Skip to main content

Advertisement

SpringerLink
Log in

A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Many homeostatic genes are thought to play a role in the susceptibility to migraine, making it a highly complex neurovascular disease. In this meta-analysis, our primary objective was to evaluate whether or not MTHFR variants (such as C677T and A1289C) and ACE I/D were associated with an increased risk of migraine. Using a PRISMA-based systematic literature-review guideline, internet sources such as PubMed and Google Scholar were searched to identify the genes of interest and migraine risk. To pool the data, odds ratios with 95% confidence intervals were calculated utilizing different genetic models. Cochran’s Q Test and I2 statistics were used to access heterogeneity, while Begg’s and Egger’s tests were used to identify publication bias. All tests were two-sided, and a p-value of < 0.05 was regarded as statistically significant. The present meta-analysis observed that the C677T variant is significantly associated with the increased risk of migraine (allele model: OR:1.19, CI [1.07–1.33], I2 = 78%) and its clinical subtype i.e., MA (allele model: OR: 1.26, CI [1.09–1.45], I2 = 80%) in the overall population. Concerning the ACE- I/D, it significantly increased the risk of overall migraine and both clinical subtypes after utilizing the dominant genetic models (OR: 1.14, CI [1.01–1.29], I2% = 32). Concerning the MTHFR A1289C, only the codominant model (HR vs HT) and recessive model significantly increased the risk of overall migraine. Therefore, the findings of the present meta-analysis showed that MTHFR-C677T is an important risk factor for migraine and its clinical subtype.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Abbreviations

ICHD-3:

International classification of headache disorder 3rd edition

MA:

Migraine aura

MWA:

Migraine without aura

CSD:

Cortical spreading depression

GWAS:

Genome-wide association study

CGAS:

Candidate gene association study

ACE :

Angiotensin-converting enzyme

MTHFR :

Methylenetetrahydrofolate reductase

ICHD-3:

International classification of headache disorders

NCBI:

National Center for Biotechnology Information

MEDLINE:

Medical literature analysis and retrieval system online

PRISMA:

Preferred Reporting Items for Systematics Reviews and Meta-Analysis

HIS:

International Headache Society

HWE:

Hardy-Weinberg Equilibrium

OR:

Odds ratio

CI:

Confidence interval

I 2 :

I Square

SNP:

Single-nucleotide polymorphism

FPRP:

False-positive report probability

References

  • Aiswarya PS, Husain RA, Kesavan P, Subramaniyan K, Ahmed SS, Ramakrishnan V (2020) Association of rs1801133 polymorphism with migraine susceptibility: a case-control study followed by updated meta-analysis and trial sequential analysis. Gene Reports 21:100881

    Article  Google Scholar 

  • Alaşehirli B, Gür M, Akçalı A, Geyik S, Bülbül B, Sayar D, Neyal M (2009) Angiotensin converting enzyme gene insertion/deletion polymorphism in migraine patients. Turkish J Neurol 15(4)

  • Alicakmak E, Cataloluk O, Yoldas T, Arslan A, Herken H, Barlas O, Yigiter R (2003) Migraine and angiotensin-converting enzyme association in Turkish patients. Pain Clin 15(4):473–477

  • Aluclu M, Unan F, Tekes S (2015) ACE gene polymorphism and of MTHFR parameters effects on migraine. J Neurol Sci 357:e446

    Article  Google Scholar 

  • An XK, Lu CX, Ma QL, Zhang XR, Burgunder JM, Lin Q, Qu HL (2013) Association of MTHFR C677T polymorphism with susceptibility to migraine in the Chinese population. Neurosci Lett 549:78–81. https://doi.org/10.1016/j.neulet.2013.06.028

    Article  PubMed  Google Scholar 

  • Azimova JE, Sergeev AV, Korobeynikova LA, Kondratieva NS, Kokaeva ZG, Shaikhaev GO, Skorobogatykh KV, Fokina NM, Tabeeva GR, Klimov EA (2013) Effects of MTHFR gene polymorphism on the clinical and electrophysiological characteristics of migraine. BMC Neurol 13:103. https://doi.org/10.1186/1471-2377-13-103

