Dataset Information

Gene variants in the folate pathway are associated with increased levels of folate receptor autoantibodies.

ABSTRACT: BACKGROUND:Folate receptors (FRs) facilitate embryonic uptake of folates and are important for proper early embryonic development. There is accumulating evidence that blocking FR autoantibodies contribute to developmental diseases. However, genetic factors associated with the expression of FR autoantibodies remain unknown. OBJECTIVE:We investigated the effects of genetic polymorphisms in folate pathway genes on FR autoantibody titers in women. METHODS:We recruited 302 pregnant women in China. The FR antigen-down immunoassay was used to measure levels of FR autoantibodies including human immunoglobulin G (IgG) and immunoglobulin M (IgM) in maternal plasma. Genotypes were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry and polymerase chain reaction methods. General linear model was used to analyze the effects of genetic variants on FR autoantibody levels. RESULTS:Significant associations were observed between genotypic variations and levels of FR autoantibodies. Plasma levels of FR autoantibodies in women with the TT genotype at MTHFR rs1801133 were significantly higher than those of women with the CC genotype (IgG: ??=?0.62, 95% CI 0.21-1.04; IgM: ??=?0.42, 95% CI 0.12-0.72). For DNMT3A rs7560488, the level of FR autoantibody IgG significantly increased in the TT genotype compared with CC genotype (??=?0.90, 95% CI 0.20-1.59). For MTHFD2 rs828903, genotype GG was associated with elevated levels of FR autoantibody IgM compared to the AA genotype (??=?0.60, 95% CI 0.10-1.10). No association was detected between genetic variants of the DHFR gene with FR autoantibodies levels. CONCLUSION:Genetic variations in MTHFR, DNMT3A, and MTHFD2 genes were associated with elevated plasma levels of FR autoantibodies.

SUBMITTER: Dong Y

PROVIDER: S-EPMC6276117 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Gene variants in the folate pathway are associated with increased levels of folate receptor autoantibodies.

Dong Yuqi Y Wang Linlin L Lei Yunping Y Yang Na N Cabrera Robert M RM Finnell Richard H RH Ren Aiguo A

Birth defects research 20180506 12

<h4>Background</h4>Folate receptors (FRs) facilitate embryonic uptake of folates and are important for proper early embryonic development. There is accumulating evidence that blocking FR autoantibodies contribute to developmental diseases. However, genetic factors associated with the expression of FR autoantibodies remain unknown.<h4>Objective</h4>We investigated the effects of genetic polymorphisms in folate pathway genes on FR autoantibody titers in women.<h4>Methods</h4>We recruited 302 pregn ...[more]

PMID: 29732742

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Project description:The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD is an autoantibody that interferes with the function of the FRα. FRα autoantibodies (FRAAs) have been reported in ASD. A systematic review was performed to identify studies reporting FRAAs in association with ASD, or the use of d,l-leucovorin in the treatment of ASD. A meta-analysis examined the prevalence of FRAAs in ASD. The pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38% (with a significant variation across studies due to heterogeneity). The etiology of CFD in ASD was attributed to FRAAs in 83% of the cases (with consistency across studies) and mitochondrial dysfunction in 43%. A significant inverse correlation was found between higher FRAA serum titers and lower 5-MTHF CSF concentrations in two studies. The prevalence of FRAA in ASD was 71% without significant variation across studies. Children with ASD were 19.03-fold more likely to be positive for a FRAA compared to typically developing children without an ASD sibling. For individuals with ASD and CFD, meta-analysis also found improvements with d,l-leucovorin in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%). Twenty-one studies (including four placebo-controlled and three prospective, controlled) treated individuals with ASD using d,l-leucovorin. d,l-Leucovorin was found to significantly improve communication with medium-to-large effect sizes and have a positive effect on core ASD symptoms and associated behaviors (attention and stereotypy) in individual studies with large effect sizes. Significant adverse effects across studies were generally mild but the most common were aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%). Taken together, d,l-leucovorin is associated with improvements in core and associated symptoms of ASD and appears safe and generally well-tolerated, with the strongest evidence coming from the blinded, placebo-controlled studies. Further studies would be helpful to confirm and expand on these findings.

Dataset Information

Gene variants in the folate pathway are associated with increased levels of folate receptor autoantibodies.

Publications

Gene variants in the folate pathway are associated with increased levels of folate receptor autoantibodies.

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