Genetic risk score for gestational weight gain.

Gestational weight gain (GWG) involves health consequences for both mother and offspring. Genetic factors seem to play a role in the GWG trait. For small effect sizes of a single genetic polymorphism (SNP), a genetic risk score (GRS) summarizing risk-associated variation from multiple SNPs can serve as an effective approach to genetic association analysis. The aim of the study was to analyze the association between genetic risk score (GRS) and gestational weight gain (GWG). GWG was calculated for a total of 342 healthy Polish women of Caucasian origin, aged 19 to 45 years. The SNPs rs9939609 (FTO), rs6548238 (TMEM18), rs17782313 (MC4R), rs10938397 (GNPDA2), rs10913469 (SEC16B), rs1137101 (LEPR), rs7799039 (LEP), and rs5443 (GNB3) were genotyped using commercial TaqMan SNP assays. A simple genetic risk score was calculated into two ways: GRS1 based on the sum of risk alleles from each of the SNPs, while GRS2 based on the sum of risk alleles of FTO, LEPR, LEP, and GNB3. Positive association between GRS2 and GWG (ß = 0.12, p = 0.029) was observed. Genetic risk variants of TMEM18 (p = 0.006, OR = 2.6) and GNB3 (p < 0.001, OR = 3.3) are more frequent in women with increased GWG, but a risk variant of GNPDA2 (p < 0.001, OR = 2.7) is more frequent in women with adequate GWG, and a risk variant of LEPR (p = 0.011, OR = 3.1) in women with decreased GWG. GRS2 and genetic variants of TMEM18, GNB3, GNPDA2, and LEPR are associated with weight gain during pregnancy.

Comprehensive Analysis of the Role of Gene Variants in Matrix Metalloproteinases and Their Tissue Inhibitors in Retinopathy of Prematurity: A Study in the Polish Population.

This study was designed to investigate the relationship between variants of matrix metalloproteinases (MMP-1 rs179975, MMP-9 rs17576 and rs17577), their tissue inhibitors (TIMP-1 rs4898, TIMP-2 rs2277698 and rs55743137) and the development of retinopathy of prematurity (ROP) in infants from the Polish population. A cohort of 100 premature infants (47% female) was enrolled, including 50 ROP cases and 50 no-ROP controls. Patients with ROP were divided into those with spontaneous remission and those requiring treatment. A positive association between MMP-1 rs179975 1G deletion allele and ROP was observed in the log-additive model (OR = 5.01; p = 0.048). Furthermore, female neonates were observed to have a negative association between the TIMP-1 rs4898C allele and the occurrence of ROP and ROP requiring treatment (codominant models with respective p-values < 0.05 and 0.043). Two and three loci interactions between MMP-1 rs1799750 and TIMP1rs4989 (p = 0.015), as well as MMP-1 rs1799750, MMP-9 rs17576 and TIMP-1 rs4989 (p = 0.0003) variants influencing the ROP risk were also observed. In conclusion, these findings suggest a potential role of MMPs and TIMPs genetic variations in the development of ROP in the Polish population. Further studies using a larger group of premature infants will be required for validation.

Guidelines of the Polish Society of Gynecologists and Obstetricians, the Polish Society for Vaccinology, and the Polish Society for Family Medicine on vaccinating women with reproductive plans and pregnant or breastfeeding women.

The following Guidelines present the most up-to-date treatment and management recommendations, which may be modified and altered after detailed analysis of a specific clinical situation, which in turn might lead to future modifications and updates.

Galectin-1 and Galectin-9 Concentration in Maternal Serum: Implications in Pregnancies Complicated with Preterm Prelabor Rupture of Membranes.

