Lack of association between MTHFR A1298C variant and Alzheimer’s disease: evidence from a systematic review and cumulative meta-analysis

Liu, Shumin; Wu, Yongfu; Liu, Xu; Zhou, Jiahui; Wang, Ziyou; He, Zhiwei; Huang, Zunnan

doi:10.1080/01616412.2017.1297340

Cited by 9 publications

(5 citation statements)

References 43 publications

(72 reference statements)

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“…Similarly, a negative variant of MTHFR should result in raised homocysteine levels that would exacerbate neurodegeneration and increase the risk of developing AD [83]. In the cases studied here, MTHFD1 is very significantly associated with AD, while MTHFR is probably only weakly associated, as already reported for this variant [84] by contrast to other studies finding 1-3 additional variants of this gene associated with AD [83,85,86]. We found a significant increase in glutathione in severe Alzheimer's cases with negative variants in MTHFD1 and/or MTHFR compared to those with positive or neutral variants (Figure 2).…”

Section: Discussionsupporting

confidence: 79%

Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile

Miyan

Buttercase

Beswick³

et al. 2022

Metabolites

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Metabolic disorders may be important potential causative pathways to Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) decreasing output, raised intracranial pressure, and ventricular enlargement have all been linked to AD. Cerebral folate metabolism may be a key player since this is significantly affected by such changes in CSF, and genetic susceptibilities may exist in this pathway. In the current study, we aimed to identify whether any single nucleotide polymorphism (SNPs) affecting folate and the associated metabolic pathways were significantly associated with AD. We took a functional nutrigenomics approach to look for SNPs in genes for the linked folate, methylation, and biogenic amine neurotransmitter pathways. Changes in metabolism were found with the SNPs identified. An abnormal SNP in methylene tetrahydrofolate dehydrogenase 1 (MTHFD1) was significantly predictive of AD and associated with an increase in tissue glutathione. Individuals without these SNPs had normal levels of glutathione but significantly raised MTHFD1. Both changes would serve to decrease potentially neurotoxic levels of homocysteine. Seven additional genes were associated with Alzheimer’s and five with normal ageing. MTHFD1 presents a strong prediction of susceptibility and disease among the SNPs associated with AD. Associated physiological changes present potential biomarkers for identifying at-risk individuals.

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Section: Discussionsupporting

confidence: 79%

Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile

Miyan

Buttercase

Beswick³

et al. 2022

Metabolites

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“…Likewise, there is no consensus in the literature about the effect of A1298C polymorphism in the development of AD. In the Mansouri's study, CC genotype of A1298C polymorphism significantly increased the risk for the development of AD [34], while in the Liu 's study, there was no significant association between A1298C polymorphism and increased risk of AD [42].…”

Section: Discussionmentioning

confidence: 90%

Allelic Distribution of Genes for Apolipoprotein E and MTHFR in Patients with Alzheimer’s Disease and Their Epistatic Interaction

Šutovský

Petrovič

Fischerova

et al. 2020

JAD

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Background: Genetic risk factors play an important role in the pathogenesis of Alzheimer’s disease (AD). However, the gene-gene interaction (epistasis) between specific allelic variants is only partially understood. Objective: In our study, we examined the presence of the ɛ4 allele of apolipoprotein E (APOE) and the presence of C677T and A1298C (rs1801133 and rs1801131) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with AD and controls. We also evaluated the epistatic interaction between MTHFR and the APOE variants. Methods: A total of 564 patients with AD and 534 cognitively unimpaired age-matched controls were involved in the study. Results: The presence of the ɛ4 allele of APOE increases the risk of developing AD in a dose-dependent manner (OR 32.7: homozygotes, 15.6: homozygotes + heterozygotes, 14.3: heterozygotes). The combination of genotypes also increases the risk of developing AD in a dose-dependent manner: OR 18.3 (APOE 4/X and 4/4 + CT rs1801133), OR 19.4 (APOE 4/X and 4/4 + CT rs1801133 + AC rs1801131), OR 22.4 (APOE 4/X and 4/4 + TT rs1801133), and OR 21.2 (APOE 4/X and 4/4 + CC rs1801131). Homozygotes for variant alleles of MTHFR as well as patients with AD had significantly higher levels of homocysteine than homozygotes for standard alleles or controls. Conclusion: Homozygotes for APOE4 and carriers of APOE4 with TT genotype of rs1801133 were found to be at the highest risk of developing AD. These findings suggest that the epistatic interaction of specific gene variants can have a significant effect on the development of AD.

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“…Likewise, the mutation of adenine (A) to cytosine (C) in this site causes glutamate to be replaced by alanine, decreasing the phosphorylation of serine and cysteine and thus affecting the expression of MTHFR as well [45]. As another MTHFR gene mutation, the relationship between MTHFR A1298C polymorphism and the risk of disease is also explored, such as Alzheimer's disease [46] and lung cancer [47]. Our study is the first meta-analysis to explore the relationship between MTHFR A1298C polymorphism and VTE susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of the relationship between methylenetetrahydrofolate reductase C677T and A1298C polymorphism and venous thromboembolism in the Caucasian and Asian

et al. 2020

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Abstract Recent years, it is a highly debated topic that whether methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and A1298C polymorphism could increase susceptibility to venous thromboembolism (VTE) in the Asian and Caucasian. Therefore, we expect to settle that controversy evidentially. Basic methods: Electronic databases (Pubmed, embase, Cochrane library, scopus, OvidSP, Wiley Online library, Springer link, EBSCO, Elsevier Science Direct, Google scholar) without date limitation were searched. Crude odds ratio (OR) along with 95% confidence interval (95% CI) was calculated to assess the association quantitatively. Finally, a total of 37 eligible studies were included, containing 31 for MTHFR C677T polymorphism and 6 for MTHFR A1298C polymorphism. The pooled results suggested that MTHFR C677T mutation may increase susceptibility to VTE in reverse recessive model (CC+CT vs TT): OR = 0.68 (0.56, 0.83), reverse dominant model (CC vs CT +TT): OR = 0.82 (0.72, 0.94), heterozygote model (CT vs TT): OR = 0.65 (0.52, 0.81), homozygote model (CC vs TT): OR = 0.73 (0.60, 0.89) and allele model (C vs T): OR = 0.80 (0.71, 0.90). Subgroup analysis about Asian also support that results, but Caucasian group not. In addition, MTHFR A1298C polymorphism may be not related to VTE in all genetic model. The results of meta-analysis indicated that MTHFR C677T polymorphism might increase the risk of VTE, especially in Asian population.

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Lack of association between MTHFR A1298C variant and Alzheimer’s disease: evidence from a systematic review and cumulative meta-analysis

Cited by 9 publications

References 43 publications

Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile

Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile

Allelic Distribution of Genes for Apolipoprotein E and MTHFR in Patients with Alzheimer’s Disease and Their Epistatic Interaction

Meta-analysis of the relationship between methylenetetrahydrofolate reductase C677T and A1298C polymorphism and venous thromboembolism in the Caucasian and Asian

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