Role of Polymorphisms on the Recurrent Pregnancy Loss: A Systematic Review, Meta-analysis and Bioinformatic Analysis

Recurrent miscarriage (RM) is a major reproductive health issue. RM is a multi-factorial disease, and is affected by environmental, genetic, and epigenetic factors. Genetics has a common role in recurrent miscarriage occurrence. It seems that molecular genetics has a great role in RSA incidence. So, in these years, RM has become for a major subject of genetics research. There are many genes that are involved in each phase for successful reproduction. This research aimed to evaluate the effect of all studied polymorphisms in studies on RSA that have not been included in any meta-analysis. PubMed, Scopus, and Web of Science databases were recruited to investigate the related articles. The systematic review results identified 143 studies worldwide. Thirteen genes have been included in assessing the case-control studies. Sixty-four SNPs were recruited to assess the association between genetic factors and RSA susceptibility. Ninety-two studies containing twenty-two SNPs (from 10 genes) were included in the quantitative analysis. Bioinformatic analysis indicated that rs12722482 showed "Damaging Status " by double servers, and rs315952 and rs854560 had "Possibly damaging " status in the PolyPhen-2 server. MethPrimer server indicated that there is "CpG Island " in the rs10895068, rs1130355, and rs41557518 variants, and rs10895068-G allele makes a CpG dinucleotide which can change the gene methylation and result in altering the gene expression. So, further studies on rs12722482 and rs10895068 can demonstrate valuable results. To the best of our knowledge, this systematic review has covered the all studied polymorphisms of HLA-C, HLA-G, PON1, AGTR1, TAFI, FAS, FAS-L, ESR1, PGR, CTLA-4, MMP-2, MMP-3, MMP-9, and IL1RN for the first time. Also, we did a novel meta-analysis for AGTR1 rs5186, TAFI rs1926447, rs3742264, HLA-G rs1063320, rs1233334, rs1736936, rs2249863, PON1 rs662, rs854560, FAS rs2234767, rs1800682, FAS-L rs763110, ESR1, rs9340799, rs3798759, PGR rs1042838, CTLA4 rs4553808, rs5742909, rs231775, rs3087243, and MMP-2 rs243865 and updated statistical finding for rs2234693 and rs371194629. Rs2234693, rs9340799, rs231775, and rs371194629 demonstrated a significant association with RSA risk. Some variations showed significant association, while further studies are suggested to confirm the results. Finally, Rs4553808 and rs5742909 revealed no significant deviation in the results. It is suggested that these SNPs may be excluded from subsequent case-control studies or other analyses.