The Importance of the FUT2 rs602662 Polymorphism in the Risk of Cardiovascular Complications in Patients after Kidney Transplantation.

The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 levels in the body. Vitamin B12 deficiency associated with hyperhomocysteinemia is a major risk factor for cardiovascular diseases (CVDs), which are one of the main causes of death in patients after kidney transplantation. The aim of our study was to determine the impact of the rs602662 (G>A) polymorphism of the FUT2 gene on the functionality of transplanted kidneys and the risk of CVD in patients after kidney transplantation. The study included 402 patients treated with immunosuppression (183 patients taking cyclosporine (CsA) and 219 patients taking tacrolimus (TAC)). The analysis of the FUT2 rs602662 (G>A) polymorphism was performed using real-time PCR. Patients with CsA were more likely to be underweight (1.64% vs. 0.91%) and obese (27.87% vs. 15.98%), while those taking TAC were more likely to be of normal weight (39.27%) or overweight (43.84%). No statistically significant differences were observed comparing the mean blood pressure, both systolic and diastolic. The renal profile showed a higher median urea nitrogen concentration in patients with CsA (26.45 mg/dL (20.60-35.40) vs. 22.95 mg/dL (17.60-33.30), p = 0.004). The observed frequency of rs602662 alleles of the FUT2 gene was similar in the analyzed groups. The A allele was present in 43.7% of patients with CsA and 41.1% of those taking TAC (OR = 0.898; 95% CI: 0.678-1.189; p = 0.453). In the group with CsA, the GG genotype was present in 32.2% of patients, the GA in 48.1% and the AA in 19.7%. A similar distribution was obtained in the TAC group: GG-33.8%, GA-50.2%, and AA-16.0%. An association of genotypes containing the G allele with a higher incidence of hypertension was observed. The G allele was present in 65% of people with hypertension and in 56% of patients with normal blood pressure (p = 0.036). Moreover, the evaluation of the renal parameters showed no effect of the FUT2 polymorphism on the risk of organ rejection because the levels of creatinine, eGFR, potassium, and urea nitrogen were prognostic of successful transplantation. Our results suggest that the rs6022662 FUT2 polymorphism may influence the risk of cardiovascular diseases.

Up-regulated mRNA expression of VEGFA receptors (FLT1 and KDR) in placentas after assisted reproductive technology fertilization.

Placental angiogenesis is a pivotal process for feto-maternal circulation and ensures efficient development of the placenta throughout pregnancy. Many factors during in vitro fertilization and embryo transfer procedures may affect placental gene expression and fetus development. The present study aimed to identify differences in angiogenesis-related gene (VEGFA, FGF2, FLT1, and KDR) expression profiles in placentas after assisted reproductive technology fertilization and natural conception in healthy women. In a case-control study, term placentas were collected from Caucasian women after assisted reproductive technology fertilization (N = 20) and after natural conception in women with uncomplicated pregnancy (N = 9). The mRNA expression in placentas was examined for VEGFA, FGF2, FLT1, and KDR genes by real-time quantitative polymerase chain reaction (RT-qPCR). Group stratification was performed for comparison of investigated genes between the type of embryo transferred (fresh/frozen), place of tissue donation (center/margin), and newborns' gender (male/female). In the ART placentas, significant down-regulation of VEGFA gene (p = 0.016) and up-regulation of FLT1 (p = 0.026) and KDR (p < 0.001) gene receptors were observed. Genes encoding VEGFA receptors were up-regulated in both fresh (ET) and frozen (FET) embryo transfer groups compared to controls. For the FLT1 gene, a statistically significant difference was observed between the frozen embryo transfer group and the controls (p = 0.032). Relative expression of KDR was significantly higher for both embryo transfer groups compared to controls (p < 0.001) and between ET and FET (p = 0.002). No statistically significant differences were observed between placental expression in different places of tissue donation and newborns' gender. We observed differences in the placental expression of VEGFA and its receptors FLT1 and KDR in pregnancies after assisted reproductive technology compared to naturally conceived pregnancies. More research is needed to clarify these alterations that may affect placental development and fetal health.

Polymorphic Variants of Genes Encoding Angiogenesis-Related Factors in Infertile Women with Recurrent Implantation Failure.

