Association between Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Risk of Autoimmune Diseases: A Systematic Review and Meta-Analysis

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a critical rate-limiting enzyme in the homocysteine/methionine metabolism pathway that is implicated in the pathogenesis and progression of autoimmune diseases. Previous association studies have been performed to investigate the effect of polymorphisms in MTHFR on the risk of autoimmune diseases with inconsistent results. Therefore, this meta-analysis was designed to assess the association between the MTHFR 677 C/T and 1298 A/C polymorphisms and the susceptibility to autoimmune diseases. We identified reports by a literature search in the following electronic databases: PubMed, Ovid, Web of science, and China National Knowledge Infrastructure. Statistical analyses of the summary odds ratios (ORs) and 95% confidence intervals (CIs) were done using STATA software. In a recessive genetic model, the MTHFR 677 C/T polymorphism was associated with an increased risk of Behcet’s disease ( OR = 1.97 , 95% CI, 1.31-2.97), multiple sclerosis ( OR = 1.57 , 95% CI, 1.03-2.38), and ankylosing spondylitis ( OR = 2.90 , 95% CI, 1.92-4.38). The MTHFR 1298 A/C polymorphism was associated an increased risk of multiple sclerosis in a heterozygote comparison ( OR = 2.36 , 95% CI, 1.29-4.30) and in a dominant model ( OR = 2.31 , 95% CI, 1.24-4.29). This meta-analysis demonstrated that the MTHFR 677 C/T was a risk factor for Behcet’s disease, multiple sclerosis, and ankylosing spondylitis, and the 1298 A/C was a risk factor for multiple sclerosis.

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

“…The growing recognition of differential methylation of DNA in the pathogenesis of autoimmune disease [121,122,123] and the linkage between autoimmune disease and elevated Hcy [124,125] raises the specter of increased autoimmune disease in those with MTHFR (methylenetetrahydrofolate reductase) variants afflicted with LC. Indeed a recent meta analysis demonstrated a direct connection between MTHFR 677 C/T and 1298 A/C polymorphisms and increased risk of autoimmune disease [126]. According to the CDC, more than half of Americans have at least one MTHFR polymorphism.…”

Genetic factors involved in the co‑occurrence of endometriosis with ankylosing spondylitis (Review)

“…The results of the literature research revealed that IL-1A rs2856836 and rs3783550 ( 66 , 67 ), IL-10 rs1800871 ( 68 , 69 ), IL-12B rs17860508 ( 70 , 71 ), protein tyrosine phosphatase non-receptor type 22 ( PTPN22 ) rs2476601 ( 16 , 72 ), cyclooxygenase ( COX )-2 and ( PTGS )-2 rs20417 ( 73 – 75 ), CYP17A1 rs743572 ( 76 , 77 ), STAT4 rs7574865 ( 78 , 79 ), Toll like receptor 4 ( TLR4 ) rs4986791 ( 76 , 80 ) and methylenetetrahydrofolate reductase ( MTHFR ) rs1801133 ( 81 – 83 ) SNPs are associated with both diseases under investigation ( Table I ). The common genetic targets and their corresponding genes have been further analyzed towards estimating the candidate gene regulatory network and the major categories of the biological pathways using the GeneMANIA and the Reactome Knowledgebase platforms, respectively ( Fig.…”

“…The 5,10-methylenetetrahydrofolate reductase ( MTHFR ) gene is located in chromosome 1p36.3, encoding a key rate-limiting, regulatory enzyme in folate and homocysteine metabolism, which catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate ( 131 ). The MTHFR rs1801133 (Ala222Val) SNP, which is located in exon 4, has been found to be significantly associated with both AS and endometriosis ( 81 – 83 ). It has been previously suggested that polymorphisms in the MTHFR gene may result in alterations in gene expression levels and protein function, thus leading to an abnormal metabolism of 5,10-methylenetetrahydrofolate ( 82 , 83 ).…”

“…The MTHFR rs1801133 (ala222Val) SnP, which is located in exon 4, has been found to be significantly associated with both aS and endometriosis (81)(82)(83). it has been previously suggested that polymorphisms in the MTHFR gene may result in alterations in gene expression levels and protein function, thus leading to an abnormal metabolism of 5,10-methylenetetrahydrofolate (82,83). Thus, the c677T missense mutation, which has been characterized as a thermally unstable one, probably influences the thermostability and activity of MHTFr protein, while it has been also reported that the rs1801133 T allele results in elevated plasma homocysteine levels, which, in combination with endothelial injury and vascular inflammation, may result in the development of cardiovascular disease, a well-known comorbidity of endometriosis (13,132).…”

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

“…The growing recognition of differential methylation of DNA and RNA in the pathogenesis of autoimmune disease [116][117][118] and the linkage between autoimmune disease and elevated Hcy [119,120] raises the specter of increased autoimmune disease in those with MTHFR (methylenetetrahydrofolate reductase) variants afflicted with LC. Indeed a recent meta analysis demonstrated a direct connection between MTHFR 677 C/T and 1298 A/C polymorphisms and increased risk of autoimmune disease [121]. According to the CDC, more than half of Americans have at least one MTHFR polymorphism.…”