A systematic review identifying seminal plasma biomarkers and their predictive ability on IVF and ICSI outcomes

The diverse nature and high molecule concentration of seminal plasma (SP) makes this fluid a good potential source for a potential biomarker that could predict assisted reproductive technology (ART) outcomes. Currently, semen quality parameters cannot accurately predict ART outcomes. A systematic literature search was conducted to identify human SP biomarkers with potential predictive ability for the outcomes of IVF and intracytoplasmic sperm injection. Observational cohort and case-control studies describing the association between biomarkers in human SP and the outcome of infertile men attending for ART were included. Forty-three studies were selected, reporting on 89 potential SP biomarkers (grouped as oxidative stress, proteins glycoproteins, metabolites, immune system components, metals and trace elements and nucleic acids). The present review supports 32 molecules in SP as potentially relevant biomarkers for predicting ART outcomes; 23 molecules were reported once and nine molecules were reported in more than one study; IL-18 and TGF-β1–IL-18 ratio were confirmed in distinct studies. This review presents the most comprehensive overview of relevant SP biomarkers to predict ART outcomes to date, which is of clinical interest for infertility investigations and assisted reproduction; nevertheless, its potential is under-exploited. This review could serve as starting point for designing an all-encompassing study for biomarkers in SP and their predictive ability for ART outcomes, and for developing a non-invasive diagnostic tool.MerckMCIN/AEI/10.13039/501100011033ESF Investing in your future: FPU19/01638Grant Endo- Map PID2021-12728OB-100 funded by MCIN/AEI/10.13039/ 501100011033 and ERFD A way of making EuropeFEDER/Junta de Andalucía-Consejería de Economía y Conocimiento: ROBIN A-CTS-614-UGR2

Analysis of SNP profiles in patients with major depressive disorder

The present study focused on 91 single-nucleotide polymorphisms (SNPs) in 21 candidate genes to find associations with major depressive disorder (MDD). In total, 160 healthy controls and 177 patients with MDD were studied. We applied arrayed primer extension (APEX) based genotyping technology followed by association and haplotype analysis. SNPs in CCKAR, DRD1, DRD2, and HTR2C genes showed nominally significant associations with MDD. None of these associations remained significant after adjustment for multiple testing. Haplotype analysis revealed CCKAR haplotypes to be associated with MDD (global p=0.004). More precisely, we found the GAGT haplotype to be associated with increased risk for MDD (OR 7.42, 95% CI 2.13–25.85, p=0.002). This haplotype effect remained significant after Bonferroni correction (p=0.04 after Bonferroni's adjustment). Altogether we were able to find some nominal associations, but due to small sample size these results should be taken as exploratory. However, the effect of GAGT haplotype on the CCKAR gene may be considered as increasing the risk for MDD

Maternal Pre-Pregnancy Obesity Is Associated with Altered Placental Transcriptome

Maternal obesity has a major impact on pregnancy outcomes. There is growing evidence that maternal obesity has a negative influence on placental development and function, thereby adversely influencing offspring programming and health outcomes. However, the molecular mechanisms underlying these processes are poorly understood. We analysed ten term placenta's whole transcriptomes in obese (n = 5) and normal weight women (n = 5), using the Affymetrix microarray platform. Analyses of expression data were carried out using non-parametric methods. Hierarchical clustering and principal component analysis showed a clear distinction in placental transcriptome between obese and normal weight women. We identified 72 differentially regulated genes, with most being down-regulated in obesity (n = 61). Functional analyses of the targets using DAVID and IPA confirm the dysregulation of previously identified processes and pathways in the placenta from obese women, including inflammation and immune responses, lipid metabolism, cancer pathways, and angiogenesis. In addition, we detected new molecular aspects of obesity-derived effects on the placenta, involving the glucocorticoid receptor signalling pathway and dysregulation of several genes including CCL2, FSTL3, IGFBP1, MMP12, PRG2, PRL, QSOX1, SERPINE2 and TAC3. Our global gene expression profiling approach demonstrates that maternal obesity creates a unique in utero environment that impairs the placental transcriptome

The Gut Microbiome in Polycystic Ovary Syndrome (PCOS) and its Association with Metabolic Traits

This work was funded by Estonian Research Council grants PUT 1371 (to E.O.), EMBO Installation grant 3573 (to E.O.) … E.O. was supported by European Regional Development Fund Project No. 15-0012 GENTRANSMED and Estonian Center of Genomics/Roadmap II project No 16-0125. S.A. was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE (SAF2017-87526-R); and by FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento: MENDO (B-CTS-500-UGR18).Purpose: Despite gut microbiome being widely studied in metabolic diseases, its role in polycystic ovary syndrome (PCOS) has been scarcely investigated. The aim of our study was to test for possible associations between gut microbiome and PCOS in late fertile age women and investigate whether changes in the gut microbiome correlate with PCOS-related metabolic parameters. Methods: We compared the 16S rRNA sequenced gut microbiome of 102 PCOS women with 201 age- and body mass index (BMI) matched non-PCOS women. Clinical and biochemical characteristics of the participants were assessed at ages 31 and 46 and analyzed in the context of gut microbiome data at the age of 46. Results: Bacterial diversity indices did not differ significantly between PCOS and controls. We identified four genera whose balance helps to differentiate between PCOS and non-PCOS. In the whole cohort, the abundance of two genera from the order Clostridiales was correlated with several PCOS-related markers. When investigating the gut microbiome composition in PCOS women with different BMI and glucose tolerance groups, prediabetic PCOS women had significantly lower alpha diversity and markedly increased abundance of genus Dorea compared to women with normal glucose tolerance. Conclusions: Our data indicate that PCOS and non-PCOS women at late fertile age with similar BMI do not signficantly differ in gut microbiota. However, there are significant microbial changes in PCOS individuals depending on their metabolic health. Further studies are needed in order to further understand these changes in more detail.Estonian Research Council grants PUT 1371EMBO Installation grant 3573European Regional Development Fund Project No. 15-0012 GENTRANSMEDEstonian Center of Genomics/Roadmap II project No 16-0125Spanish Ministry of Economy, Industry and Competitiveness (MINECO) European Regional Development Fund (FEDER) RYC-2016-21199 and ENDORE (SAF2017-87526-R)FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento: MENDO (B-CTS-500-UGR18