    Article  PubMed  PubMed Central  Google Scholar 

  • Bahadir A, Eroz R, Dikici S (2013) Investigation of MTHFR C677T gene polymorphism, biochemical and clinical parameters in Turkish migraine patients: association with allodynia and fatigue. Cell Mol Neurobiol 33(8):1055–1063. https://doi.org/10.1007/s10571-013-9972-1

    Article  PubMed  Google Scholar 

  • Benigni A, Cassis P, Remuzzi G (2010) Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2(7):247–257. https://doi.org/10.1002/emmm.201000080

    Article  PubMed  PubMed Central  Google Scholar 

  • Bokhari FA, Shakoori TA, Hassan SA, Qureshi HJ, Qureshi GA (2010) Plasma homocysteine in patients of migraine without aura. J Ayub Med College, Abbottabad : JAMC 22(2):52–55

    PubMed  Google Scholar 

  • Bottini F, Celle ME, Calevo MG, Amato S, Minniti G, Montaldi L, Di Pasquale D, Cerone R, Veneselli E, Molinari AC (2006) Metabolic and genetic risk factors for migraine in children. Cephalalgia : Int J Headache 26(6):731–737. https://doi.org/10.1111/j.1468-2982.2006.01107.x

    Article  PubMed  Google Scholar 

  • Brewster UC, Perazella MA (2004) The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med 116(4):263–272. https://doi.org/10.1016/j.amjmed.2003.09.034

    Article  PubMed  Google Scholar 

  • Bron C, Sutherland HG, Griffiths LR (2021) Exploring the hereditary nature of migraine. Neuropsychiatr Dis Treat 17:1183–1194. https://doi.org/10.2147/NDT.S282562

    Article  PubMed  PubMed Central  Google Scholar 

  • Brustolin S, Giugliani R, Félix TM (2010) Genetics of homocysteine metabolism and associated disorders. Brazilian journal of medical and biological research = Revistabrasileira de pesquisasmedicas e biologicas, 43(1):1–7. https://doi.org/10.1590/s0100-879x2009007500021

  • Dalkara T, Nozari A, Moskowitz MA (2010) Migraine aura pathophysiology: the role of blood vessels and microembolisation. Lancet Neurol 9(3):309–317

    Article  PubMed  PubMed Central  Google Scholar 

  • de Tommaso M, Difruscolo O, Sardaro M, Losito L, Serpino C, Pietrapertosa A, Santeramo MT, Dicuonzo F, Carella A, Lamberti P, Livrea P (2007) Influence of MTHFR genotype on contingent negative variation and MRI abnormalities in migraine. Headache 47(2):253–265. https://doi.org/10.1111/j.1526-4610.2006.00690.x

    Article  PubMed  Google Scholar 

  • Ekinci FU, Aluclu MU, Ekinci MH (2021) Investigation of the effects of ACE gene polymorphism and MTHFR parameter on migraine. Analytical and Quantitative Cytopathology and Histopathology 43(5):327–336

    Google Scholar 

  • Essmeister R, Kress HG, Zierz S, Griffith L, Lea R, Wieser T (2016) MTHFR and ACE polymorphisms do not increase susceptibility to migraine neither alone nor in combination. Headache 56(8):1267–1273. https://doi.org/10.1111/head.12893

    Article  PubMed  Google Scholar 

  • Ferro A, Castro MJ, Lemos C, Santos M, Sousa A, Pereira-Monteiro J, Sequeiros J, Maciel P (2008) The C677T polymorphism in MTHFR is not associated with migraine in Portugal. Dis Markers 25(2):107–113. https://doi.org/10.1155/2008/178679

    Article  PubMed  PubMed Central  Google Scholar 

  • Fleming I (2006) Signaling by the angiotensin-converting enzyme. Circ Res 98(7):887–896. https://doi.org/10.1161/01.RES.0000217340.40936.53

    Article  PubMed  Google Scholar 

  • Fu Y, Wang X, Kong W (2018) Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets. Br J Pharmacol 175(8):1173–1189. https://doi.org/10.1111/bph.13988

