Genetic effect of MTHFR C677T, A1298C, and A1793G polymorphisms on the age at onset, plasma homocysteine, and white matter lesions in Alzheimer's disease in the Chinese population

Abstract

Background: Three polymorphisms in the Methylenetetrahydrofolate reductase (MTHFR) gene (C677T, A1298C, and A1793G) were reported associated with AD. However, their genotype distributions and associations with age at onset (AAO), homocysteine, and white matter lesions (WML) were unclear in the Chinese AD population. Method: We determined the presence of C677T, A1298C, and A1793G polymorphisms in the MTHFR gene using Sanger sequencing in a Chinese cohort comprising 721 AD patients (318 early-onset AD patients (EOAD) and 403 late-onset AD patients (LOAD)) and 365 elderly controls. Additionally, the homocysteine level and WML were evaluated in 121 AD patients. Results: The frequency of allele T of C677T polymorphism was significantly higher in AD patients than in controls ( P = 0.040), while no statistical difference was observed in A1298C and A1793G ( P > 0.05). Besides, genotype distributions of C677T and A1298C polymorphisms statistically varied between AD patients and controls ( P = 0.021, P = 0.012). Moreover, the AAO was significantly lower in CT/TT (C677T) genotypes carriers ( P = 0.042) and higher in AC/CC (A1298C) and AG/GG (A1793G) genotypes carriers ( P = 0.034, P = 0.009) in patients with LOAD. We also found that patients with CT/TT (C677T) genotypes were prone to present an increased homocysteine level ( P = 0.036) and higher Fazekas score ( P = 0.024). In comparison, patients with AG/GG genotypes (A1793G) had a significantly lower Fazekas score ( P = 0.013). Conclusions: The genotype distributions of C677T and A1298C polymorphisms are associated with AD in the Chinese population. Moreover, AD patients with C677T polymorphism are prone to present an earlier onset, higher homocysteine level, and more severe WML.

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

“…Thus, a negative variant of MTHFD1 should have a remarkable effect on folate metabolic balance, decreasing the 5mTHF pool and potentially leading to homocysteine and formate toxicity and errors/reduced DNA synthesis and repair. 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].…”

“…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).…”

Associations between methylenetetrahydrofolate reductase polymorphisms and hepatocellular carcinoma risk

“…protein). [19,20] Both of the 2 polymorphisms were reported to be associated with a lower MTHFR activity, [21][22][23][24][25][26][27][28] and the reduced enzymatic activity can promote or inhibit the occurrence of HCC by affecting DNA methylation and synthesis, which indicated these 2 polymorphisms could be associated with HCC risk.…”

“…Two functional single nucleotide polymorphisms (SNPs) in MTHFR were identified: the MTHFR rs1801133 (C677T) polymorphism (a C to T transition at nucleotide 677 at exon 4, resulting in an alanine-to-valine conversion in protein) and MTFHR rs1801131 (A1298C) polymorphism (a A to C transition at nucleotide 1298 at exon ten, causing a glutamate-to-alanine change in protein) [19,20] . Both of the 2 polymorphisms were reported to be associated with a lower MTHFR activity, [21–28] and the reduced enzymatic activity can promote or inhibit the occurrence of HCC by affecting DNA methylation and synthesis, which indicated these 2 polymorphisms could be associated with HCC risk.…”