Preterm prelabor rupture of membranes (pPROM) accounts for nearly half of premature births. Although several risk factors have been identified, no markers allowing for effective prevention have been discovered. In this study, we investigated how the maternal serum levels of galectin-1 and galectin-9 change in patients with pPROM in comparison to uncomplicated pregnancies. A total of 75 patients were enrolled to both study and control group (37 vs. 38, respectively). The serum concentration of galectin-1 and galectin-9 were assayed in duplicate using an enzyme-linked immunoassay. All analyses were performed using PQ Stat v. 1.8.4 software. Galectin-1 levels were significantly higher in the controls (13.32 vs. 14.71 ng/mL, p = 0.02). Galectin-9 levels were similar in both groups (13.31 vs. 14.76 ng/mL, p = 0.30). Lower galectin levels were detected for early pPROM (before 32nd GW) in comparison to late pPROM and the controls (8.85 vs. 14.45 vs. 14.71 ng/mL, p = 0.0004). Similar trend was observed in galectin-9 levels, although no statistical significance was found (11.57 vs. 14.25 vs. 14.76 ng/mL, p = 0.26). Low galectin-1 maternal serum level is associated with the incidence of preterm prelabor rupture of membranes. Galectin-9 maternal serum levels were not significantly correlated with pPROM. However, in order to investigate gal-1 and gal-9 levels as potential, promising markers of pPROM, further clinical studies on larger groups are required.

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.

Genetic variants of progesterone receptor in etiology of preterm delivery.

OBJECTIVES: Preterm delivery (PTD) accounts for around 11% of pregnancies worldwide. Unfortunately, no diagnostic indicator, specific mechanism or genetic predisposition has yet been identified. One of the hypotheses suggest local or functional progesterone decrease as a potential reason for preterm uterine contractions leading to preterm delivery. It is believed that any change in progesterone receptor DNA may be crucial for higher risk of preterm delivery due to abnormal response to prostaglandins, normally inhibited by properly built progesterone. The aim of this study was to determine whether there is an association between progesterone gene polymorphisms (PROGINS and +331G/A) and preterm birth. MATERIAL AND METHODS: A total of 230 women were enrolled, including 115 cases of preterm deliveries (between 22 and 36 weeks of gestation) and 115 healthy mothers of full-term infants. Genomic DNA was isolated from the blood sample. Polymerase chain reaction (PCR) amplification was carried out in a final volume of 25 µL. Genotyping was assayed by PCR. Statistical analysis of the results was conducted with p < 0.05 accepted as statistically significant. RESULTS: For both PROGINS (Alu ins/del) and +331G/A (rs10895068) polymorphisms were equally frequent in case and control group. The prevalence of PGR alleles in both groups was also comparable. CONCLUSIONS: The results of our study showed no association between progesterone gene polymorphisms (PROGINS and +331G/A) and risk of preterm delivery. Identifying mechanisms to prolong the length of gestation, particularly in women at risk for preterm delivery, will improve both maternal and fetal outcomes.

Polymorphisms of fibronectin-1 (rs3796123; rs1968510; rs10202709; rs6725958; and rs35343655) are not associated with bronchopulmonary dysplasia in preterm infants.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that mainly affects premature newborns. Many different factors, increasingly genetic, are involved in the pathogenesis of BPD. The aim of the study is to investigate the possible influence of fibronectin SNP on the occurrence of BPD. The study included 108 infants born between 24 and 32 weeks of gestation. BPD was diagnosed based on the National Institutes of Health Consensus definition. The 5 FN1 gene polymorphisms assessed in the study were the following: rs3796123; rs1968510; rs10202709; rs6725958; and rs35343655. BPD developed in 30 (27.8%) out of the 108 preterm infants. Incidence of BPD was higher in infants with lower APGAR scores and low birthweight. Investigation did not confirm any significant prevalence for BPD development in any genotypes and alleles of FN1. Further studies should be performed to confirm the role of genetic factors in etiology and pathogenesis of BPD.

The role of galectins in obstetrics with particular emphasis on premature preterm rupture of membranes.

Premature rupture of membranes (pPROM) affects about 4% of pregnancies and remains the main cause of preterm delivery (PTD). We currently lack a method for screening patients at high risk of pPROM as well as causal treatment for this yet not fully understood pathology of pregnancy. Promising, potential markers are proteins from a family of lectins-galectins. To date, 13 subtypes have been identified in humans. Particular galectins inhibit the mother's immune response to the fetus, thus enabling the maintenance of pregnancy and delivering at term. So far, the role of some galectins has been proven in relation to early pregnancy complications, hypertension and preeclampsia, fetal growth disturbances (including fetuses small for gestational age, fetal growth restriction and macrosomia) and even in physiological processes which occur during healthy pregnancy. In reference to pPROM galectins seem to be linked to pathomechanisms leading to weakening of the structure of membranes and in result their rupture. Examination of galectins appears to be crucial for understanding certain pathologies of pregnancy and gives hope for the effective identification of risk groups and future causal treatment.

