MTHFR C677T and MTR A2756G gene polymorphism in neural tube defect patients and its association with red blood cell folate level in Eastern Indian Population

Abstract

Introduction: Single-nucleotide polymorphism (SNP) is a single-nucleotide change in a deoxyribose nucleic acid (DNA) sequence that occurs in >1% of population. Methylene tetra hydro folate reductase (MTHFR) C677T (rs1801133) and methionine synthase enzyme (MTR) A2756G (rs1805087) are two such SNPs occurring in coding sequence of the respective genes, which are frequently seen with neural tube defects (NTDs). MTHFR and MTR genes are involved in folate metabolism. The folate level in the course of pregnancy is treated as vital in the etiopathogenesis of NTDs. This study aims to explore the association of SNPs of both genes and red blood cell (RBC) folate levels in the predisposition to NTDs. Aims and Objective: The purpose of this investigation was to determine the relationship of NTDs with polymorphisms in MTHFR and MTR genotype and to estimate and compare the RBC folate levels in NTD patients and controls. Materials and Methods: A total of 397 individuals were enrolled (163 patients and 234 controls) for this observational study. Genotyping to find out MTHFR C677T and MTR A2756G was performed by polymerase chain reaction–restriction fragment length polymorphism technique from DNA extracted from the subject's blood. RBC folate level was estimated by chemiluminescence immunoassay method with the same blood sample. Results: The total RBC folate levels were significantly less among cases compared to controls ( P = 0.020). A significant difference for RBC folate was observed between case and control groups of various genotypes of MTHFR C677T, except heterozygote CT ( P = 0.459). Among MTR A2756G, genotypes with only homozygous AA have significant difference ( P = 0.003) for RBC folate levels. Among different types of NTDs, there were no significant differences for RBC folate levels. Among MTHFR C677T, T allele possessed 1.9 times risk compared to C allele for the occurrence of NTDs. In MTR A2756G polymorphism, the odds of developing NTDs were 1.6 times in heterozygous AG compared to homozygous AA. Similarly, the risk for NTDs was three times higher in subjects with both heterozygous AG and CT genotypes compared to wild-type homozygous AA and CC genotypes. Conclusion: The total RBC folate levels were significantly less among cases compared to controls, and the genotypes had no such effect in decrease in RBC folate levels. The presence of mutant allele in homozygous or heterozygous condition for both SNPs had increased risk associated with NTDs.

Exploring research hotspots and future directions in neural tube defects field by bibliometric and bioinformatics analysis

“…MTHFR rs1801133 (677 C > T), MTRR rs1801394 (66 A > G), and BHMT rs3733890 (716 G > A) maybe potential risk factors for NTD in Chinese population ( Liu et al, 2014 ; Fang et al, 2018 ). MTHFR rs1801133 (677 C > T) and MTR rs1805087 (2,756 A > G) had increased risk associated with NTDs in Eastern Indian population ( Kumari et al, 2022 ). SLC19A1 rs1051266 (80G > A) has been shown to be associated with MM risk in sample populations from Italy, the United States, and China ( Findley et al, 2017 ).…”

Double whammy: the genetic variants in CECR2 and high Hcy on the development of neural tube defects

“…For instance, variants in the CYP26B1 gene, occurring concurrently with other variants in neural tube-related genes such as CELSR3 and REST, were hypothesized to be associated with the craniorachischisis phenotype (Zou et al, 2020). The risk of NTDs was three times greater in subjects carrying both heterozygous MTHFR C677T and MTR A2756G genotypes compared to those with wild-type Frontiers in Genetics frontiersin.org homozygous AA and CC genotypes (Kumari et al, 2022). Moreover, an accumulation of approximately nine SloFVs (singleton loss-offunction variants) represents a genomic threshold for NTD risk, regardless of genetic background or ethnicity (Chen et al, 2018).…”

Neural Tube Defects Are Not Only Associated with Polymorphisms in MTHFR or MTR but with Pathogenic Variants in Numerous Other Genes

“…The article by Kumari et al . [ 1 ] on the association between neural tube defects (NTDs) and MTHFR or MTR polymorphisms is compelling but has limitations.…”

“…A limitation of the study is that no cytogenetic studies were performed and that numerical and structural chromosomal aberrations (translocation, deletion, duplications, inversion, isomerization, ring chromosomes) were not excluded as causes of NTD. [ 1 ]…”