Scientific Papers

Association of Tumor Necrosis Factor-α -308G>A, -238G>A and -376G>A polymorphisms with recurrent pregnancy loss risk in the Greek population | Fertility Research and Practice

Our study demonstrates the presence of TNF-α 238 and TNF-α 308 polymorphisms in the Greek women population, while TNF-α 376 variant was absent. Notably, no significantly statistical association emerged between each polymorphism studied and the occurrence of recurrent pregnancy loss. Additionally, when TNF-α 238 and TNF-α 308 genotypes were combined no correlation with recurrent abortions was disclosed.

The association between TNF-α polymorphisms and RPLs has been investigated in many studies; however, the results remain contradictory and unreliable. Population diversity could explain such opposing conclusions. In particular, previous meta-analyses have shown that the risk of RPLs is significantly associated with the incidence of TNF-α −308G > A and − 238G > A polymorphisms in the overall population [25], while in another meta-analysis no association emerged between TNF-α −308G > A and RPL as investigated in Caucasian and Asian subjects [26]. On the other hand, a recent meta-analysis of 10 case-control studies in Asian and European populations provided diverse conclusions for TNF-α gene polymorphisms and RPL. In particular, TNF-α -308G > A polymorphism was found to be associated with an increased risk of developing RPL, whereas no statistical correlation was observed between TNF-α -238G > A polymorphism and RPL. The combined results of the studies revealed that women who are homozygous (GG) and heterozygous (GA) for TNF-α -308G > A polymorphism have an increased risk of developing RPL compared to women who carry the wild-type allele. In addition, when stratifying the results according to the geographical origin of the participants, Asian populations show a stronger association between TNF-α -308G > A polymorphism and RPL occurrence than European populations. In contrast, for TNF-α -238G > A polymorphism, no statistically significant difference was observed in the incidence of homozygous (AA), heterozygous (GA) and homozygous for the wild-type allele (GG) genotypes between women who have experienced recurrent pregnancy loss and fertile women [21].

In a prospective cohort study the frequency of TNF-α -308G > A variant was investigated in 1652 pregnant women with intrauterine fetal death, preeclampsia, preterm labor before 34 gestational weeks, and small-for-gestational-age (SGA) infants. The researchers concluded that there was no statistically significant difference in the incidence of TNF-α -308G > A between the group with the above-mentioned pregnancy complications and the control group [27]. Similar results have been revealed in a Chinese population by Liu and his colleagues [23], where it has been shown that TNF-α 308 did not correlate with women with a history of RPL and recurrent implantation failures (RIF) in IVF attempts. However, TNF-α 238 GG genotype was present more frequently in patients with unexplained recurrent spontaneous abortion (URSA), suggesting that it could be a risk factor in Chinese RSA patients. Consistent with our findings are the results of a recent case-control study where a clear lack of statistical significance was revealed between the genotype distribution of TNF-α -238G > A and -308G > A polymorphisms and the risk of recurrent miscarriages [28]. On the contrary, a patient-control study conducted in the Korean population showed that TNF-α -238G > A polymorphism could serve as a possible genetic risk factor for RPL [22].

Regarding TNF-α -376G > A polymorphism, Palmirrotta and his colleagues showed no association with recurrent miscarriages in Caucasian Italian women, but TNF-α -376G/−308A/−238G haplotype was associated with low TNF-α levels (P = 0.021) and miscarriage (P = 0.023) [24]. However, in another population, Bahraini women carrying the 376A genotype showed a statistically significant (P = 0.011) risk for recurrent miscarriages. Additionally, there were significant differences in the frequency distribution of -376G > A genotype (P = 0.002) between patients and control group [18]. All the observed differences in TNF-α gene polymorphism distribution could be attributed to genetic heterogeneity of the studied populations, since population-to-population differences are common in genetic association studies. Such discrepancies exist in different ethnic groups, and may affect the influence of the polymorphism on recurrent miscarriage risk. Moreover, differences in sample sizes, selection and exclusion criteria and specific study group recruitment could affect TNF-α allele frequencies and the resulting associations with RPL occurrence.

An interesting observation emerged upon association of TNF-α 238 and 308 polymorphisms and parity status in RPL patients, since parity was less reported in patients carrying the A allele. A similar disclosure has been published for susceptibility to pre-eclampsia, wherein an analysis by parity revealed that carriers of A allele and AA genotype frequency of maternal TNF-α -308G > A polymorphism were associated with an increased risk of pre-eclampsia [29].

Remarkably, elevated levels of TNF-α at the maternal-fetal interface induce activation of natural killer cells (NK cells) and subsequent damage to placental growth [30, 31]. Investigating a possible association between a TNF-α gene polymorphism spectrum and the levels of the respective protein and therefore its function, may elucidate the potential link to recurrent abortions. Additionally, the establishment of a panel of cytokine gene polymorphisms associated with recurrent abortions would serve as an important biomarker for the prediction of miscarriages, promoting the individualized treatment of women with a history of recurrent pregnancy loss, thus increasing successful pregnancy potential. It is a common observation that patients with the same diagnosis may respond differently to therapies and it is becoming increasingly evident that this differential responsiveness may be due to specific DNA variations at the genomic level. New technologies such as next-generation sequencing (NGS), and bioinformatics, will enable a better understanding of the role of various genetic polymorphisms that will facilitate the next breakthrough toward further improving the clinical success for each individual RPL patient. Consequently, the challenge for future medicine is to move from a population-based view to an individually-based one through the implementation of novel technologies in the daily medical practice, establishing the Precision Medicine in human reproduction [32, 33].

To our knowledge, the present work firstly reports the distribution of TNF-α gene polymorphisms in Greek women with recurrent pregnancy loss, while revealing lack of association between the above-mentioned variants and the development of RPL in the Greek population. Such novel findings could help to further elucidate the pathophysiology of RPL in the Greek population, highlighting the importance of genetic profiling of each RPL patient.

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