Genetic Architecture of Pregnancy Loss: Co-inheritance of Risk Factors in Bosnian Women.

Pregnancy-related complications (PRC) re-present a serious public health and healthcare challenge. In European countries, infertility among couples varies from 5 to 24 %. The cause of PRC may include autoimmune and metabolic factors, correctness of the karyotype and variants of selected genes. The impact magnitude of genetic variants in one of PRC, pregnancy loss (PL), is still unexplored. Therefore, in this study, raw data on 12 single-nucleotide polymorphisms (SNPs) that were published separately in 2017-2019 were re-examined. We analysed the co-inheritance of 12 SNPs: rs6025 FV, rs429358 and rs7412 ApoE, rs1799752 ACE, rs1799889 PAI-1, rs1799963 PT, rs1801133 MTHFR, rs9468 and rs1800547 INV 17q21.31, rs731236 and rs1544410 VDR, and rs10421768 HAMP. Each time, the same study group of 154 women with PL, mean age 33 (± 5.4) years, and 154 mothers without PL, mean age 31.4 (± 6.7) years, with at least one live-born child, a control group, was investigated. In Bosnian women, no relationship of the co-inheritance pattern of any of the studied variants with PL was confirmed: P was in the range 0.248-1.0. In conclusion, the role of co-inheritance of heterozygotes and homozygotes or homozygotes of selected genes in PL has not been fully confirmed.

Genetic diversity of CYP3A5 and ABCB1 variants in East-Central and South European populations.

BACKGROUND: CYP3A5 enzyme encoded by CYP3A5 is important for drug metabolism in gut and liver, whereas P-glycoprotein by ABCB1, is an ATP-dependent drug efflux pump which exports endo- and exogenous substances outside the cell. AIM: The study was to assess the prevalence of CYP3A5 alleles: *1, *2, *3, *4, *6 and *7, and C and T of ABCB1 in Poles, Belarusians and Bosnians and to compare it with the data reported from other European populations. SUBJECTS AND METHODS: Overall, 511 unrelated healthy subjects from Poland (n = 239), Belarus (n = 104) and Bosnia and Herzegovina (n = 168) were included in this study. Allele frequencies and statistical parameters (AMOVA version 2.9.3) were determined. RESULTS: In Poles, Belarusians and Bosnians the *3 allele of CYP3A5 was the most common, and wild-type allele *1, were: 5.8%, 1.6% and 2.1%, respectively. Allele *2 was very rare, and alleles *4, *6 and *7 were not detected. For the populations mentioned above, the ABCB1 allele C was: 48.1%, 51.4%, 52.4%, respectively. CONCLUSION: In compared populations, the distribution of CYP3A5 variants but not ABCB1, differed significantly. Alleles *4, *6 and *7 of CYP3A5 did not occur or occurred rarely.

Uric Acid Values Along with Doppler Sonography Findings as a Tool for Preeclampsia Screening.

INTRODUCTION: Preeclampsia is defined as hypertension (systolic pressure ≥140 mmHg or diastolic pressure ≥90 mmHg) after week 20 of gestation with one or more of the following symptoms: proteinuria, organ dysfunction (including renal, hepatologic, hematologic or neurological complications) and in case of stagnation of fetal development. So far, there are no valid clinical tools or tests that can tell with sufficient sensitivity and specificity in early pregnancy which pregnant woman will develop preeclampsia or have unwanted outcomes. AIM: To present the properties of biochemical parameter, uric acid, in patients with signs of preclampsia, which was confirmed by Doppler sonography. METHODS: The study included 60 female subjects in the second trimester of pregnancy who were examined or were hospitalized at the Clinic of Gynecology and Obstetrics, Clinical Center University of Sarajevo. Pregnant women who had normal Doppler sonography scan of the uterine arteries in the second trimester of pregnancy were included in the control group, while pregnant women with pathologic Doppler sonographic findings in the second trimester of pregnancy were included in the group of pregnant women at risk of preeclampsia, i.e. the study group. RESULTS: There is statistically significant difference between the average value of uric acid in the control and in the study group (213.36 ± 28.96 µmol / L vs 249.73 ± 47.06 µmol / L) (F = 12.991; p = 0.001). Applying the Wilcoxon non-parametric paired test to the average uric acid values during all measurements within the control group, no statistically significant difference was found. There was a statistically significant increase in the study group between all measurements, from 18.04 µmol / L between the first and second measurement (Z = -1.955; p = 0.043), 29.10 µmol / L between the second and third measurement (Z = -2.973; p = 0.003), 37.27 µmol / L between the third and fourth measurement (Z = -4.325; p = 0.001) and 109.87 µmol / L at the end of the study in comparison to values from the start of the study (Z = -4.309; p = 0.001). CONCLUSION: Uric acid values should become part of a broad biochemical range in screening and optimizing the treatment of patients diagnosed with early preeclampsia.

