Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Association of the Apolipoprotein E polymorphism with migraine: a meta-analysis

Contributed equally
BMC Neurology201515:138

https://doi.org/10.1186/s12883-015-0385-2

Received: 14 October 2014

Accepted: 17 July 2015

Published: 12 August 2015

Abstract

Background

Apolipoprotein E (ApoE) gene has been reported to be associated with migraine and tension-type headache (TTH), but the results are conflicting. This study aimed to evaluate the association of ApoE with migraine by a meta-analysis.

Methods

MEDLINE, ISI Web of Knowledge, The Cochrane Central Register of Controlled Trials, and EMBASE databases were searched to identify eligible studies published in English from 2000 to 2014. Data were extracted using standardized forms. The association was assessed by relative risk (RR) with 95 % confidence intervals (CIs) using a fixed or random effects model.

Results

Four studies, comprising 649 migraineurs, 229 TTH subjects and 975 controls, met all the criteria and were included in the meta-analysis. No significant difference was found comparing genotypic and allelic frequencies in the case of migraineurs versus controls and TTH subjects versus controls. Only when migraineurs and TTH subjects were considered as a whole group, ApoE4 was found to increase the relative risk of headache by 1.48 (95 % CI 1.16, 1.90; P = 0.002), compared to controls.

Conclusions

ApoE ε4 allele is not associated with migraine susceptibility, but is positively related to headache (including migraine and TTH).

Background

Migraine is a common neurovascular disorder, characterized by recurrent episodes of headache and the dysfunction of the autonomic nervous system, affecting 10–20 % of the population [1, 2]. Although the pathophysiology of migraine is largely unknown, a neurogenic hypothesis of migraine has been proposed [3]. In particular, the genes involved in regulation of the endothelin system are proved to be promising candidates in migraine susceptibility [4, 5].

Apolipoprotein E (ApoE) is a 299 amino acid protein, encoded by a gene located on chromosome 19cen-q13.2 [6, 7]. ApoE gene has three common alleles (ɛ2, ɛ3, ɛ4) that encode three isoforms (APOE2, APOE3, APOE4). Several studies have shown a relationship between APOE polymorphism and the expression of the cytokines involved in migraine and TTH [8, 9]. Moreover, several studies investigated the association between APOE single nucleotide polymorphism (SNP) and migraine, but the results are conflicting [1013].

Therefore, to define further the disease risk associated with APOE polymorphism, in this study we performed a meta-analysis of all related studies that evaluated allelic and genotypic frequencies of ApoE polymorphism in migraine.

Methods

Selection of studies

Eligible studies were identified by searching on web-based databases (MEDLINE 2000 to 2014, ISI Web of Knowledge 2000 to 2014, The Cochrane Central Register of Controlled Trials 2000 to 2014, and EMBASE) with no language restrictions. Search terms were “apolipoprotein E”, “APOE”, “ɛ2”, “ɛ3”, “ɛ4”, “APOE2”, “APOE3”, “APOE4”, “migraine”, “headache” and “Polymorphism”. Potentially relevant studies were retrieved and reviewed by 2 reviewers. All case–control studies with extractable data were included. Included studies were published as full-length articles in peer-reviewed journals.

Data extraction and quality assessment

Studies were included for meta-analysis if they met the following criteria: (1) the association between APOE and migraine was examined by using a population-based, case–control design; (2) migraine was diagnosed using an international standard; (3) genotype or allele frequencies were reported in both cases and controls; (4) the genotype frequencies in control groups were consistent with Hardy-Weinberg equilibrium.

Statistical analysis

Heterogeneity across the eligible studies was tested using Q-test, and it was considered statistically significant when P < 0.1. Heterogeneity was also quantified with I2 test (I2 = (Q− df) / Q × 100 %. I2 values of above 25 %, 50 %, and 75 % were taken as indicators of mild, modest, and high heterogeneities, respectively. When the effects were assumed to be homogeneous (P >0.1, I2 < 50 %), the fixed-effects model was used; otherwise, the random-effects model was more appropriate. The meta-analyses were performed using Stata Version 12.0 software (Stata Corp., College Station, TX, USA).

