Maternal SNPs in the p53 Pathway: Risk Factors for Trisomy 21?

Abstract

Abstract. The p53 family and its regulatory pathway play an important role as regulators of developmental processes, limiting the propagation of aneuploid cells. Its dysfunction or imbalance can lead to pathological abnormalities in humans. The aim of this study was to evaluate the effect of maternal polymorphisms TP53 c.215G>C (P72R), TP73 4 c.-30G>A and 14 c.-20C>T, MDM2 c.14+309T>G (SNP309), MDM4 c.753+572C>T and USP7 c.2719-234G>A as risk factors for Down Syndrome (DS) birth. A case-control study was conducted with 263 mothers of DS children and 196 control mothers. The distribution of these genotypic variants was similar between case and control mothers. However, the combined alleles TP53 C and MDM2 G, and TP53 C and USP7 A increased the risk of having offspring with DS (OR = 1.84 and 1.77; 95% CI; P < 0.007 and 0.018, respectively). These results suggest that, although the individual polymorphisms were not associated with DS birth, the effect of the combined genotypes among TP53, MDM2 and USP7 genes indicates a possible role of TP53 and its regulatory pathway as a risk factor for aneuploidy.

Association of TP53 rs1042522 G > C, MDM2 rs2279744 T > G, and miR-34b/c rs4938723 T > C polymorphisms with aneuploidy pregnancy susceptibility

“…TP53 rs1042522 G > C has also been associated with fetal trisomy 21. C allele and CC genotype are common in the mother with trisomy 21 offspring [ 5 , 19 ]. This finding was in line with the results in the younger subgroup of our study but contrary to those in the advanced maternal age group perhaps for the coeffect with other environmental factors.…”

“…To date, seldom study has analyzed the MDM2 rs2279744 T > G polymorphism and fetal aneuploidy. Previous studies have shown a close association of MDM2 rs2279744 T > G with the human polycystic ovarian syndrome and human reproduction [ 5 , 23 ]. Strikingly, MDM2 rs2279744 T > G polymorphism is the key element in maintaining the genomic stability of somatic cells [ 4 , 22 ], which was not revealed in female gametes and embryos.…”

“…However, the mechanism underlying this intolerance of nondiploid genomes of cell is yet unknown. A potential role of TP53 pathway gene mutations was as a risk factor for human aneuploidy; it protects diploid cells and limits the proliferation of aneuploidy in humans [ 4 , 5 ]. TP53 plays a role in female reproduction by maintaining germ-cell integrity and various steps of mice and humans [ 6 ].…”

“…A vital TP53 gene polymorphism c.215G > C (rs1042522) is related to the accumulation of aneuploidy cells. TP53 rs1042522 G > C is located at codon 72, leading to a transversion from arginine (Arg) to proline (Pro) bringing about the changed structure and function of TP53 [ 8 ], which impairs apoptosis [ 9 ] and may promotes the continual development of aneuploidy cells [ 5 , 7 ]. Wild-type TP 53 is regulated by mouse double minute 2 (MDM2) via a negative feedback regulatory loop, which plays a critical role in the expression level within cells that revealed differential outcomes [ 10 , 11 ].…”

Effects ofMDM2promoter polymorphisms on the development of cervical neoplasia in a Southeastern Brazilian population

“…In our study, conducted in the city of Rio de Janeiro (Rio de Janeiro State, Southeast region of Brazil), the SNP309 G frequency was 0.26, an intermediate value between those of Europeans and Africans (Hu et al, 2007b), with no significant difference between self-declared Caucasian and mixed-ethnic participants (0.27 and 0.26, respectively). Different variant allele frequencies were found in Natal (Rio Grande do Norte State, Brazilian Northeast region) (European-descendant: 0.35; African-mixed descendant: 0.48) (Meissner et al, 2007), and in Porto Alegre (Rio Grande do Sul State, Brazilian South region) (0.39) (Bouquet et al, 2013). Such differences could be explained by the high ethnic heterogeneity of Brazilian populations (Saloum et al, 2013).…”