Genetic variants in the p53 pathway influence implantation and pregnancy maintenance in IVF treatments using donor oocytes.

PURPOSE: Single-nucleotide polymorphisms (SNPs) in the p53 pathways have shown to play a role in endometrial receptivity and implantation in infertile women undergoing in vitro fertilization (IVF). The present study aimed to assess the influence of these gene variants over pregnancy success through a receptivity model in recipients of egg donation treatments, when factors such as age and quality of the oocytes are standardized. METHODS: A nested case-control study was performed on 234 female patients undergoing their first fresh IVF treatment as recipients of donor oocytes. Genotyping of TP53 Arg72Pro (rs1042522), LIF (rs929271), MDM4 (rs1563828), and USP7 (rs1529916) SNPs in the recipients allowed comparison of allele and genotype frequencies and their association with the IVF treatment outcome. RESULTS: Grouped by genotypes, patients showed differences in IVF outcomes after the embryo transfer. Arg72Pro (rs1042522) gene variant was associated to changes in implantation and clinical pregnancy rates. The polymorphisms USP7 (rs1529916) and MDM4 (rs1563828) were associated to differential ongoing pregnancy rates and variable miscarriage events, respectively. CONCLUSIONS: This study highlights the association between gene polymorphisms related to P53 function and their influence over IVF reproductive outcomes. Arg72Pro variant may influence early events, as lower implantation rates were found in homozygous for Pro72 allele. By contrast, MDM4 (rs1563828) and USP7 (rs1529916) gene variants were associated with the later maintenance of pregnancy.

Differential behavior of serum and red blood cell folate during a treatment with levofolinic acid. Gender differences.

BACKGROUND: Folates are essential nutrients that maintain nucleotide synthesis and methylation reactions. Folate levels depend essentially on the diet. In the present work, the changes in the folate-homocysteine (Hcy) metabolic axis were studied in response to treatment with levofolinic acid. METHODS: 49 college students (23 men and 26 women) underwent a treatment voluntarily with 5 mg/day levofolinic acid for one month. Serum and red blood cell folate, vitamin B12, and Hcy levels were determined on days 2, 5, 10, and 30 during treatment and 30 days after completion of treatment. RESULTS: Serum folate and Hcy levels showed a plateau beginning on day 10, while red blood cell folate increased towards treatment completion. Gender differences were found in basal levels of Hcy, these differences remaining until the 10th day of treatment and reappearing 30 days after the treatment was finished. Between gender differences in treatment evolution were found only in percentage changes in red blood cell folate in women and men at day 30 of treatment. CONCLUSIONS: There is a compartmentalization of folates in the body that presents a plateau in serum and an erythrocyte reservoir. Folate metabolism presents differential features between genders. The greater physiological need for folate in women of childbearing age could be the determining factor in this difference.

Genetic polymorphisms of serotonin transporter and receptor 1A could influence success during embryo implantation and maintenance of pregnancy.

OBJECTIVE: To explore whether serotonin-related gene polymorphisms influence clinical outcomes of IVF treatment in recipients using donated oocytes. DESIGN: Nested case-control study. SETTING: University-affiliated infertility clinic. PATIENT(S): Two hundred forty-five women undergoing IVF treatment with donated oocytes. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotype and haplotype analysis of the serotonin transporter-linked polymorphic region (5-HTTLPR), rs1800532, rs6295, rs6313, and rs3813929, between recipients grouped according to the results of the oocyte donation for IVF treatment. RESULT(S): No differences were found between genotype distribution of the tryptophan hydroxylase 1, serotonin receptor 2A, and serotonin receptor 2C polymorphisms. Recipients carrying the LL genotype for 5-HTTLPR had lower clinical pregnancy rates (PR) and higher biochemical pregnancy loss (BPL) events. Lower implantation rates were found in CC carriers for 5-HT1A.rs6295 who also presented higher BPL rates. A lower incidence of clinical pregnancy was observed for LC haplotypes, corresponding to an increase in BPL rates. CONCLUSION(S): A strong association was found between early pregnancy loss and recipients carrying the 5-HTTLPR and rs6295 genetic variants. Identifying biological processes involving serotonin and embryo implantation may help to understand the dynamics of the maternal-embryo dialogue.

Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder.

BACKGROUND: Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. METHODS: A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated. RESULTS: Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161). CONCLUSIONS: Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome.

Human genetic selection on the MTHFR 677C>T polymorphism.

BACKGROUND: The prevalence of genotypes of the 677C>T polymorphism for the MTHFR gene varies among humans. In previous studies, we found changes in the genotypic frequencies of this polymorphism in populations of different ages, suggesting that this could be caused by an increase in the intake of folate and multivitamins by women during the periconceptional period. The aim was to analyze changes in the allelic frequencies of this polymorphism in a Spanish population, including samples from spontaneous abortions (SA). METHODS: A total of 1305 subjects born in the 20th century were genotyped for the 677C>T polymorphism using allele specific real-time PCR with Taqman probes. A section of our population (n = 276) born in 1980-1989 was compared with fetal samples (n = 344) from SA of unknown etiology from the same period. RESULTS: An increase in the frequency of the T allele (0.38 vs 0.47; p < 0.001) and of the TT genotype (0.14 vs 0.24; p < 0.001) in subjects born in the last quarter of the century was observed. In the 1980-1989 period, the results show that the frequency of the wild type genotype (CC) is about tenfold lower in the SA samples than in the controls (0.03 vs 0.33; p < 0.001) and that the frequency of the TT genotype increases in the controls (0.19 to 0.27) and in the SA samples (0.20 to 0.33 (p < 0.01)); r = 0.98. CONCLUSION: Selection in favor of the T allele has been detected. This selection could be due to the increased fetal viability in early stages of embryonic development, as is deduced by the increase of mutants in both living and SA populations.