Results

Study inclusion and characteristics

As a result of our literature search, a total of four published articles reported on the relationship between APOE SNP and migraine and met the inclusion criteria. Rainero et al. divided the subjects into three subgroups: migraine with aura; migraine without aura; and mixed headaches (migraine associated with tension-type headache) [10]. Stuart et al. separated migraineurs into MA and MO groups. The other two reports investigated a possible association of APOE polymorphism with migraine and TTH [11, 12].

Results of meta-analyses

Total 649 migraineurs, 229 TTH subjects and 975 controls were genotyped for APOE polymorphism. In the four studies, the distribution of the genotypes in control groups was in Hardy–Weinberg equilibrium (P < 0.05).

No significant difference was found between genotypic and allelic frequencies in the case of migraineurs versus controls and TTH subjects versus controls. Exclusively in the comparison between subjects with the allele E2 vs. E3 + E4, pooled RR with fixed effect was 1.49 (95 % CI 1.11, 2.01; P = 0.009, I2 = 74.1 %). This significance disappeared with random effect (RR1.82; 95 %CI 0.92, 3.61). While E4 gene increased the relative risk of headache by1.48 (95 % CI 1.16, 1.90; P = 0.002), they did not show any effect when migraineurs and TTH subjects were taken as a reference category (Figs. 1 and 2).
Fig. 1

Forest plot of comparison: SNP APOE E3 of migraineurs and TTHs versus control. SNP APOE E3 was shown to have no significant association with migraineurs and TTH

Fig. 2

Forest plot of comparison: SNP APOE E4 of migraineurs and TTHs versus control. SNP APOE E4 was shown to have significant association with migraineurs and TTH

Meta-analysis of subgroups

To determine genetic heterogeneity of E2, MO and MA subgroups were also compared vs. controls. No significant difference between cases and controls was observed (Figs. 3 and 4).
Fig. 3

Forest plot of comparison: SNP APOE E2 of migraineurs of MO versus control. SNP APOE E2 was shown to have no significant association with migraineurs and TTH

Fig. 4

Forest plot of comparison: SNP APOE E2 of migraineurs of MA versus control. SNP APOE E2 was shown to have no significant association with migraineurs and TTH

Discussion

The results of this meta-analysis suggest that there is no association between migraine and APOE polymorphism, even in subgroups analyses. However, when migraineurs and TTH subjects as a whole headache group were examined, a significant association was found between headache and E4 gene polymorphism. Migraineurs and TTH subjects carrying the allele E4, using fixed effects, showed a modest heterogeneity but significantly increased disease risk. The modest heterogeneity is the most likely explanation for the differences in ethnicity or in sample characteristics. Our data therefore partially confirm previous studies suggesting that this polymorphism represents a genetic risk factor for patients with migraine or TTH.

Nitric oxide (NO) plays an essential role in the pathogenesis of both migraine and TTH [14, 15]. Moreover, the production of NO is dependent on APOE HhaI polymorphism [16]. NO production is greater in APOE4 carriers with characteristically high levels of oxidative stress than in APOE3 carriers after closed head injury and stroke [17]. In addition, higher inflammation activity was associated with APOE ɛ4 gene compared to APOE ɛ3 gene [18]. Furthermore, APOE polymorphism influences the expression of the cytokines involved in migraine and TTH [8, 9, 19]. These results suggest that APOE4 may be associated with more serious tissue damage and higher disease susceptibility. Similarly, we found that APOE4 increased the relatively higher risk of headache compared to APOE3.

There are some limitations in our study. First, since migraine is a complex and heterogeneous disorder with a wide clinical spectrum, patients with different clinical phenotypes may not sufficiently capture this variability and may result in misclassification. Second, we only chose three genotypes in our study, despite various genotypes of APOE. Third, the lack of individual data has restricted further adjustments for the subgroup analysis for TTH. Fourth, the analysis was performed on a relatively small number of retrospective case–control studies, and the subjects included in these studies are also limited. Further population-based studies with larger sample size are necessary to confirm our conclusions.

Conclusions

In summary, the evidence from the present meta-analysis showed that APOE4 is not associated with migraine or TTH, but is related to headache (including migraine and TTH), suggesting a nonspecific role for the risk of headache.

