with aura and the ACE I/D polymorphism stratified by
16