Recurrent implantation failure (RIF) is a global health issue affecting a significant number of infertile women who undergo in vitro fertilization (IVF) cycles. Extensive vasculogenesis and angiogenesis occur in both maternal and fetal placental tissues, and vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family molecules and their receptors are potent angiogenic mediators in the placenta. Five single nucleotide polymorphisms (SNPs) in the genes encoding angiogenesis-related factors were selected and genotyped in 247 women who had undergone the ART procedure and 120 healthy controls. Genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A variant of the kinase insertion domain receptor (KDR) gene (rs2071559) was associated with an increased risk of infertility after adjusting for age and BMI (OR = 0.64; 95% CI: 0.45-0.91, p = 0.013 in a log-additive model). Vascular endothelial growth factor A (VEGFA) rs699947 was associated with an increased risk of recurrent implantation failures under a dominant (OR = 2.34; 95% CI: 1.11-4.94, padj. = 0.022) and a log-additive model (OR = 0.65; 95% CI 0.43-0.99, padj. = 0.038). Variants of the KDR gene (rs1870377, rs2071559) in the whole group were in linkage equilibrium (D' = 0.25, r2 = 0.025). Gene-gene interaction analysis showed the strongest interactions between the KDR gene SNPs rs2071559-rs1870377 (p = 0.004) and KDR rs1870377-VEGFA rs699947 (p = 0.030). Our study revealed that the KDR gene rs2071559 variant may be associated with infertility and rs699947 VEGFA with an increased risk of recurrent implantation failures in infertile ART treated Polish women.

Expression of ABCA1 Transporter and LXRA/LXRB Receptors in Placenta of Women with Late Onset Preeclampsia.

BACKGROUND: Appropriate levels of cholesterol are necessary for the mother and developing fetus, but theirexcess may cause preeclampsia. The ABCA1 transporter mediates the secretion of cholesterol and is highly regulated at the transcriptional level via the nuclear liver X receptors (LXRs). METHODS: Sixteen preeclamptic and 39 normotensives healthy women with uncomplicated pregnancies were involved in the case-control study. The placental levels of ABCA1, LXRA and LXRB mRNA were quantified by real-time quantitative PCR. The concentrations of ABCA1, LXRA and LXRB proteins from the placenta were determined using an enzyme-linked immunosorbent assay Results: We found in the logistic regression model significantly lower placental expression of LXRB mRNA (crude OR = 0.26, 95% CI: 0.07-0.94, p = 0.040) and LXRA protein level (crude OR = 0.19, 95% CI: 0.05-0.69, p = 0.012) in late-onset preeclamptic women compared to healthy pregnant women. The values remained statistically significant after adjustment for possible confounders. CONCLUSIONS: Our results suggest that high placenta LXRA mRNA and LXRA protein expression levels decrease the risk of late-onset preeclampsia. These nuclear receptors could play a role in the development of preeclampsia through disturbances of lipid metabolism.

Effects of TIMP1 rs4898 Gene Polymorphism on Early-Onset Preeclampsia Development and Placenta Weight.

Introduction: Some evidence indicates that the improper trophoblast invasion of maternal spiral arteries could be caused by an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), leading to preeclampsia (PE) development. This study aimed to assess the potential role of MMP1, MMP9, TIMP1 and TIMP2 gene polymorphisms in the pathogenesis of PE. Materials and methods: A total of 308 Polish women, 115 preeclamptic (55 with early-onset preeclampsia [EOPE], 60 with late-onset preeclampsia [LOPE]) and 193 healthy pregnant women, all of Caucasian origin, were recruited to the study. PE was diagnosed following the ACOG criteria. The polymorphic variants of the MMP-TIMP pathway (MMP1 rs1799750, MMP9 rs17576, MMP9 rs17577, TIMP1 rs4898, TIMP2 rs2277698, TIMP2 rs55743137) were genotyped by polymerase chain reaction and restriction fragment length polymorphism. Results: Analyzing all SNPs in the MMP-TIMP pathway, no significant differences in allele frequencies between preeclamptic women and controls were observed. However, comparing the EOPE and LOPE groups with each other, we observed a statistically significant difference between them for the TIMP1 rs4898 variant. In the whole group of 308 women, the mean placenta weight was the lowest in carriers of the rs4898 CC genotype. Post hoc analysis revealed significant differences between CC-CT (p = 0.0209) and CC-TT (p = 0.0469). Additionally, during allele analysis, a statistically significant difference in the mean placenta weight (for C allele 529.32 ± 157.11 g, for T allele 560.24 ± 162.24 g, p = 0.021) was also observed. Conclusion: Our findings suggest a relationship between TIMP1 rs4898 (372T > C) polymorphism and increased risk of early-onset preeclampsia in a population of pregnant Polish women. Our data suggest that the TIMP1 rs4898 C allele might be associated with increased risk for early-onset, but not for late-onset preeclampsia. To evaluate the role of the TIMP1 polymorphic variants in the etiopathology of preeclampsia, further studies with a larger sample size are needed.

