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Aim: Recurrent spontaneous abortion (RSA) is defined as three or more consecutive pregnancy losses before the 22nd week of gestation. It affects approximately 1% of couples and can be caused by several factors. However, the cause remains unidentified in about 50% of the cases, which are classified as idiopathic (IRSA). Among various possible etiological factors, aberrant DNA methylation has been suggested to be one of the possible causes of IRSA. Considering the growing evidence of the important roles of DNA methylation in gametogenesis and early pregnancy, as well as the results of multiple studies that indicate abnormal methylation patterns in the endometrium, spermatozoa and placenta of patients with IRSA, our aim was to investigate the potential association of DNA methyltransferase gene polymorphisms (DNMT1 rs2228611, DNMT3A rs1550117 and DNMT3B rs1569686) with IRSA in Slovenian reproductive couples. Patients and methods: 146 couples with ≥3 idiopathic spontaneous abortions and 149 control women and men were included in this case-control study. Genotyping was performed using polymerase chain reaction and restriction fragment length polymorphism methods. Results: We found a statistically significant higher frequency of the DNMT3B rs1569686 GG genotype (X2=7.37, P=0.025) and G allele (X2=6.33, P=0.012) in women with IRSA compared to controls. Additionally, the odds for IRSA in women were increased under the recessive genetic model (GGvsTG+TT: OR=1.92 ; 95% CI=1.18-3.09 ; P=0.008). There were no statistically significant differences in genotype and allele frequencies of any other tested polymorphism between IRSA patients and controls. Moreover, no significant associations occurred between the DNMT1 rs2228611 and DNMT3A rs1550117 polymorphisms and the risk of IRSA. Conclusion: Our results suggest that the GG genotype of the rs1569686 polymorphism in the DNMT3B gene in women might be a genetic marker for IRSA.

Recurrent spontaneous abortion (RSA) is a common clinical problem with a complex etiology of genetic and non-genetic causes, which remains to be fully determined. IGF-2 stimulates trophoblast invasion, proliferation and maturation of placenta, while H19 RNA suppresses growth. As genomic imprinting plays a critical role in the development of placenta and embryo, our aim was to evaluate the possible role of variations in IGF-2 and H19 imprinted genes as factors of predisposition for RSA. A case– control study was conducted to determine the association between IGF-2 and H19 gene polymorphisms and the susceptibility to RSA in 113 couples with RSA and 226 controls. PCR/RFLP were performed to analyze IGF-2 ApaI and H19 HhaI polymorphisms. Results We found a statistically significant difference in the genotype frequency distribution of IGF-2 ApaI polymorphism between males from couples with RSA and healthy males (Chi Square(2) = 45.12 ; P < 0.0001). There were no differences in the genotype and allele distribution of H19 polymorphism frequencies, or for the IGF-2 ApaI polymorphism between female groups. The presence of IGF-2 ApaI polymorphism in partners of RSA women could affect IGF-2 level of expression in placenta and embryo and represent a risk factor for RSA susceptibility.

Gene variability can affect expression, structure and function of key molecules in pregnancy and subsequently, gene polymorphisms in men and women can represent the possible factors of predisposition to recurrent spontaneous abortion (RSA). The aim of this study was to evaluate the possible role of polymorphisms in genes undergoing the phenomenon of genomic imprinting, a functional difference in the allelic expression that depends upon the parental origin of inheritance. We investigated important genes that regulate the process of implantation and placentation, paternally expressed Igf2 and maternally expressed H19. A case-control study was conducted to determine the association between Igf2 and H19 gene polymorphisms and the susceptibility to RSA in 113 couples with RSA and 226 fertile controls. PCR was performed to analyse DNA for Igf2 ApaI polymorphism and H19 HhaI polymorphism. Statistically significant difference was found for Igf2 ApaI polymorphism in male partners of RSA women. Their genotype frequencies compared with controls' were: 13%/56% (AA) ; 39%/20% (GG) ; 48%/25% (AG) ; when following dominant model (AA+AG vs GG), OR=0.38 [0.20-0.69] ; p=0.001 ; when following recessive model (AA vs GG+AG), OR=0.12 [0.06-0.23] ; p=0.000. Considering that Igf2 gene is expressed only from paternal allele, the presence of ApaI polymorphism in partners of RSA women could affect Igf2 level of expression in placenta and lead to RSA. The research on genes undergoing the phenomenon of genomic imprinting and including male partners in the study, represents a new approach in the research of genetic etiology of idiopathic RSA.