The Significance of VDR Genetic Polymorphisms in the Etiology of Preeclampsia in Pregnant Polish Women.

For the first time in the Polish population, we aimed to investigate associations between the VDR gene single-nucleotide polymorphisms (SNPs) BsmI (rs15444410), ApaI (rs7975232), FokI (rs19735810), and TaqI (rs731236) and the development of preeclampsia (PE). A case-control study surveyed 122 preeclamptic and 184 normotensive pregnant women. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed to examine the maternal VDR FokI, BsmI, TaqI, and ApaI polymorphisms. The VDR BsmIAA homozygous genotype was statistically significantly more frequent in preeclamptic women compared to the control group (p = 0.0263), which was also associated with a 2-fold increased risk of PE (OR = 2.06, p = 0.012). A correlation between the VDR BsmI polymorphism with systolic and diastolic blood hypertension was noted. Furthermore, 3-marker haplotype CTA (TaqI/ApaI/BsmI) was associated with significantly higher systolic (p = 0.0075) and diastolic (p = 0.0072) blood pressure. Association and haplotype analysis indicated that the VDR BsmI A allele could play a significant role in the PE pathomechanism and hence could be a risk factor for PE development in pregnant Polish women. These results indicate the importance of the VDR BsmI polymorphism and reveal that this variant is closely associated with a higher predisposition to hypertension.

Vitamin D3 and its receptor in selected obstetrical complications.

Vitamin D3 (VD3) and its steroidal nuclear receptor are necessary for proper development of a pregnancy. They play a key role in implantation, modulate the mother's immune response to the developing fetus, influence the final development of a placenta, and regulate blood pressure and glucose tolerance. VD3 deficiency can lead to the occurrence of obstetric complications such as recurrent miscarriages, preeclampsia, intrauterine growth restriction, gestational diabetes and preterm labor. VD3 deficiency is a common phenomenon across the globe; because of the higher demand placed on their bodies, pregnant women are more likely to develop VD3 deficiency. During pregnancy, VD3 supplementation is a safe method of treatment without risk of side effects or intoxication. To obtain the greatest efficacy, VD3 supplementation should start at the pregnancy planning stage, under control of the VD3 serum concentration, which should exceed 30 ng/mL (75 nmol/L); this is to start the positive effect of the optimal VD3 concentration from the beginning of a pregnancy.

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.

Single nucleotide vitamin D receptor polymorphisms (FokI, BsmI, ApaI, and TaqI) in the pathogenesis of prematurity complications.

The vitamin D receptor (VDR), coded by the VDR gene, plays a pivotal role in executing cellular functions when bound by the active form of vitamin D. Gene polymorphisms in this receptor have been increasingly associated with a heightened state of vulnerability to certain diseases. However, limited data is available concerning the role of VDR gene polymorphisms in preterm infant complications. In 114 premature infants (< 32 weeks gestation) we analyze four single nucleotide VDR polymorphisms (rs2228570 (FokI), rs1544410 (BsmI), rs797532 (ApaI), rs731236 (TaqI)) for their association with respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP). The results show that BPD was almost four times more likely in infants with the genotype CC of ApaI (rs7975232) (OR 3.845; p = 0.038). While both BPD and NEC were 2.1 times more likely to occur in preterm infants with the allele C of ApaI (rs7975232) (respectively: OR 2.111 and OR 2.129, p < 0.05). The ApaI VDR polymorphism appears to influence incidence of BPD and NEC in preterm infants. Considering VDR polymorphisms in future genetic investigations, in preterm complications, may prove clinically relevant.

Role of Fibronectin-1 polymorphism genes with the pathogenesis of intraventricular hemorrhage in preterm infants.

