RESUMEN
XRCC1 is involved in repair of single-strand breaks generated by mutagenic exposure. Polymorphisms within XRCC1 affect its ability to efficiently repair DNA damage. Polycyclic aromatic hydrocarbons or PAHs are genotoxic compounds which form bulky DNA adducts that are linked with infertility. Few reports suggest combined role of XRCC1 polymorphisms and PAHs in infertility. Present study investigates association of three XRCC1 polymorphisms (p.Arg194Trp, p.Arg280His, p.Arg399Gln) with male and female infertility in a North-West Indian population using case-control approach. Additionally, in silico approach has been used to predict whether XRCC1 polymorphisms effect interaction of XRCC1 with different PAHs. For case-control study, XRCC1 polymorphisms were screened in peripheral blood samples of age- and gender-matched 201 infertile cases (â-100, â-101) and 201 fertile controls (â-100, â-101) using PCR-RFLP method. For in silico study, AutoDock v4.2.6 was used for molecular docking of B[a]P, BPDE-I, ( ±)-anti-BPDE, DB[a,l]P, 1-N, 2-N, 1-OHP, 2-OHF with XRCC1 and assess effect of XRCC1 polymorphisms on their interaction. In case-control study, statistical analysis showed association of XRCC1 p.Arg280His GA genotype (p = 0.027), A allele (p = 0.019) with reduced risk of male infertility. XRCC1 p.Arg399Gln AA genotype (p = 0.021), A allele (p = 0.014) were associated with reduced risk for female primary infertility. XRCC1 p.Arg194Trp T allele was associated with increased risk for female infertility (p = 0.035). In silico analysis showed XRCC1-PAH interaction with non-significant effect of XRCC1 polymorphisms on predicted binding. Therefore, present study concludes that XRCC1 polymorphism-modified risk for male and female infertility in North-West Indians without significant effect on predicted XRCC1-PAH interactions. This is the first report on XRCC1 in female infertility.
RESUMEN
RAD51 is a highly conserved recombinase involved in the strand invasion/exchange of double-stranded DNA by homologous single-stranded DNA during homologous recombination repair. Although a majority of existing literature associates RAD51 with the pathogenesis of various types of cancer, recent reports indicate a role of RAD51 in maintenance of fertility. The present study reviews the role of RAD51 and its interacting proteins in spermatogenesis/oogenesis and additionally reports the findings from the molecular genetic screening of RAD51 135 G > C polymorphism in infertile cases and controls. Fifty-nine articles from PubMed and Google Scholar related to the reproductive role of RAD51 were reviewed. For case-control study, the PCR-RFLP method was used to screen the RAD51 135 G > C polymorphism in 201 infertile cases (100 males, 101 females) and 201 age- and gender-matched healthy controls (100 males, 101 females) from Punjab, North-West India. The review of literature shows that RAD51 is indispensable for spermatogenesis and oogenesis in animal models. Reports on the role of RAD51 in human fertility are limited, however it is involved in the pathogenesis of infertility in both males and females. Molecular genetic analyses in the infertile cases and healthy controls showed no statistically significant difference in the genotypic and allelic frequencies for RAD51 135 G > C polymorphism, even after segregation of the cases by type of infertility (primary/secondary). Therefore, the present study concluded that the RAD51 135 G > C polymorphism was neither associated with male nor female infertility in North-West Indians. This is the first report on RAD51 135 G > C polymorphism and infertility.
RESUMEN
BACKGROUND: The cause of infertility remains unclear in a significant proportion of reproductive-age couples who fail to conceive naturally. Chromosomal aberrations have been identified as one of the main genetic causes of male and female infertility. Structural chromosomal aberrations may disrupt the functioning of various genes, some of which may be important for fertility. The present study aims to identify candidate genes and putative functional interaction networks involved in male and female infertility using cytogenetic data from cultured peripheral blood lymphocytes of infertile patients. METHODS: Karyotypic analyses was done in 201 infertile patients (100 males and 101 females) and 201 age and gender matched healthy controls (100 males and 101 females) after 72 h peripheral lymphocyte culturing and GTG banding, followed by bioinformatic analysis using Cytoscape v3.8.2 and Metascape. RESULTS: Several chromosomal regions with a significantly higher frequency of structural aberrations were identified in the infertile males (5q2, 10q2, and 17q2) and females (6q2, 16q2, and Xq2). Segregation of the patients based on type of infertility (primary v/s secondary infertility) led to the identification of chromosomal regions with a significantly higher frequency of structural aberrations exclusively within the infertile males (5q2, 17q2) and females (16q2) with primary infertility. Cytoscape identified two networks specific to these regions: a male specific network with 99 genes and a female specific network with 109 genes. The top enriched GO terms within the male and female infertility networks were "skeletal system morphogenesis" and "mRNA transport" respectively. PSME3, PSMD3, and CDC27 were the top 3 hub genes identified within the male infertility network. Similarly, UPF3B, IRF8, and PSMB1 were the top 3 hub genes identified with the female infertility network. Among the hub genes identified in the male- and female-specific networks, PSMB1, PSMD3, and PSME3 are functional components of the proteasome complex. These hub genes have a limited number of reports related to their respective roles in maintenance of fertility in mice model and humans and require validation in further studies. CONCLUSION: The candidate genes predicted in the present study can serve as targets for future research on infertility.