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 Table of Contents  
Year : 2016  |  Volume : 53  |  Issue : 2  |  Page : 130-134

Angiotensin-converting enzyme gene polymorphism in migraine

1 Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Genetics and Molecular Biology, Faculty of Agriculture, Ain Shams University, Cairo, Egypt
3 Department of Neurology, Faculty of Medicine, Helwan University, Cairo, Egypt

Date of Submission20-Jan-2016
Date of Acceptance27-Jan-2016
Date of Web Publication2-Jun-2016

Correspondence Address:
Magdy A Mostafa
MD, Department of Neurology, Faculty of Medicine, Ain Shams University, Cairo, 11591
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-1083.183450

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The pathophysiology of migraine is influenced by many factors. Multiple genetic and environmental factors may contribute to the etiology of migraine. The beneficial effects of angiotensin-converting enzyme (ACE) inhibitor drugs on migraine attack frequency have been shown, and hence ACE gene polymorphism was studied for its possible effect on migrainous patients.
We aimed to study the relationship between the ACE gene polymorphism and migraine pathophysiology.
Patients and methods
The ACE genotypes of 30 migraine patients (17 cases of migraine without aura and 13 cases of migraine with aura) and 30 age-matched and sex-matched normal volunteers as a control group were studied. All patients were subjected to full clinical assessment to calculate the score on the Migraine Disability Assessment Test as an indicator of the severity of migraine and its impact on the patient life.
The frequency of DD genotype of ACE gene was significantly higher in migraine patients, including both cases of migraine with aura and those without aura compared with the control group, but no association was found between any of the genotypes of ACE gene and the degree of migraine severity or disability.
ACE gene polymorphism may confer risk for the occurrence of migraine attacks, without affecting the symptomology or the severity of migraine.

Keywords: Angiotensin-converting enzyme, genetic, migraine, polymorphism

How to cite this article:
Mostafa MA, Edrees S, Abdulghani KO. Angiotensin-converting enzyme gene polymorphism in migraine. Egypt J Neurol Psychiatry Neurosurg 2016;53:130-4

How to cite this URL:
Mostafa MA, Edrees S, Abdulghani KO. Angiotensin-converting enzyme gene polymorphism in migraine. Egypt J Neurol Psychiatry Neurosurg [serial online] 2016 [cited 2023 Nov 29];53:130-4. Available from: http://www.ejnpn.eg.net/text.asp?2016/53/2/130/183450

  Introduction Top

Migraine is a chronic neurovascular disorder, characterized by episodic and disabling headaches with autonomic symptoms. Migraine affects 10-20% of the general population, affecting women up to four times more often than men. Migraine is a chronic disorder with complex pathophysiology, involving both the neuronal and vascular mechanisms [1]. The most important forms of migraine are migraine without aura and migraine with aura. A strong familial association and early onset of the disorder suggest that there is also a genetic basis [2].

Despite much effort to elucidate the underlying mechanisms by seeking susceptibility genes related to neurotransmitter pathways, inflammation, pain, and vascular factors, the molecular and genetic basis of migraine is still far from completely understood [3].

Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin-aldosterone system (RAS). The ACE insertion/deletion (I/D) polymorphism, which results from the insertion (I) or deletion (D) of a 287-bp sequence in intron 16, influences the expression level and activity of ACE [4],[5]. Clinical research has suggested that serum levels of ACE are higher in people with migraine than in healthy controls who are free of headache [6]. Similarly, the expression level of ACE was higher in people with the DD genotype than in people with the DI or II genotypes [4]. In addition, ACE inhibitors were demonstrated to have efficacy in migraine prophylaxis [7].

Many studies investigated the association between ACE (I/D) polymorphism and migraine; however, the results are contradictory.

Aim of the work

The aim of this study was to investigate the ACE gene polymorphism as a possible risk factor for migraine (both with and without aura) compared with controls. In addition, we tried to study the effect of this polymorphism on migraine severity and patient's disability.

  Patients and methods Top

This was a case-control study performed on 30 patients with the diagnosis of migraine headache, who were recruited from the outpatient clinic of Ain Shams University Hospitals during the period from July 2015 to October 2015. The only exclusion criterion was the evidence of other underlying medical or neurological diseases by means of either history or clinical examination. The patients were divided into two groups: the first comprised 17 patients without symptoms suggestive of aura before the migrainous headache, and the second group included 13 patients experiencing aura before the attack of headache.

All patients were subjected to full clinical assessment including history taking and full general and neurological examination to exclude the possibility of other medical or neurological disorders. Moreover, migraine severity and its impact on patient's life was assessed using the Migraine Disability Assessment Test (MIDAS) [8].

Besides, 30 clinically apparent healthy individuals without a history of migrainous attacks were recruited. They were matched with the patient groups as regards age and sex.

ACE genotyping was performed for all patients and controls in the Department of Genetics, Faculty of Agriculture, Ain Shams University. Peripheral venous blood samples (3 ml) were drawn and diluted with EDTA in special tubes. Genomic DNA was isolated from human leukocytes using DNA extraction kit (Axyprep Blood Genomic DNA Miniprep kit, AP-MN-BL-GDNA-50; Axygen Bioscience, New York, USA). PCR was performed to detect ACE gene polymorphism using the method described by Rigat et al [9].