Notes

Declarations

Acknowledgements

We thank Dr. Yingqun Wang from Biomedsci (Biomedsci.net) who kindly proofread the manuscript.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Neurology, Affiliated Zhongshan Hospital of Xiamen University
(2)
Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University
(3)
College of Computer Engineering, Jimei University

References

  1. Silberstein SD. Migraine. Lancet. 2004;363(9406):381–91.View ArticlePubMedGoogle Scholar
  2. Haut SR, Bigal ME, Lipton RB. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol. 2006;5(2):148–57.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neurosci. 2003;4(5):386–98.View ArticlePubMedGoogle Scholar
  4. Moskowitz MA. Pathophysiology of headache--past and present. Headache. 2007;47 Suppl 1:S58–63.View ArticlePubMedGoogle Scholar
  5. Lemos C, Neto JL, Pereira-Monteiro J, Mendonca D, Barros J, Sequeiros J, et al. A role for endothelin receptor type A in migraine without aura susceptibility? A study in Portuguese patients. Eur J Neurol. 2011;18(4):649–55.View ArticlePubMedGoogle Scholar
  6. Lynch JR, Morgan D, Mance J, Matthew WD, Laskowitz DT. Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response. J Neuroimmunol. 2001;114(1-2):107–13.View ArticlePubMedGoogle Scholar
  7. Kaur M, Balgir PP. APOE2 and consanguinity: a risky combination for Alzheimer's disease. J Alzheimers Dis. 2005;8(3):293–7.PubMedGoogle Scholar
  8. Perini F, D'Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, et al. Plasma cytokine levels in migraineurs and controls. Headache. 2005;45(7):926–31.View ArticlePubMedGoogle Scholar
  9. Tsoi LM, Wong KY, Liu YM, Ho YY. Apoprotein E isoform-dependent expression and secretion of pro-inflammatory cytokines TNF-alpha and IL-6 in macrophages. Arch Biochem Biophys. 2007;460(1):33–40.View ArticlePubMedGoogle Scholar
  10. Rainero I, Grimaldi LM, Salani G, Valfre W, Savi L, Rivoiro C, et al. Apolipoprotein E gene polymorphisms in patients with migraine. Neurosci Lett. 2002;317(2):111–3.View ArticlePubMedGoogle Scholar
  11. Joshi G, Pradhan S, Mittal B. Vascular gene polymorphisms (EDNRA -231 G > A and APOE HhaI) and risk for migraine. DNA Cell Biol. 2011;30(8):577–84.View ArticlePubMedGoogle Scholar
  12. Gupta R, Kumar V, Luthra K, Banerjee B, Bhatia MS. Polymorphism in apolipoprotein E among migraineurs and tension-type headache subjects. J Headache Pain. 2009;10(2):115–20.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Stuart S, Donges B, Murrell M, Haupt LM, Lea RA, Griffiths LR. Investigation of APOE isoforms and the association between APOE E3 and E4 with migraine in the Australian Caucasian population. Neuroreport. 2013;24(10):499–503.View ArticlePubMedGoogle Scholar
  14. Olesen J, Thomsen LL, Lassen LH, Olesen IJ. The nitric oxide hypothesis of migraine and other vascular headaches. Cephalalgia. 1995;15(2):94–100.View ArticlePubMedGoogle Scholar
  15. Ashina M. Neurobiology of chronic tension-type headache. Cephalalgia. 2004;24(3):161–72.View ArticlePubMedGoogle Scholar
  16. Czapiga M, Colton CA. Microglial function in human APOE3 and APOE4 transgenic mice: altered arginine transport. J Neuroimmunol. 2003;134(1-2):44–51.View ArticlePubMedGoogle Scholar
  17. Colton CA, Brown CM, Cook D, Needham LK, Xu Q, Czapiga M, et al. APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress. Neurobiol Aging. 2002;23(5):777–85.View ArticlePubMedGoogle Scholar
  18. Guo L, LaDu MJ, Van Eldik LJ. A dual role for apolipoprotein e in neuroinflammation: anti- and pro-inflammatory activity. J Mol Neurosci. 2004;23(3):205–12.View ArticlePubMedGoogle Scholar
  19. Tziakas DN, Chalikias GK, Antonoglou CO, Veletza S, Tentes IK, Kortsaris AX, et al. Apolipoprotein E genotype and circulating interleukin-10 levels in patients with stable and unstable coronary artery disease. J Am Coll Cardiol. 2006;48(12):2471–81.View ArticlePubMedGoogle Scholar

Copyright

© Miao et al. 2015

Advertisement