    Article  PubMed  Google Scholar 

  • Gasparini CF, Sutherland HG, Griffiths LR (2013) Studies on the pathophysiology and genetic basis of migraine. Curr Genomics 14(5):300–315. https://doi.org/10.2174/13892029113149990007

    Article  PubMed  PubMed Central  Google Scholar 

  • Gerasimova E, Yakovleva O, Enikeev D, Bogatova K, Hermann A, Giniatullin R, Sitdikova G (2022) Hyperhomocysteinemia increases cortical excitability and aggravates mechanical hyperalgesia and anxiety in a nitroglycerine-induced migraine model in rats. Biomolecules 12(5):735. https://doi.org/10.3390/biom12050735

    Article  PubMed  PubMed Central  Google Scholar 

  • Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7(2):195–200. https://doi.org/10.1038/ng0694-195

    Article  PubMed  Google Scholar 

  • Guan X, Dong X, Yan Y, Zhang C, Liu D, Wan Q (2017) ACE I/D and 5-HTT STin2 VNTR polymorphisms in migraine: a meta-analysis. Int J Clin Exp Med 10(1)

  • Güllüoğlu H, Gökçay F, Durmaz A, Akin H, Calli C, Köse t (2015) ACE I/D and MTHFR C677T Gene Polymorphisms and matrix metalloproteinase-9 gene expression in migraine patients with and without aura and correlation with cranial magnetic resonance imaging findings: a case-control study. J Neurol Sci 32(2)

  • Hamdan F, Jabir APDAK (2020) Study the biochemical and molecular role of angiotensin converting enzyme in migraine and non-migraine headache. Int J Pharm Res 12(2)

  • Hautakangas H, Winsvold BS, Ruotsalainen SE, Bjornsdottir G, Harder AVE, Kogelman LJA, Thomas LF, Noordam R, Benner C, Gormley P, Artto V, Banasik K, Bjornsdottir A, Boomsma DI, Brumpton BM, Burgdorf KS, Buring JE, Chalmer MA, de Boer I, Dichgans M, Pirinen M (2022) Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nature Gen 54(2):152–160. https://doi.org/10.1038/s41588-021-00990-0

  • Hemat K, Haghjooy Javanmard S, Saadatnia M, Rafiee L, Zandifar A, Tajaddini M (2012) Genetic polymorphisms of C677T MTHFR gene in migraine patients compared with controls. Journal of Isfahan Medical School 30(214):1935–1941

    Google Scholar 

  • Hesami O, Asadollahi M, Lima BS (2017) Correlation between MTHFR Genotype polymorphisms and different types of migraine headache in iranian patients: a case control study. ARCHIVOS DE MEDICINA 8(S4):228

    Google Scholar 

  • Hoffmann J, Charles A (2018) Glutamate and its receptors as therapeutic targets for migraine. Neurother: J Am Soc Exp Neurother 15(2):361–370. https://doi.org/10.1007/s13311-018-0616-5

  • Horasanlı B, Ataç FB, Çöven İ, Karakurum Goksel B, Benli S (2012) Angiotensin I-converting enzyme gene (I/D) polymorphism in patients with migraine. Headache: J Head Face Pain 53(1):161–164. https://doi.org/10.1111/head.12008

  • Ibrahim SMH, Magzoub MSE, Abdalla SF, Mohamed HS, Ibrahim ME (2018) The Methylene tetrahydrofolate reductase gene variant C677T is not associated with migraine in twelve sudanese pedigrees with migraine. J Neurol Stroke 8(1):00279. https://doi.org/10.15406/jnsk.2018.08.00279

    Article  Google Scholar 

  • Ishii M, Shimizu S, Sakairi Y, Nagamine A, Naito Y, Hosaka Y, Naito Y, Kurihara T, Onaya T, Oyamada H, Imagawa A, Shida K, Takahashi J, Oguchi K, Masuda Y, Hara H, Usami S, Kiuchi Y (2012) MAOA, MTHFR, and TNF-β genes polymorphisms and personality traits in the pathogenesis of migraine. Mol Cell Biochem 363(1–2):357–366. https://doi.org/10.1007/s11010-011-1188-4

