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Headache. 2019 May 2. doi: 10.1111/head.13540. [Epub ahead of print]

Effects of MTHFR C677T and A1298C Polymorphisms on Migraine Susceptibility: A Meta-Analysis of 26 Studies.

Author information

Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Neurology, Center Hospital of Weihai, School of Medicine, Qingdao University, Weihai, China.
Pharmacy Intravenous Admixture Services, Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China.



Multiple studies have evaluated the associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and migraine risk with conflicting results. Therefore, we conducted a meta-analysis on this theme.


We searched the electronic databases of PubMed, EmBase, ScienceDirect, and Cochrane Library for all relevant studies published until April 6, 2018. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) in allelic, dominant, recessive, homozygous, and heterozygous models were calculated using random effects model to assess the strength of associations. We also performed subgroup analyses stratified by ethnicity and migraine subtypes, respectively.


Twenty-six studies (20 in Caucasians, 3 in Asians, 2 in Indians, and 1 in Pakistanis) with 10,228 migraineurs and 28,608 controls were included in this meta-analysis. In the overall population, the allele 677T and TT genotype were associated with an increased risk for total migraine and migraine with aura (MA) (total migraine: T vs C: OR = 1.19, 95%CI = 1.06-1.33, P = .004; TT vs CC: OR = 1.32, 95%CI = 1.07-1.64, P = .011; MA: T vs C: OR = 1.28, 95%CI = 1.09-1.51, P = .003; TT vs CC: OR = 1.51, 95%CI = 1.09-2.08, P = .012), but not for migraine without aura (MO). Subgroup analysis stratified by ethnicity revealed similar findings in Caucasians. In Asians, the association was detected only in recessive model in total migraine (TT vs CT + CC: OR = 1.80, 95%CI = 1.14-2.85, P = .012). Results in Indians did not suggest any association in either total migraine or its subtypes. Pooled results of 5 studies (4 in Caucasians and 1 in Indians) on A1298C polymorphism indicated a significant association between the CC genotype and migraine risk (CC vs AA: OR = 1.78, 95%CI = 1.03-3.07, P = .038), which only appeared for MO (CC vs AA: OR = 2.83, 95%CI = 1.30-6.16, P = .009).


Our meta-analysis suggested that allele 677T in MTHFR C677T polymorphism might be a genetic risk factor for MA in Caucasians, and genotype 1298CC might contribute to MO susceptibility.


MTHFR; meta-analysis; migraine; polymorphism


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