In short, the genomic region encompassing the polymorphic site was PCR amplified and resolved on a 2% agarose gel. Electrophoresis was used to reveal the bands visualized using ethidium bromide staining. In relation to DNA marker, the ACE gene polymorphism was evident as a 490-bp product in the presence of insertion (I allele) and as a 190-bp fragment in the absence of the insertion (D allele). Thus, each DNA sample revealed one of the three possible patterns: a 490-bp band (genotype II), a 190-bp band (genotype DD), or both a 490-bp and a 190-bp band (genotype ID).

Statistical analysis

IBM SPSS statistics (V. 23.0, 2015; IBM Corp., USA) was used for data analysis. Data were expressed as mean ± SD for quantitative parametric measures, in addition to both number and percentage for categorized data. Comparison between the two independent mean groups for parametric data was made using the Student t-test. In addition, we used the χ2 -test to study the association between two variables, or comparison between two independent groups as regards the categorized data. The probability of error (P value) at 0.05 was considered significant, and at 0.01 and 0.001 it was highly significant.

  Results Top

Thirty patients with migrainous headache were studied, including 20 female (66.7%) and 10 male patients (33.3%). Their ages ranged from 17 to 36 years, with a mean value of 27.367 years. The patients were divided into two groups: the first group included 17 patients without aura before the attack of migraine, and the second included 13 patients experiencing symptoms suggestive of aura. The range, mean value, and the SDs for age in each group are shown in [Table 1]. The sex distribution of each group is shown in [Table 2]. There was no significant difference between the two groups with regard to age or sex distribution, as shown in [Table 1] and [Table 2].
Table 1: Age distribution of both patient groups

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Table 2: Sex distribution of both patient groups

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On studying the ACE genotyping in both patient groups, there was no significant difference between patients with aura before the attack of migraine and those without [Table 3].
Table 3: Distribution of angiotensin - converting enzyme genotypes in both patient groups

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In contrast, on comparing the patients as a whole and the control group with regard to the distribution of ACE genotypes, DD genotype was significantly more common in both patient groups than in the control group, whereas ID genotype was more common in the control group than in the patient groups. The same result was reached on comparing the control group with each patient group separately [Table 4],[Table 5] and [Table 6].
Table 4 Distribution of angiotensin - converting enzyme genotypes in the case groups and the control group

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Table 5 Distribution of angiotensin - converting enzyme genotypes in both group I and the control group

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Table 6 Distribution of angiotensin - converting enzyme genotypes in both group II and the control group

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On assessing the severity of migrainous attack and its impact on patient's life using MIDAS, 20 patients (66.7%) were found to have moderate disability, whereas 10 patients (33.3%) had severe attacks of migrainous headache. There was a significant difference between the patient groups with regard to the severity of migrainous attacks in the form that these patients with preceding aura before the headache are more liable to have severe attacks with worse impact on their lives [Table 7]. In contrast, there was no significant difference between different ACE genotypes with regard to the severity of migrainous attacks [Table 8].
Table 7: Comparison between the patient groups with regard to severity of migraine

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Table 8: Comparison between different angiotensin-converting enzyme genotypes with regard to severity of migraine

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  Discussion Top

Because of vascular involvement in the pathophysiology of migraine [10], 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. Therefore, we performed the current study to evaluate this association in Egyptian population.

This study showed an association between the DD genotype of ACE gene and both types of migraine (migraine with aura or migraine without aura), whereas ID genotype was more common in the control group compared with the patient groups. This suggests that the ID genotype may decrease the risk for migraine with or without aura in the Egyptian population.

However, ACE polymorphism was found to have no effect on the severity of migraine and subsequent disability. These findings did not coincide with those of other studies conducted in different areas around the world.

A recent meta-analysis carried out in 2015, including many studies investigating the effect of ACE polymorphism on the pathophysiology of migraine, did not show any positive correlation [11]; the result is consistent with another previous meta-analysis conducted in 2010 [12]. Moreover, genome-wide association studies of migraine did not identify a genetic variant in ACE [13-15]. However, stratification with regard to ethnicity revealed that the frequency of the II genotype among Turkish migraine patients was significantly different from the DD or ID genotypes. This suggests that the II genotype may decrease the risk for migraine either with or without aura in the Turkish population. These findings are different from those of the previous meta-analysis [12]. However, in view of the small sample number in the Turkish subgroup, the results remain to be validated.

It is important here to mention that Barley and colleagues reported that allele frequencies of the ACE polymorphism vary among various populations. The frequency of the D allele in White populations is higher than that in non-White populations. In contrast, it was reported that there is a considerably higher I allele frequency in the Polynesian and South American native populations. The D allele frequency in Oriental populations has an intermediate value compared with White, Polynesian, and South American populations [16]. The possibility of the presence of equal frequency of both DD and ID genotypes in the normal Egyptian population was suggested in a study by Hamdy and colleagues. They found ID genotype in 45.5% of the studied sample, DD genotype in 45.5%, and II genotype in only 9% of the studied sample [17].