    Article  PubMed  Google Scholar 

  • Jasrotia R, Raina JK, Sharma M, Panjaliya RK, Kundal BR, Kumar P (2018) Relationship of MTHFR and ACE gene variations with migraine susceptibility: a case-control study in the population of North India (Jammu). Biosci, Biotechnol Res Asia 15(4):851–860

    Article  Google Scholar 

  • Jewell NP (2003) Statistics for epidemiology. CRC Press

    Book  Google Scholar 

  • Jorgensen TJ, Ruczinski I, Kessing B, Smith MW, Shugart YY, Alberg AJ (2009) Hypothesis-driven candidate gene association studies: practical design and analytical considerations. Am J Epidemiol 170(8):986–993. https://doi.org/10.1093/aje/kwp242

    Article  PubMed  PubMed Central  Google Scholar 

  • Joshi G, Pradhan S, Mittal B (2009) Role of the ACE ID and MTHFR C677T polymorphisms in genetic susceptibility of migraine in a north Indian population. J Neurol Sci 277(1–2):133–137. https://doi.org/10.1016/j.jns.2008.11.002

    Article  PubMed  Google Scholar 

  • Kara I, Ozkok E, Aydin M, Orhan N, Cetinkaya Y, Gencer M, Tireli H (2007) Combined effects of ACE and MMP-3 polymorphisms on migraine development. Cephalalgia 27(3):235–243

  • Kara I, Sazci A, Ergul E, Kaya G, Kilic G (2003) Association of the C677T and A1298C polymorphisms in the 5,10 methylenetetrahydrofolate reductase gene in patients with migraine risk. Brain Res Mol Brain Res 111(1–2):84–90. https://doi.org/10.1016/s0169-328x(02)00672-1

    Article  PubMed  Google Scholar 

  • Kaunisto MA, Kallela M, Hämäläinen E, Kilpikari R, Havanka H, Harno H, Nissilä M, Säkö E, Ilmavirta M, Liukkonen J, Teirmaa H, Törnwall O, Jussila M, Terwilliger J, Färkkilä M, Kaprio J, Palotie A, Wessman M (2006) Testing of variants of the MTHFR and ESR1 genes in 1798 Finnish individuals fails to confirm the association with migraine with aura. Cephalalgia: Int J Headache 26(12):1462–1472. https://doi.org/10.1111/j.1468-2982.2006.01228.x

  • Kaur S, Ali A, Pandey AK, Singh B (2018) Association of MTHFR gene polymorphisms with migraine in North Indian population. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 39(4):691–698. https://doi.org/10.1007/s10072-018-3276-7

    Article  PubMed  Google Scholar 

  • Kim BK, Kim M, Kang L, Bae HJ, Koo JS, Kwon O, Lee SS (2005) Methylenetetrahydrofolate reductase gene polymorphism in Korean patients with migraine or ischemic stroke. J Korean Neurol Assoc 176–180

  • Kowa H, Fusayasu E, Ijiri T, Ishizaki K, Yasui K, Nakaso K, Nakashima K (2005) Association of the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients of migraine with aura. Neurosci lett 374(2):129–131

  • Kowa H, Yasui K, Takeshima T, Urakami K, Sakai F, Nakashima K (2000) The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine. Am J Med Genet 96(6):762–764. https://doi.org/10.1002/1096-8628(20001204)96:6%3c762::aid-ajmg12%3e3.0.co;2-x

    Article  PubMed  Google Scholar 

  • Lea RA, Ovcaric M, Sundholm J, MacMillan J, Griffiths LR (2004) The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura. BMC Med 2:3. https://doi.org/10.1186/1741-7015-2-3

    Article  PubMed  PubMed Central  Google Scholar 

  • Lea RA, Ovcaric M, Sundholm J, Solyom L, MacMillan J, Griffiths LR (2005) Genetic variants of angiotensin converting enzyme and methylenetetrahydrofolate reductase may act in combination to increase migraine susceptibility. Mol Brain Res 136(1–2):112–117

    Article  PubMed  Google Scholar 

  • Leclerc D, Rozen R (2007) Génétiquemoléculaire de MTHFR: les polymorphismes ne sont pas tousbénins [Molecular genetics of MTHFR: polymorphisms are not all benign]. Medecinesciences : M/s 23(3):297–302. https://doi.org/10.1051/medsci/2007233297