BACKGROUND/INTRODUCTION: Intraventricular hemorrhage (IVH) is a dangerous complication facing a significant proportion of preterm infants. It is multifactorial in nature, and an observed fibronectin deficiency in the germinal matrix basal lamina is among the most prominent factors that influence such rupture. Better understanding of the FN1 gene polymorphisms and their role in IVH may further clarify the presence of a genetic susceptibility of certain babies to this complication. The aim of this study was to assess if 5 single nucleotide polymorphisms of the fibronectin gene may be linked to an increased incidence of IVH. MATERIAL AND METHODS: The study included 108 infants born between 24 and 32 weeks of gestation. IVH was diagnosed using cranial ultrasound performed on the 1st,3rd, and 7th day after birth and classified according to Papile et al. IVH classification. The 5 FN1 gene polymorphisms assessed in the study were the following: rs3796123; rs1968510; rs10202709; rs6725958; and rs35343655. RESULTS: IVH developed in 51 (47.2%) out of the 108 preterm infants. This includes, 18 (35.3%) with stage I IVH, 19 (37.3%) with stage II, 11 (21.6%) with stage III, and 3 (5.9%) with stage IV IVH. Incidence of IVH was higher in infants with lower APGAR scores, low gestational age, and low birthweight. Analysis showed that IVH stage II to IV was approximately seven times more likely to occur in infants with the genotype TT FN1 rs10202709 (OR 7237 (1046-79.59; p = 0,044)). No other significant association was found with the rest of the polymorphisms. CONCLUSION: The results of our study indicate a sevenfold increased genetic susceptibility to IVH in preterm infants with the TT FN1 rs10202709 gene polymorphism. The fibronectin gene polymorphism may therefore be of crucial importance as a genetic risk factor for IVH in preterm infants. Further studies are warranted.

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.

Inflammation-associated gene polymorphisms and clinical variables in the incidence and progression of retinopathy of prematurity.

INTRODUCTION: A growing body of evidence shows that genetics plays a vital role in the development and progression of retinopathy of prematurity (ROP). Perinatal inflammation is also considered an important risk factor of ROP. Therefore, understanding the interplay of genetics and susceptibility to inflammation might shed light on the pathogenesis of ROP and make its screening and treatment more effective in preventing visual impairment in premature infants. MATERIAL AND METHODS: This study investigated the correlation of inflammation-associated gene polymorphisms: IL-1ß +3953 C>T, IL-1RN VNTR 86 bp, IL-6 -174 G>C, IL-6 -596 G>A, and TNF-α -308 G>A as well as demographic and clinical characteristics of ROP in preterm infants (n = 90). RESULTS: Our results demonstrate that IL-1RN rs2234663 1/1 genotype prevails in infants with ROP that regresses without intervention, when compared to those requiring laser photocoagulation/anti-VEGF injection (p = 0.031). Genotype 2/2 of IL-1RN occurs more frequently in children with severe ROP (28.6%) than in the group in which ROP regressed spontaneously (4.0%). The analysis revealed also differences between the genotypes of IL-1RN in ROP patients with intrauterine infection and in patients who had ROP without intrauterine infection; however, this was not statistically significant. Other studied polymorphisms were not associated with ROP development or its progression. CONCLUSIONS: These results suggest that different genotypes of IL-1RN might have an impact on the course of ROP. Genotype 2/2 of IL-1RN gene may predispose to ROP progression.

Associations between folate and choline intake, homocysteine metabolism, and genetic polymorphism of MTHFR, BHMT and PEMT in healthy pregnant Polish women.

AIM: Physiological homocysteine (Hcy) concentrations depend on several factors, both dietary (including folate and choline intake) and biological (such as polymorphism of the genes involved in Hcy metabolism). This study aimed to thus test the associations between genes functionally linked with Hcy metabolism (MTHFR, BHMT and PEMT), folate and choline intakes, and total Hcy (tHcy) concentrations of healthy pregnant women. METHODS: One hundred and three healthy Polish women aged 18-44 years, in the third trimester of pregnancy, were enrolled. RESULTS: Mean blood tHcy and glutathione (GSH) concentrations were 8.08 ± 3.25 µM and 4.84 ± 1.21 µM, respectively. Concentrations of tHcy were found to be lower in the women who were taking folic acid supplements than in those who did not take these supplements (7.42 ± 1.78 µM vs 9.28 ± 4.42 µM, P < 0.05). There were no associations found between the examined parameters and BHMT (rs7356530), MTHFR (rs1801133) and PEMT (rs12325817) alone. However, blood tHcy concentrations differed in the PEMT genotype subgroups when choline and folate intakes were considered: respectively, 25% and 20% lower levels were observed in the C allele carriers who met their needs of choline or folate than in those who did not take enough these nutrients (P < 0.05 for both associations). CONCLUSIONS: This study suggests that choline and folate intakes might interact with MTHFR, BHMT and PEMT polymorphisms to determine tHcy and GSH blood concentrations in healthy pregnant women.