Brojna istraživanja mehanizama trudnoće nisu dala jasne smjernice koje bi pomogle praktičarima kao dijagnostičko ili terapijsko sredstvo u rješavanju problema učestalih spontanih pobačaja nepoznate etiologije. Učestali spontani pobačaji tri su ili više uzastopnih spontanih prekida trudnoće s istim partnerom prije 23. tjedna gestacije. Značajan su klinički problem budući da se javljaju u 0,5–3% žena i da je njihov uzrok nepoznat u oko 40–50% slučajeva. Poznati uzroci učestalih spontanih pobačaja raznorodni su i uključuju negenetičke i genetičke čimbenike. Iako je njihov veći dio uzrokovan genetički, genskim ili kromosomskim abnormalnostima, pokušaj liječenja zasad je moguć jedino u skupini negenetičkih uzroka. Cilj je ovog rada prikazati sadašnje spoznaje o genetičkim razlozima učestalih spontanih pobačaja, o čemu se vrlo malo zna. Upozorit ćemo na HLA-podudarnost u roditelja, monogenske nasljedne bolesti i na gensku varijabilnost u obliku genskih polimorfizama, kao na moguće čimbenike predispozicije za učestale spontane pobačaje. Opisat ćemo čimbenike koji su ušli u kliničku praksu, kao i nove čimbenike, dobivene asocijacijskim studijama poput gena povezanih s imunosnim sustavom, koagulacijom i vaskularizacijom. Naposljetku, naš doprinos sustavnom istraživanju uloge genskih čimbenika u etiologiji učestalih spontanih pobačaja razvijat ćemo kroz projekt HuMGeN (Human Miscarriage Genetic Network) koji smo pokrenuli na međunarodnoj razini., Despite much research into the mechanism of pregnancy and pregnancy loss, few diagnostic or therapeutic procedures for the evaluation of recurrent spontaneous abortion (RSA) can be offered. RSA is generally defined as three or more consecutive spontaneous terminations of pregnancy (with the same biological partner) occurring prior to the 23rd gestational week. RSA presents an important clinical challenge as it occurs in 0.5% to 3% of all pregnancies, and in 40% to 50% of these cases, without any known cause. The known causes of spontaneous pregnancy loss vary, including those of both non-genetic and genetic etiology. The goal of this work is to discuss the current knowledge of genetic causes of RSA, which is a rapidly developing field. The mechanism of HLA incompatibility, monogenetic disease, as well as genetic variance in genetic polymorphisms, as possible factors in causing a predisposition to RSA will be presented. The contributing factors to RSA that are already known in the present clinical practice as well as the more recent suspected factors which have been demonstrated in associated studies, such as genetic variation in genes associated with the immune system, coagulation and vascularization, will also be discussed. In conclusion, our contribution to the systematic research of genetic factors contributing to RSA through the international “HuMGeN” (Human Miscarriage Genetic Network) project will be presented.

Brojna istraživanja mehanizama trudnoće nisu dala jasne smjernice koje bi pomogle praktičarima kao dijagnostičko ili terapijsko sredstvo u rješavanju problema učestalih spontanih pobačaja nepoznate etiologije. Učestali spontani pobačaji tri su ili više uzastopnih spontanih prekida trudnoće s istim partnerom prije 23. tjedna gestacije. Značajan su klinički problem budući da se javljaju u 0,5–3% žena i da je njihov uzrok nepoznat u oko 40–50% slučajeva. Poznati uzroci učestalih spontanih pobačaja raznorodni su i uključuju negenetičke i genetičke čimbenike. Iako je njihov veći dio uzrokovan genetički, genskim ili kromosomskim abnormalnostima, pokušaj liječenja zasad je moguć jedino u skupini negenetičkih uzroka. Cilj je ovog rada prikazati sadašnje spoznaje o genetičkim razlozima učestalih spontanih pobačaja, o čemu se vrlo malo zna. Upozorit ćemo na HLA-podudarnost u roditelja, monogenske nasljedne bolesti i na gensku varijabilnost u obliku genskih polimorfizama, kao na moguće čimbenike predispozicije za učestale spontane pobačaje. Opisat ćemo čimbenike koji su ušli u kliničku praksu, kao i nove čimbenike, dobivene asocijacijskim studijama poput gena povezanih s imunosnim sustavom, koagulacijom i vaskularizacijom. Naposljetku, naš doprinos sustavnom istraživanju uloge genskih čimbenika u etiologiji učestalih spontanih pobačaja razvijat ćemo kroz projekt HuMGeN (Human Miscarriage Genetic Network) koji smo pokrenuli na međunarodnoj razini. Despite much research into the mechanism of pregnancy and pregnancy loss, few diagnostic or therapeutic procedures for the evaluation of recurrent spontaneous abortion (RSA) can be offered. RSA is generally defined as three or more consecutive spontaneous terminations of pregnancy (with the same biological partner) occurring prior to the 23rd gestational week. RSA presents an important clinical challenge as it occurs in 0.5% to 3% of all pregnancies, and in 40% to 50% of these cases, without any known cause. The known causes of spontaneous pregnancy loss vary, including those of both non-genetic and genetic etiology. The goal of this work is to discuss the current knowledge of genetic causes of RSA, which is a rapidly developing field. The mechanism of HLA incompatibility, monogenetic disease, as well as genetic variance in genetic polymorphisms, as possible factors in causing a predisposition to RSA will be presented. The contributing factors to RSA that are already known in the present clinical practice as well as the more recent suspected factors which have been demonstrated in associated studies, such as genetic variation in genes associated with the immune system, coagulation and vascularization, will also be discussed. In conclusion, our contribution to the systematic research of genetic factors contributing to RSA through the international “HuMGeN” (Human Miscarriage Genetic Network) project will be presented.