    Article  Google Scholar 

  • Lievers KJ, Boers GH, Verhoef P, den Heijer M, Kluijtmans LA, van der Put NM, Trijbels FJ, Blom HJ (2001) A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med (berl) 79(9):522–528. https://doi.org/10.1007/s001090100253

    Article  PubMed  Google Scholar 

  • Lin J, Wang P, Chen C, Yueh K, Lin S, Harn H (2005) Homozygous deletion genotype of angiotensin converting enzyme confers protection against migraine in man. Acta NeurologicaTaiwanica 14(3):120

    Google Scholar 

  • Liu A, Menon S, Colson NJ, Quinlan S, Cox H, Peterson M, Tiang T, Haupt LM, Lea RA, Griffiths LR (2010) Analysis of the MTHFR C677T variant with migraine phenotypes. BMC Res Notes 3:213. https://doi.org/10.1186/1756-0500-3-213

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu L, Yu Y, He J, Guo L, Li H, Teng J (2019) Effects of MTHFR C677T and A1298C polymorphisms on migraine susceptibility: a meta-analysis of 26 studies. Headache 59(6):891–905. https://doi.org/10.1111/head.13540

    Article  PubMed  Google Scholar 

  • Liu R, Geng P, Ma M, Yu S, Yang M, He M, Dong Z, Zhang W (2014) MTHFR C677T polymorphism and migraine risk: a meta-analysis. J Neurol Sci 336(1–2):68–73. https://doi.org/10.1016/j.jns.2013.10.008

    Article  PubMed  Google Scholar 

  • Lorenz AL, Kahre T, Mihailov E, Nikopensius T, Lotman EM, Metspalu A, Kolk A (2014) Are methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms C677T and A1298C associated with higher risk of pediatric migraine in boys and girls?. J Biomed Sci Eng 2014

  • Magis D, Allena M, Coppola G, Di Clemente L, Gérard P, Schoenen J (2007) Search for correlations between genotypes and electrophysiological patterns in migraine: the MTHFR C677T polymorphism and visual evoked potentials. Cephalalgia: Int J Headache 27(10):1142–1149. https://doi.org/10.1111/j.1468-2982.2007.01412.x

  • Osman MM, Elzoghby DM, Heba H, Randa M, Dalia ME, Nehal EM, Ahmad Sweed MD (2019) Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (677CT) and increased susceptibility to migraine in egyptian population: a case-control study. Med J Cairo Univ 87(December):4165–4173

  • Oterino A, Toriello M, Valle N, Castillo J, Alonso-Arranz A, Bravo Y, Ruiz-Alegria C, Quintela E, Pascual J (2010) The relationship between homocysteine and genes of folate-related enzymes in migraine patients. Headache 50(1):99–168. https://doi.org/10.1111/j.1526-4610.2009.01484.x

    Article  PubMed  Google Scholar 

  • Oterino A, Valle N, Bravo Y, Muñoz P, Sánchez-Velasco P, Ruiz-Alegría C, Castillo J, Leyva-Cobián F, Vadillo A, Pascual J (2004) MTHFR T677 homozygosis influences the presence of aura in migraineurs. Cephalalgia : an International Journal of Headache 24(6):491–494. https://doi.org/10.1111/j.1468-2982.2004.00692.x

    Article  PubMed  Google Scholar 

  • Oterino A, Valle N, Pascual J, Bravo Y, Muñoz P, Castillo J, Ruiz-Alegría C, Sánchez-Velasco P, Leyva-Cobián F, Cid C (2005) Thymidylate synthase promoter tandem repeat and MTHFD1 R653Q polymorphisms modulate the risk for migraine conferred by the MTHFR T677 allele. Brain Res Mol Brain Res 139(1):163–168. https://doi.org/10.1016/j.molbrainres.2005.05.015

    Article  PubMed  Google Scholar 

  • Ozbey U, Etem E, Ozel S, Berilgen MS (2010) Is there a relation between insertion/deletion polymorphism of the angiotensin converting enzyme gene in patients of migraine with aura and migraine without aura in region of eastern Turkey. TurkiyeKlinikleri J Med Sci 30(2):502–506