Therefore, the difference in genetic background among populations may be a possible explanation for the discrepancy in the association of migraine with the ACE polymorphism. This could also be attributed to differences in the sample size and selection bias. In other words, to compare the exact allele frequencies among populations, large sample sizes are required, to maintain the statistical power that will make it possible to identify polymorphism distributions among homogenous racial or ethnic populations in a more exact way. Furthermore, population admixture may cause a false-positive genetic association.

In addition, there are other factors that may be responsible for the differences in results between studies. The differences in the study design, where in some of these were of case-control design and others were cross-sectional comparative studies, and the different ways of migraine classification may be responsible for these contradictory results.

However, the previous results based on genetic variation cannot fully explain the clinical relationship between ACE and migraine. The following pathophysiological mechanism may give a clue. 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 [18]. ACE inhibitors may act on RAS to exert efficacy in migraine prophylaxis. Second, the level of ACE may be regulated through the ACE I/D genetic pathway [19]. This might partially explain the higher serum level of ACE in migraine patients when compared with controls free from headache.

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 migraine with aura and chronic migraine carrying II genotype had a lower use of preventative treatments [20]. It suggested that ACE polymorphism would be associated with the therapeutic response in migraine patients. Thus, future studies should also define whether the ACE genotype represents a marker of cardiovascular risk or in predicting the response to therapy in migraine patients [18]. Several limitations of this study should be considered. First, migraine is an extremely 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 stratify the data with regard to sex. In addition, the small sample size of both the patient and control groups is another important limitation. Finally, there was not enough information to estimate gene-gene and gene-environment interactions in migraine susceptibility.

  Conclusion Top

ACE gene polymorphism may affect the migraine pathophysiology. The DD genotype may confer additional risk for developing attacks of migraine without affecting its severity. These results need further confirmation. More studies should clarify whether the ACE genotype might be a marker of cardiocerebrovascular risk or predicting the therapeutic response in migraine patients.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Michael Welch K, Michael Cutrer F, Goadsby PJ. Migraine pathogenesis, neuronal and vascular mechanisms. Neurology 2003; 60:9-14.  Back to cited text no. 1
Mulder EJ, Van Baal C, Gaist D, Kallela M, Kaprio J, Svensson DA, et al. Genetic and environmental influences on migraine: a twin study across six countries. Twin Res 2003; 6(5):422-431.  Back to cited text no. 2
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Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, Soubrier F Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992; 51(1):197-205.  Back to cited text no. 4
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Rigat B, Hubert C, Corvol P, Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 1992; 20(6):1433.  Back to cited text no. 9
Dalkara T, Nozari A, Moskowitz MA. Migraine aura pathophysiology: the role of blood vessels and microembolisation. Lancet Neurol 2010; 9(3):309-317.  Back to cited text no. 10
Wan D, Wang C, Zhang X, Tang W, Chen M, Dong Z, et al. Association between angiotensin-converting enzyme insertion/deletion polymorphism and migraine: a meta-analysis. Int J Neurosci 2015;5:28-31.  Back to cited text no. 11
Schuerks M, Rist PM, Kurth T. MTHFR 677C>T and ACE D/I polymorphisms in migraine: a systematic review and meta-analysis. Headache 2010; 50:588-599.  Back to cited text no. 12
Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS, et al. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nat Genet 2010; 42(10):869-873.  Back to cited text no. 13
Chasman DI, Schürks M, Anttila V, de Vries B, Schminke U, Launer LJ, et al. Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nat Genet 2011; 43(7):695-698.  Back to cited text no. 14
Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM, et al. Genome-wide association analysis identifies susceptibility loci for migraine without aura. Nat Genet 2012; 44(7):777-782.  Back to cited text no. 15
Barley J, Blackwood A, Carter ND, Crews DE, Cruickshank JK, Jeffery S, et al. Angiotensin converting enzyme insertion/deletion polymorphism: association with ethnic origin. J Hypertens 1994; 12(8):955-957.  Back to cited text no. 16
Hamdy SI, Hiratsuka M, Narahara K, El-Enany M, Moursi N, Ahmed MS, et al. Allele and genotype frequencies of polymorphic DCP1, CEIP, ADRB2, and HTR2A in the Egyptian population. Eur J Clin Pharmacol 2002; 58:29-36.  Back to cited text no. 17
Ripa P, Ornello R, Pistoia F, Carolei A, Sacco S. The renin-angiotensin system: a possible contributor to migraine pathogenesis and prophylaxis. Expert Rev Neurother 2014; 14(9):1043-1055.  Back to cited text no. 18
Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990; 86(4):1343-1346.  Back to cited text no. 19
Palmirotta R, Barbanti P, Ludovici G, De Marchis ML, Ialongo C, Egeo G, et al. Association between migraine and ACE gene (insertion/deletion) polymorphism: the BioBIM study. Pharmacogenomics 2014; 15(2):147-155.  Back to cited text no. 20


  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]


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