Maternal gastric intrinsic factor A68G and paternal cubilin C758T variants increase the risk for neural tube defects in the fetus: A family-triad study from South India

Background: Neural tube defects (NTDs) are the leading cause of infant deaths worldwide. Gastric Intrinsic Factor (GIF) and Cubilin (CUBN) genes essential for early fetal development have not been extensively studied in NTDs. In view of this, present study aimed to evaluate association of GIF A68G and CUBN C758T variants with NTD risk using family-based triad approach. Methods: A total of 924 subjects including 124 NTD case-parent trios and 184 healthy control-parent trios diagnosed at Institute of Genetics and Hospital for Genetic Diseases, Hyderabad were considered for the study. Blood samples from study group parents and umbilical cord tissue samples from NTD cases and controls were genotyped for GIF A68G (rs35211634) and CUBN C758T (rs1801222) variants for their association with NTDs. Serum holo-transcobalamin (holo-TC) levels were measured using ELISA. Results: Assessment of maternal-paternal genotype incompatibility risk for NTD revealed maternal AG genotype in combination with paternal AA genotype of GIF A68G (AGxAA=AG,OR=2.92,p=.006) and maternal CC genotype with paternal CT genotype combination of CUBN C758T (CCxCT=CT,OR=3.71,p<.001) significantly increased the risk for NTDs. Allelic gene-gene interactions of GIF A68G and CUBN C758T showed significant association of maternal G-C (OR=6.34,p<.001) and paternal A-T alleles (OR=2.61,p=.001) for the occurrence of NTDs. Further, parent-of-origin effects also revealed significant transmission of maternal 'G' allele (OR=3.50,p=.015) and paternal 'T' allele (OR=2.57,p=.016) to NTDs. Correlation of serum holo-TC levels with GIF A68G and CUBN C758T genotypes revealed significant association of paternal CT genotype of C758T variant with decreased holo-TC levels compared to controls (p=.013). However, GIF A68G variant showed no significant association with holo-TC levels. Conclusion: The present family-based triad study provides the first report on the risk of NTD susceptibility being potentially influenced by maternal GIF A68G and paternal CUBN C758T variants.