    Google Scholar 

  • Palmirotta R, Barbanti P, Ludovici G, De Marchis ML, Ialongo C, Egeo G, Guadagni F (2014) Association between migraine and ACE gene (insertion/deletion) polymorphism: the BioBIM study. Pharmacogenomics 15(2):147–155

  • Pandith AA, Wani IY, Qasim I, Shah ZA, Sheikh S (2017) Evaluation of risk related to MTHFR 677C> T gene polymorphism in migraine patients in Kashmiri population. Open J Prev Med 7(8):151–161

    Article  Google Scholar 

  • Paterna S, Di Pasquale P, D’Angelo A, Seidita G, Tuttolomondo A, Cardinale A, Licata G (2000) Angiotensin-converting enzyme gene deletion polymorphism determines an increase in frequency of migraine attacks in patients suffering from migraine without aura. Eur Neurol 43(3):133–136

  • Pezzini A, Grassi M, Del Zotto E, Giossi A, Monastero R, Dalla Volta G, Archetti S, Zavarise P, Camarda C, Gasparotti R, Magoni M, Camarda R, Padovani A (2007) Migraine mediates the influence of C677T MTHFR genotypes on ischemic stroke risk with a stroke-subtype effect. Stroke 38(12):3145–3151. https://doi.org/10.1161/STROKEAHA.107.491506

    Article  PubMed  Google Scholar 

  • Pizza V, Bisogno A, Lamaida E, Agresta A, Bandieramonte G, Volpe A, Capasso A (2010) Migraine and coronary artery disease: an open study on the genetic polymorphism of the 5, 10 methylenetetrahydrofolate (MTHFR) and angiotensin I-converting enzyme (ACE) genes. Cent Nerv Syst Agents Med Chem (formerly current medicinal chemistry-central nervous system agents) 10(2):91–96

  • Rai V, Kumar P (2022) Relation between methylenetetrahydrofolate reductase polymorphisms (C677T and A1298C) and migraine susceptibility. Indian Journal of Clinical Biochemistry : IJCB 37(1):3–17. https://doi.org/10.1007/s12291-021-01000-0

    Article  PubMed  Google Scholar 

  • Riordan JF (2003) Angiotensin-I-converting enzyme and its relatives. Genome Biol 4(8):225. https://doi.org/10.1186/gb-2003-4-8-225

    Article  PubMed  PubMed Central  Google Scholar 

  • Saeedeh S, Ali Akbar O, Mohammad A, Majid G, Ahmad E, Mohammad Sadegh F (2015) MTHFR Gene polymorphisms and susceptibility to migraine attacks

  • Salehi M, Amin-Beidokhti M, Safarpour Lima B, Gholami M, Javadi GR, Mirfakhraie R (2018) The rs4846049 polymorphism in the 3’UTR region of the MTHFR gene increases the migraine susceptibility in an Iranian population. J Pain Res 11:145–149. https://doi.org/10.2147/JPR.S152930

    Article  PubMed  PubMed Central  Google Scholar 

  • Samaan Z, Gaysina D, Cohen-Woods S, Craddock N, Jones L, Korszun A, Owen M, Mente A, McGuffin P, Farmer A (2011) Methylenetetrahydrofolate reductase gene variant (MTHFR C677T) and migraine: a case control study and meta-analysis. BMC Neurol 11:66. https://doi.org/10.1186/1471-2377-11-66

    Article  PubMed  PubMed Central  Google Scholar 

  • Scher AI, Eiriksdottir G, Garcia M, Feit P, Smith AV, Harris TB, Roecklein KA, Gudmundsson LS, Gudnason V, Launer LJ (2013) Lack of association between the MTHFR C677T variant and migraine with aura in an older population: could selective survival play a role?. Cephalalgia: Int J Headache 33(5):308–315. https://doi.org/10.1177/0333102412469739

  • Scher AI, Terwindt GM, Verschuren WM, Kruit MC, Blom HJ, Kowa H, Frants RR, van den Maagdenberg AM, van Buchem M, Ferrari MD, Launer LJ (2006) Migraine and MTHFR C677T genotype in a population-based sample. Ann Neurol 59(2):372–375. https://doi.org/10.1002/ana.20755