Relationship of Postoperative Pain and PONV after Minimally Invasive Surgery with the Serotonin Concentrations and Receptors' Gene Polymorphisms.

(1) Background: there is a steady increase in the number of procedures performed via minimally invasive surgery, which have many benefits, but post-operative nausea and vomiting (PONV) and significant pain are still a common problem (2) Methods: 300 infertile women (18-40 years old) undergoing minimal invasive surgery. Interventions: laparoscopy and hysteroscopy performing, evaluation of postoperative symptoms, serotonin concentrations assessment, identify genetic polymorphisms. (3) Results: serotonin concentrations were significantly lower among women who required opioids (p = 0.006). The presence of the GG genotype in the rs6318 polymorphism of the 5HTR2C gene had a protective effect on PONV (OR = 0.503; C.I. = [0.300-0.841]; p = 0.008), when the GG variant of the rs11214763 polymorphism of the 5HTR3B gene, when the risk of PONV was 1.65-fold higher (OR = 1.652; C.I. = [1.003-2.723]; p = 0.048). Pain intensity was significantly higher among women with GG genotype of the rs6296 polymorphism of the 5HTR1B gene (OR = 1.660; C.I. = [1.052-2.622]; p = 0.029).; (4) Conclusions: the evaluation of serotonin concentration predicts requirement for opioid pain relief medication. The polymorphisms of the serotonin receptors affect the intensity of postoperative complaints.

Biomolecular Markers of Recurrent Implantation Failure-A Review.

Currently, infertility affects 8-12% of reproductive age couples worldwide, a problem that also affects women suffering from recurrent implantation failure (RIF). RIF is a complex condition resulting from many physiological and molecular mechanisms involving dynamic endometrium-blastocyst interaction. The most important are the endometrial receptivity process, decidualization, trophoblast invasion, and blastocyst nesting. Although the exact multifactorial pathogenesis of RIF remains unclear, many studies have suggested the association between hormone level imbalance, disturbances of angiogenic and immunomodulatory factors, certain genetic polymorphisms, and occurrence of RIF. These studies were performed in quite small groups. Additionally, the results are inconsistent between ethnicities. The present review briefly summarizes the importance of factors involved in RIF development that could also serve as diagnostic determinants. Moreover, our review could constitute part of a new platform for discovery of novel diagnostic and therapeutic solutions for RIF.

Vitamin D receptor gene polymorphisms and haplotypes in the etiology of recurrent miscarriages.

A few years ago it was shown that disturbed metabolism of the vitamin D/receptor (VD/VDR) complex may be important in the etiology of spontaneous abortion, as well as in the etiology of recurrent miscarriages (RM). The goal of this study was to investigate the association between four maternal VDR polymorphisms as well as haplotypes settings and RM occurrence in a Polish population of women in reproductive age. A total of 230 women were recruited to this study (110 with RM, 120 consecutively recruited age-matched healthy women with at least two full-term pregnancies and with no history of miscarriages). DNA samples were genotyped for VDR polymorphisms: FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236). Significant differences in genotype distributions and allele frequencies between case and control groups were observed in VDR BsmI polymorphism (GG vs. GA and AA, OR = 0.56, p = 0.036 and OR = 1.49, p = 0.035, respectively). The best evidence of an association with RM prevention was observed for the TTGT haplotype, which was more frequent among controls than cases even after permutation test (0.09 vs. 0.017, p = 0.0024). Other haplotypes were also significantly more frequent in the control group: TGT (rs7975232, rs1544410, rs2228570), TG (rs7975232, rs1544410), TTG (rs731236, rs7975232, rs1544410), TT (rs731236, rs7975232). Our research indicated the possible role of VDR BsmI genetic polymorphism in RM etiology, suggesting at the same time the active role of maternal VD metabolism and its influence on pregnancy outcome. The significant influence of several maternal haplotypes was shown to prevent RM occurrence.

