From bench to <i>in silico</i> and backwards: What have we done on genetics of recurrent pregnancy loss and implantation failure and where should we go next?

Gomes, Flavia Gobetti; Boquett, Juliano André; Kowalski, Thayne Woycinck; Bremm, João Matheus; Michels, Marcus Silva; Pretto, Luiza; Rockenbach, Marília Körbes; Vianna, Fernanda Sales Luiz; Schuler-Faccini, Lavinia; Sanseverino, Maria Teresa Vieira; Fraga, Lucas Rosa

doi:10.1590/1678-4685-GMB-2023-0127

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60 years of the PPGBM UFRGS - Special Issue • Genet. Mol. Biol. 46 (3 Suppl 1) • 2023 • https://doi.org/10.1590/1678-4685-GMB-2023-0127 linkcopy

From bench to in silico and backwards: What have we done on genetics of recurrent pregnancy loss and implantation failure and where should we go next?

Authorship SCIMAGO INSTITUTIONS RANKINGS

Human reproduction goes through many challenges to its success and in many cases it fails. Cases of pregnancy loss are common outcomes for pregnancies, and implantation failures (IF) are common in assisted reproduction attempts. Although several risk factors have already been linked to adverse outcomes in reproduction, many cases remain without a definitive cause. Genetics of female reproduction is a field that may bring some pieces of this puzzle; however, there are no well-defined genes that might be related to the risk for recurrent pregnancy loss (RPL) and IF. Here, we present a literature review of the studies of genetic association in RPL and IF carried out in the Brazilian population and complemented with a database search to explore genes previously related to RPL and IF, where a search for genes previously involved in these conditions was performed in OMIM, HuGE, and CTD databases. Finally, we present the next steps for reproductive genetics investigation, through genomic sequencing analyses and discuss future plans in the study of RPL genetics. The combined strategy of looking for literature and databases is useful to raise hypotheses and to identify underexplored genes related to RPL and IF.