    Article  PubMed  Google Scholar 

  • Schieffer B (2003) Interaction of interleukin-6 and angiotensin II in atherosclerosis: culprit for inflammation?. Eur Heart J Suppl 5(suppl_A):A25-A30

  • Schürks M, Rist PM, Kurth T (2010) MTHFR 677C>T and ACE D/I polymorphisms in migraine: a systematic review and meta-analysis. Headache 50(4):588–599. https://doi.org/10.1111/j.1526-4610.2009.01570.x

    Article  PubMed  Google Scholar 

  • Schürks M, Zee RY, Buring JE, Kurth T (2008) Interrelationships among the MTHFR 677C>T polymorphism, migraine, and cardiovascular disease. Neurology 71(7):505–513. https://doi.org/10.1212/01.wnl.0000316198.34558.e5

    Article  PubMed  Google Scholar 

  • Schürks M, Zee RY, Buring JE, Kurth T (2009) ACE D/I polymorphism, migraine, and cardiovascular disease in women. Neurology 72(7):650–656

    Article  PubMed  PubMed Central  Google Scholar 

  • Seo JH, Kim HJ, Lee IH, Kim OJ, Choi BO (2004) Association between migraine with aura and both homocysteine and MTHFR C677T polymorphism. J Korean Neurol Assoc 200–205

  • Sipahi T, Güldiken B, Kabayel L, Palabiyik O, Özkan H, Kiliç TO, Süt N, Turgut N (2013) Endothelial nitric oxide synthase and angiotensin converting enzyme gene polymorphisms in migraine patients. Noropsikiyatriarsivi 50(3):274–278. https://doi.org/10.4274/npa.y6665

    Article  Google Scholar 

  • Škovierová H, Vidomanová E, Mahmood S, Sopková J, Drgová A, Červeňová T, Halašová E, Lehotský J (2016) The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci 17(10):1733. https://doi.org/10.3390/ijms17101733

    Article  PubMed  PubMed Central  Google Scholar 

  • Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z, The L, Burden: the Global Campaign against Headache (2020) Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J Headache Pain 21(1):137. https://doi.org/10.1186/s10194-020-01208-0

    Article  PubMed  PubMed Central  Google Scholar 

  • Sudershan A, Mahajan K, Singh K, Dhar MK, Kumar P (2022) The complexities of migraine: a debate among migraine researchers: a review. Clin Neurol Neurosurg 214:107136. https://doi.org/10.1016/j.clineuro.2022.107136

    Article  PubMed  Google Scholar 

  • Sudershan A, Pushap AC, Younis M, Sudershan S, Bhagat S, Kumar H, Panjalyia RK, Kumar P (2023c) Neuroepidemiology study of headache in the region of Jammu of north Indian population: a cross-sectional study. Front Neurol 13:1030940. https://doi.org/10.3389/fneur.2022.1030940

    Article  PubMed  PubMed Central  Google Scholar 

  • Sudershan A, Sudershan S, Younis M, Bhagat M, Pushap AC, Kumar H, Kumar P (2023a) Enlightening the association between TNF-α -308 G > A and migraine: a meta-analysis with meta-regression and trial sequential analysis. BMC Neurol 23(1):159. https://doi.org/10.1186/s12883-023-03174-x

    Article  PubMed  PubMed Central  Google Scholar 

  • Sudershan A, Younis M, Sudershan S, Kumar P (2023b) Migraine as an inflammatory disorder with microglial activation as a prime candidate. Neurol Res 45(3):200–215. https://doi.org/10.1080/01616412.2022.2129774

    Article  PubMed  Google Scholar 

  • Szczygioł D, Motta E, Gołba A, Stęposz A, Witecka J, Dębski M, Sieroń, A (2012) Frequency of the C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene in patients with migraine with or without aura–a preliminary report. NeurologiaiNeurochirurgia Polska 46(5):443–449

  • Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J (2005) A method for meta-analysis of molecular association studies. Stat Med 24(9):1291–1306. https://doi.org/10.1002/sim.2010

