ORIGINAL RESEARCH

Associations between SNPs in the genes encoding urokinase system proteins and the risk of placental insufficiency

Revina DB1, Balatskiy AV1,2, Larina EB3, Oleynikova NA1, Mishurovsky GA1, Malkov PG1, Samokhodskaya LM1, Panina OB1, Tkachuk VA1,2
About authors

1 Lomonosov Moscow State University, Moscow, Russia

2 National Medical Research Center for Cardiology, Moscow, Russia

3 Lapino Clinical Hospital "Mother and Child", Moscow, Russia

Correspondence should be addressed: Daria B. Revina
Lomonosovsky prospect, 27, k.1, Moscow, 119192; moc.liamg@airad.ayaksnizol

About paper

Funding: this study was conducted under the state assignment for Lomonosov Moscow State University using the equipment acquired as part of the Scientific Development Program of Lomonosov Moscow State University.

Acknowledgement: the authors thank Mamedov NN, PhD Med, an Assistant Professor at the Department of Obstetrics and Gynecology (Faculty of Fundamental Medicine, Lomonosov Moscow State University) for his help in creating the collection of biosamples (umbilical cord fragments, blood samples).

Author contribution: Revina DB, Balatskiy AV, Larina EB, Samokhodskaya LM, Panina OB, Tkachuk VA — study design; Revina DB, Balatskiy AV, Larina EB, Oleynikova NA, Mishurovsky GA — collection and processing of biosamples and clinical datal; Revina DB, Balatskiy AV, Mishurovsky GA — statistical analysis; Revina DB, Balatskiy AV — interpretation of the results; Revina DB, Balatskiy AV, Oleynikova NA, Mishurovsky GA — manuscript preparation; Malkov PG, Samokhodskaya LM, Panina OB, Tkachuk VA — manuscript revision; Revina DB and Balatskiy AV equally contributed to the study.

Received: 2019-10-31 Accepted: 2019-11-18 Published online: 2019-12-07
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Placental insufficiency (PI) and its complications are multifactorial conditions that cause perinatal morbidity and mortality. Since the urokinase system is involved in placentation, it should have a role in PI pathogenesis. The aim of this work was to study the associations between single nucleotide polymorphisms (SNPs) of genes coding for protein components of the urokinase system and PI, as well as investigate their effect on the expression of these proteins in the placenta and placental structure. We examined 114 women with uncomplicated pregnancy and delivery, 48 female patients with pre-eclampsia and/or intrauterine growth restriction (IUGR), and 95 newborns, (pre-eclampsia and/or IUGR: n = 60; uncomplicated pregnancy and delivery: n = 35). Maternal and fetal DNAs were genotyped using real-time PCR. Placenta fragments were subjected to morphometry and immunohistochemistry. We discovered the associations between PI and the maternal C allele of rs4065 (PI group: СС-СТ 64.1%, TT 35.9%; controls: СС-СТ 25.6%, TT 74.49%; OR (95%CI): 6.83 (2.63–17.79)), the maternal A allele of rs2302524 (GG-GA 20.5%, AA 79.5% vs. GG-GA 48.1%, AA 51.9%, OR (95%CI): 0.27 (0.1–0.71)), the fetal C allele of rs4065 (СС-СТ 76.4 %, TT 23.6% vs. СС-СТ 69.6%, TT 30.4%, OR (95%CI): 1.37 (0.45–4.17)), and the fetal C allele of rs344781 (TT-TC 69.1%, СС 30.9% vs. TT-TC 95.7%, СС 4.3%, OR (95% CI): 5.02 (1.07–23.6)). The multivariate analysis confirmed the significance of the fetal rs4065 genotype. In patients with PI, uPA expression was lower (ME (95%CI): 116.45 (100.5; 128.74) vs. 126.09 (113.76; 139.19); р < 0.05). No associations were established between SNPs and protein expression. The degree of vascularization depended on the maternal rs4065 genotype (the stroma-to-vessel ratio for the CC genotype was 0.17 (0.15; 0.19); for the CT genotype, 0.18 (0.15; 0.21) and for the TT genotype, 0.23 (0.2; 0.27); p < 0.05). We conclude that high placental uPA and the presence of the fetal TT rs4065 genotype are protective against the risk of PI.

Keywords: single nucleotide polymorphism, placental insufficiency, pre-eclampsia, intrauterine growth restriction, urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, angiogenesis

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