FokI vitamin D receptor polymorphism as a protective factor in intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis in pregnancy (ICP) is a pregnancy-specific liver disorder. Its etiology is not fully understood. Increasing evidence indicates the important role of vitamin D and the vitamin D receptor (VDR) in this disorder. The presence of polymorphic variants in the VDR gene could influence its activity and susceptibility to ICP development. The goal of the study was to investigate the role of four genetic polymorphisms of the VDR gene - Fok (rs731236), Bsm (rs1544410), Apa (rs7975232), and Taq (rs731236) - in the etiology of ICP in Polish women. MATERIAL AND METHODS: Ninety-eight women with confirmed ICP and 215 healthy pregnant women as a control group were recruited to the study. We examined four SNPs of the VDR gene: BsmI (rs7975232), TaqI (rs1544410), ApaI (rs228570), FokI (rs731236). Genotyping was performed using the PCR/RFLP method. RESULTS: We observed higher frequency (borderline significant) of the Ff-ff genotypes containing at least one mutated allele of the VDR FokI polymorphism in the control group compared to the ICP group (p = 0.045, OR = 1.71, 95% CI 1.01-2.88). The frequency of the mutated f allele was slightly higher in controls (49.1%) than in the ICP group (43.4%) (OR = 1.26, 95% CI 0.90-1.77), but the difference was not statistically significant (p = 0.196). CONCLUSIONS: Our results showed that the maternal VDR FokI polymorphism could play a protective role in ICP development and probably modulate the risk of ICP occurrence in pregnant women in the Polish population. In the future, to confirm these observations, research in larger, ethnically stratified and clinically analyzed groups is necessary.

The relevance of IL-1ß and IL-1RN gene polymorphisms in the etiology of preterm delivery in the population of Polish women.

OBJECTIVES: Preterm delivery (PTD) is one of the important challenges for perinatal medicine due to prematurity and associated complications. The mechanisms leading to the PTD occurrence are not fully clarified and it is assumed that PTD is a complex phenomenon caused by many different pathophysiological factors. Nowadays, an important role is attributed to genetic determinants of PTD, pointing to possible relevance of polymorphic variants of candidate genes to participate in the etiology of PTD. The aim of the study was to assess the relevance of +3953C > T IL-1ß and 86 bp VNTR IL-1RN gene polymorphisms in the etiology of PTD in Polish women. MATERIAL AND METHODS: Study group consisted of 150 women (mean age 29.2 ± 5.6 years, mean weeks of gestational age 33.7 ± 2.8 gw.) with preterm delivery (22 + 0 - 36 + 6 gw.). To the control group 150 healthy pregnant women (mean age 29.0 ± 3.7 years, mean weeks of gestational age 39.3 ± 1.2 gw.) who delivered > 37 gw. were enrolled. All investigated polymorphisms were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The interesting observation was the notice of overrepresentation of 2/2 genotype of IL-1RN gene in the control group (8.0 vs. 3.3%, p = 0.06) and 2 allele in the control group (25.0 vs. 20.0%, p = 0.07). CONCLUSIONS: The +3953C > T polymorphism of IL-1ß gene probably is not connected with the risk of preterm delivery. The study results points to the possible modulating effect of mutated IL-1RN* 2 allele (86 bp VNTR polymorphism) of IL-1RN gene in decreased risk of preterm delivery.

Coexistence of the 677C>T and 1298A>C MTHFR polymorphisms and its significance in the population of Polish women.

OBJECTIVES: The aim of the study was to evaluate the frequency of the 677C>T and 1298A>C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, as well as the coexistence of both these genetic variants in women from the Polish population. MATERIAL AND METHODS: A total of 662 women from the Polish population were enrolled in the study group. The frequency of the investigated genotypes of the 677C>T and 1298A>C polymorphisms of the MTHFR gene was analyzed with the use of PCR/RFLP methods. RESULTS: The frequency of the 677CC, 677CT and 677TT genotypes in the studied population of women was 50.60%, 39.88% and 9.52%, respectively As to the 1298AA, 1298AC and 1298CC genotypes, the obtained results were as follows: 42.75%, 47.88% and 9.37%, respectively (Tables II and III). Simultaneous analysis revealed the most frequent coexistence of 677CC/1298AC (28.85%), 677CT/1298AA (20.85%) and 677CT/1298AC (19.03%) genotypes. The coexistence of 677CC/1298AA (12.39%), 677CC/1298CC (9.37%) and 677TT/1298AA (9.51%) genotypes was observed less frequently In the studied population of Polish women, the coexistence of 677CT/1298CC, 677TT/1298AC and 677TT/1298CC genotypes has been not observed. CONCLUSIONS: The frequency and coexistence of genotypes of the 677C>T and 1298A>C MTHFR gene polymorphisms in the studied population of Polish women is similar to other North-European populations. Women carriers of the mutated variants of both, 677C>T and 1298A>C polymorphisms of the MTHFR gene should receive special perinatal care in order to prevent fetal defects and thrombosis-related complications during pregnancy It is vital to emphasize the significance of proper education of folate supplementation, especially in pregnant patients and women of reproductive age.