    Article  PubMed  Google Scholar 

  • Thomas ASS, Saraswathy R, Thayanithy M (2022) Association of MTHFR (C677T and A1298C) gene variants polymorphisms with migraineurs: a case-control study. Appl Sci Eng Prog 15(3):5531–5531

    Google Scholar 

  • Tietjen GE, Herial NA, Utley C, White L, Yerga-Woolwine S, Joe B (2009) Association of von Willebrand factor activity with ACE I/D and MTHFR C677T polymorphisms in migrainecha. Cephalalgia 29(9):960–968

    Article  PubMed  Google Scholar 

  • Todt U, Freudenberg J, Goebel I, Netzer C, Heinze A, Heinze-Kuhn K, Göbel H, Kubisch C (2006) MTHFR C677T polymorphism and migraine with aura. Ann Neurol 60(5):621–622. https://doi.org/10.1002/ana.20911

    Article  PubMed  Google Scholar 

  • Tronvik E, Stovner LJ, Bovim G, White LR, Gladwin AJ, Owen K, Schrader H (2008) Angiotensin-converting enzyme gene insertion/deletion polymorphism in migraine patients. BMC Neurol 8(1):1–5

    Article  Google Scholar 

  • Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96(6):434–442. https://doi.org/10.1093/jnci/djh07

    Article  PubMed  PubMed Central  Google Scholar 

  • Wan D, Hou L, Zhang X, Han X, Chen M, Tang W, Liu R, Dong Z, Yu S (2015) DNA methylation of RAMP1 gene in migraine: an exploratory analysis. J Headache Pain 16(1). https://doi.org/10.1186/s10194-015-0576-7

  • Wan D, Wang C, Zhang X, Tang W, Chen M, Dong Z, Yu S (2016) Association between angiotensin-converting enzyme insertion/deletion polymorphism and migraine: a meta-analysis. Int J Neurosci 126(5):393–399

    Article  PubMed  Google Scholar 

  • Wani IY, Sheikh S, Shah ZA, Pandith AA, Wani M, Asimi R, Wani M, Sheikh S, Mehraj I (2016) Association of ACE Gene I/D polymorphism with migraine in Kashmiri population. Ann Indian Acad Neurol 19(1):89–93. https://doi.org/10.4103/0972-2327.167698

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are highly thankful to the Institute of Human Genetics, the University of Jammu, and the Department of Human Genetics (Sri Pratap College, Srinagar, Cluster University Srinagar) for the support in the present study.

Author information

Authors and Affiliations

  1. Institute of Human Genetics, University of Jammu, Jammu and Kashmir 180006, Gujarbasti, Jammu, India

    Amrit Sudershan & Parvinder Kumar

  2. Department of Human Genetics, Sri Pratap College, Cluster University of Srinagar, Jammu and Kashmir, Kashmir, 190001, India

    Amrit Sudershan

  3. Department of Education, Dakshina Bharat Hindi Prachar Sabha, Madras, 600017, India

    Agar Chander Pushap

  4. Department of Neurology, Super Specialty Hospital, Jammu and Kashmir 180006, Jammu, India

    Hardeep Kumar

  5. Department of Zoology, University of Jammu, Jammu and Kashmir 180006, Gujarbasti, Jammu, India

    Parvinder Kumar

Authors
  1. Amrit Sudershan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Agar Chander Pushap
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hardeep Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Parvinder Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Detail of the authors’ contribution according to the CRediT (Contributor Roles Taxonomy) System: PK and AS conceptualized the study and provided supervision; AS and ACP downloaded and filtered the data; AS and PK conducted all the statistical analysis and interpretation, drafted the manuscript, and edited the pictures and tables; HK and PK edited the manuscript; and PK finalize the manuscript. All authors provided critical feedback on the drafts and approved the final manuscript.

Corresponding author

Correspondence to Parvinder Kumar.

Ethics declarations

Ethics Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 254 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sudershan, A., Pushap, A.C., Kumar, H. et al. A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression. J Mol Neurosci 73, 884–911 (2023). https://doi.org/10.1007/s12031-023-02164-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-023-02164-5

Keywords

Search

Navigation