Keywords:
Embryo loss; embryology; genomics; miscarriage; bioinformatics

Study Id / Region	Sample	Genes investigated	Physiological effect / Pathway	Main findings
*RPL*
Souza et al., 1999 / Ribeirão Preto, SP	56 case × 384 ctrl	FVL, FII	Thrombophilia	FVL G1691A and FII G20210A variants were more prevalent in RPL patients in comparison with controls
Daher et al., 2003 / São Paulo, SP	48 case × 108 ctrl	IFN-γ, TNF-α, IL-6, IL-10	IFN-γ and TNF-α inhibit trophoblast growth and differentiation; interleukins may promote embryo development and placentation	Lack of association of the variants investigated in the population studied.
Barbosa et al., 2004 / Campinas, SP	86 case × 86 ctrl	FXIII	Blood clotting	The prevalence of the studied variants did not differ between RPL patients and controls
Couto et al., 2005 / Campinas, SP	88 case × 88 ctrl	MTHFR, FVL, FII	Thrombophilia	MTHFR C677T variant was statistically associated with RPL.
von Linsingen et al., 2005 / Curitiba, PR	57 case × 74 ctrl	IL6, TGFB1	Cytokine production	The frequency of the IL6 (-174G/C) C/C genotype was increased in case women in comparison with controls.
Aléssio et al., 2008 / Campinas, SP	75 case × 179 ctrl	ESR1, ESR2	Estrogen receptor	There was no association between RPL and ESR polymorphisms.
Nunes et al., 2011 / São José do Rio Preto, SP	129 case × 182 ctrl	ADA	Affects the methylation process, cell growth and differentiation, apoptosis, DNA replication and immune function	ADA∗2 allele is associated with a low risk for recurrent spontaneous abortions, but this association is dependent on older age.
Traina et al., 2011 / São Paulo, SP	89 case × 191 ctrl	PGR (PROGINS), IL-1R1, VEGF	Implantation, trophoblastic invasion, maternal-fetal immune tolerance, angiogenesis and growth factor	No correlations were found in any of the investigated polymorphisms.
Vargas et al., 2011 / Curitiba, PR	60 case × 68 ctrl	HLA-G	Maternal-fetal interface tolerance	Haplotypic combinations of HLA-G alleles and the 14 bp segment (HLA-G01:01:08/+14 and HLA-G01:01:A/+14) may be associated with RPL.
Bompeixe et al., 2012 / Curitiba, PR	61 case × 75 ctrl	HLA-DRB1, HLA-DQB1, IFN-γ, TNF-α, IL-10	Maternal-fetal interface tolerance, trophoblast growth and differentiation; embryo development and placentation	HLA-DQB102:02, 03:01 alleles significantly decreased and HLA-DRB111:04 allele significantly increased among patients.
Banzato et al., 2013 / São Paulo, SP	129 case × 235 ctrl	FAS, FAS-L	FAS-FAS-L system is one important inducer of apoptosis	Significant differences in the FAS-L 844 C/T frequencies between women case and controls, suggesting that FAS-L gene polymorphism is associated with increased susceptibility to RPL.
Dutra et al., 2014 / Porto Alegre, RS	145 case × 135 ctrl	MTHFR, FVL, FII, eNOS	Thrombophilia	Lack of association of the variants investigated in the population studied.
Fraga et al., 2014b / Porto Alegre, RS	120 case × 143 ctrl	TP53, MDM2, LIF	p53 pathway (apoptosis)	The combination of TP53 Arg/Arg (rs1042522) and MDM2 TT (rs2279744) genotypes may be a risk factor for RPL.
Fraga et al., 2014a / Porto Alegre, RS	153 case × 143 ctrl	TP63, TP73, MDM2	Cycle cell arrest and apoptosis	Interaction between the TP63 and MDM2 variants shown to increase the risk of RPL.
Lino et al., 2015 / São Paulo, SP	112 case × 98 ctrl	MTHFR, FVL, FXIII, PTM, PAI-1	Thrombophilia	No correlations were found in any of the investigated polymorphisms.
Bilibio et al., 2015 / Porto Alegre, RS	20 case × 31 ctrl	DRD2	Prolactin secretion	An excess homozygosity of the DRD2 variant (rs6277) suggests a genetic predisposition to RPL, which could result in a mild serum prolactin increase.
Silva et al., 2015 / São Luís, MA	100 case × 100 ctrl	HLA-A, HLA-B, HLA-DRB1	Maternal-fetal interface tolerance	HLA-A34 allele is a risk factor for RPL; HLA-A24 and HLA-B*35 alleles are associated with protection.
Vilas Boas et al., 2015 / Salvador, BA	89 case × 150 ctrl	MTHFR, MS, CBS	Folate and vitamin B12-dependent homocysteine metabolisms	Lack of association of the variants investigated in the population studied
Gonçalves et al., 2016 / Salvador, BA	137 case × 100 ctrl	MTHFR, FVL, FII	Thrombophilia	Lack of association of the variants investigated in the population studied
Michita et al., 2016 / Porto Alegre, RS	156 case × 140 ctrl	HLA-G	Maternal-fetal interface tolerance	HLA-G 3’UTR plays important role in RPL
Fortis et al., 2018 / Porto Alegre, RS and Salvador, BA	149 case × 208 ctrl	NOS2, PTGS2, VEGFA	Angiogenesis and oxidative stress	The variant genotypes of the SNP rs2779249 in the NOS2 promoter are a potential risk for RPL
Michita et al., 2019 / Porto Alegre, RS	140 case × 156 ctrl	FAS, FAS-L, BAX, BCL-2	Extrinsic and intrinsic apoptosis pathways	Association of BAX-248 G/A with RPL susceptibility
Bremm et al., 2021 / Porto Alegre, RS	149 case × 159 ctrl	SMAD3	Smad3-dependent signaling pathway (steroid hormone regulation and implantation)	Association of variant rs17293443 with the RPL
Bremm et al., 2021 / Porto Alegre, RS	149 case × 159 ctrl	TDGF1, CFC1	EGF-CFC family genes exert function in the formation of the body axes in the embryo	Lack of association of the variants investigated in the population studied
IF
Costa et al., 2012 / Curitiba, PR	38 case × 14 ctrl	HLA-G	Maternal-fetal tolerance	No differences were observed in the allelic or genotypic frequencies between the success and failure groups. HLA-G Haplotype 2 is significantly presented in case women with failure implantation.
Paskulin et al., 2012 / Porto Alegre, RS	115 case × 134 ctrl	LIF, TP53	Blastocyst implantation; p53 pathway (apoptosis)	TP53 PIN3 and PEX4 variants were associated with IVF when compared with control women. Haplotypes D-C and N-C were related to higher risk for failure of IVF when compared with the fertile group.
Nardi et al., 2012 / Porto Alegre, RS and Curitiba, PR	82 case × 166 ctrl (female) 162 case × 224 ctrl (couples)	HLA-G	Maternal-fetal tolerance	Lack of association in HLA-G alleles in case and control females. The frequency of the HLA-G*01:03:01 allele was increased in the IF couples.
Vagnini et al., 2015 / Ribeirão Preto, SP	120 case × 89 ctrl	HAUSP, LIF, TP53, VEGF, gp130	Blastocyst implantation; p53 pathway (apoptosis); angiogenesis and vascularization	Association between the VEGF -1154G/A polymorphism and recurrent IF.
Nardi et al., 2016 / Porto Alegre, RS and Curitiba, PR	49 case × 34 ctrl	HLG-G	Maternal-fetal tolerance	The 14-bp deletion allele is more frequent in IF women.
Vagnini et al., 2019 / Ribeirão Preto, SP	44 case × 63 ctrl(1) and 65 ctrl(2)	ESR1, ESR2, LIF, MMP2, TP63, VEGFA	ESR1 and ESR2 are estrogen receptors; LIF is important mediator of embryo implantation; MMP2 play roles in remodeling extracellular matrix during ovarian follicular growth and ovulation; TP63 is a regulator of the quality and maturation of oocytes; VEGFA acts in angiogenesis and vasculogenesis.	The ESR1/AA (rs12199722) and LIF/GT (rs929271) genotypes was more frequent in the case group.

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