Association Between - 675 ID, 4G/5G PAI-1 Gene Polymorphism and Pregnancy Loss: A Systematic Review.

INTRODUCTION: Several analysis for different population conclude that endothelial plasminogen activator inhibitor 1 gene polymorphism, -675 ID, 4G/5G PAI-1 (ref SNP ID: rs1799889, also described as rs34857375, has merged into rs1799762) may increase risk of pregnancy loss (PL). However, there is a disagreement as to the association 4G allele with pregnancy loss. AIM: Therefore, we decided to investigate the -675 ID, 4G/5G PAI-1 as a potential genetic factor linked to PL in European and worldwide populations. A systematic review of the scientific literature was conducted with the use of the PubMed and Scopus electronic databases (1991-present), using the following search terms: pregnancy loss, miscarriage, genetic risk of thrombophilia, rs1799889 PAI-1 gen, 4G/5G PAI-1 gene polymorphism, PAI-1 gene locus 4G/5G polymorphism. RESULTS: Among European populations, the statistically significant association between 4G allele and recurrent PL only in Czechs and Bulgarian women was found (p<0.002 and p=0.018, respectively); while, among populations outside Europe in Iranian, Tunisian and Turkish women (each p<0.001). CONCLUSIONS: We concluded, that both in Europe and elsewhere in the world, the high frequency of 4G allele in population, is not unambiguously linked with the risk of pregnancy loss.

Prevalence of F5 1691G>A, F2 20210G>A, and MTHFR 677C>T polymorphisms in Bosnian women with pregnancy loss.

The relationship between genetic risk factors of thrombophilia and pregnancy loss (PL) is being discussed. The focus has been on F5 1691G>A, F2 20210G>A, and MTHFR 677C>T polymorphisms that may predispose women to microthrombosis during the stages of embryo implantation and placentation. Although, the frequencies of these polymorphisms were reported in different populations, such studies have not yet been performed in Bosnian population. In this study, we determined the prevalence of F5 G>A (rs6025), F2 G>A (rs1799963) and MTHFR C>T (rs1801133) polymorphisms in Bosnian women. A total of 154 women with PL, mean age 33 (±5.4) years, were enrolled in the study. As a control group, 154 mothers [mean age 31.4 (±6.7) years] with at least one live-born child were included. We used real-time polymerase chain reaction (PCR) to determine the frequencies of F5 G>A and F2 G>A genotypes, and PCR-restriction fragment length polymorphism (RFLP) for analyzing MTHFR C>T genotypes. The frequency of heterozygotes for F5 and F2 was significantly higher in women with venous thrombosis (VT) compared to women without VT (p = 0.047 and p = 0.001, respectively). There was no significant difference in the distribution of MTHFR genotypes and alleles between these two groups. In addition, we observed no significant differences in the genotype and allele frequencies between the group with PL and control group, for all investigated polymorphisms. The allele frequencies for 1691A (F5), 20210A (F2), and 677T (MTHFR) reported in this study are consistent with the data obtained for other European countries, however, we were not able to confirm the association between the three polymorphisms and PL in Bosnian women.