Is there an association between ACTN3 R577X polymorphism and muscle power phenotypes in young, non-athletic adults?

We investigated the association between ACTN3 R577X polymorphism and jumping (vertical squat and counter-movement jump tests) and sprint ability (30 m dash) in non-athletic, healthy young adults [N=284 (217 male), mean (SD) age: 21 (2) years]. We analyzed the differences in the study phenotypes among ACTN3 R577X genotypes by one-way analysis of covariance before and after adjusting for sex, age, weight and height (confounders). We also compared the genotype and allele frequencies between those with the best and worst results in the aforementioned tests (≥90th vs 0.05). In summary, α-actinin-3 deficiency does not negatively influence the ability to generate explosive leg muscle power in a young non-athletic population

Association of accelerometer-determined physical activity and sedentary behavior with the gut microbiome in middle-aged women: A compositional data approach

The beneficial effects of physical activity (PA) on gut microbiome have been reported, nevertheless the findings are inconsistent, with the main limitation of subjective methods for assessing PA. It is well-accepted that using an objective assessment of PA reduces the measurement error and allows also objective assessment of sedentary behavior (SB). We aimed to study the associations between accelerometer-assessed behaviors (i.e., SB, light-intensity physical activity -LPA- and moderate-to-vigorous physical activity -MVPA) with the gut microbiome using compositional data analysis, a novel approach that enables to study these behaviors accounting for their inter-dependency. This cross-sectional study included 289 women from the Northern Finland Birth Cohort 1966. Physical activity was measured during 14 days by wrist-worn accelerometers. Analyses based on the combined effect of MVPA and SB, and compositional data analyses in association with the gut microbiome data were performed. The microbial alpha- and beta-diversity were not significantly different between the MVPA-SB groups, and no differentially abundant microorganisms were detected. Compositional data analysis did not show any significant associations between any movement behavior (relative to the others) on microbial alpha-diversity. Butyrate-producing bacteria such as Agathobacter and Lachnospiraceae CAG56 were significantly more abundant when reallocating time from LPA or SB to MVPA (γ=0.609 and 0.113, both p-values=0.007). While PA and SB were not associated with microbial diversity, we found associations of these behaviors with specific gut bacteria, suggesting that PA of at least moderate intensity (i.e., MVPA) could increase the abundance of short-chain fatty acids-producing microbes.CTS-1123, Depto. BBM

How Contemporary Human Reproductive Behaviors Influence the Role of Fertility-Related Genes: The Example of the P53 Gene

Studies on human fertility genes have identified numerous risk/protective alleles involved in the occurrence of reproductive system diseases causing infertility or subfertility. Investigations we carried out in populations at natural fertility seem to suggest that the clinical relevance that some fertility genes are now acquiring depends on their interaction with contemporary reproductive behaviors (birth control, delayed childbearing, and spacing birth order, among others). In recent years, a new physiological role in human fertility regulation has emerged for the tumor- suppressor p53 gene (P53), and the P53 Arg72Pro polymorphism has been associated with recurrent implantation failure in humans. To lend support to our previous observations, we examined the impact of Arg72Pro polymorphism on fertility in two samples of Italian women not selected for impaired fertility but collected from populations with different (premodern and modern) reproductive behaviors. Among the women at near-natural fertility (n = 98), the P53 genotypes were not associated with different reproductive efficiency, whereas among those with modern reproductive behaviors (n = 68), the P53 genotypes were associated with different mean numbers of children [Pro/Pro = 0.75<Pro/Arg = 1.7<Arg/Arg = 2, (p = 0.056)] and a significant negative relationship between the number of children and P53 Pro allele frequencies (p = 0.028) was observed. These results are consistent with those of clinical studies reporting an association between the P53 Pro allele and recurrent implantation failure. By combining these findings with previous ones, we suggest here that some common variants of fertility genes may have become “detrimental” following exposure to modern reproductive patterns and might therefore be associated with reduced reproductive success. Set within an evolutionary framework, this change could lead to the selection of a set of gene variants fitter to current reproductive behaviors as the shift to later child-bearing age in developed countries

The relationship between fertility and lifespan in humans

Evolutionary theories of aging predict a trade-off between fertility and lifespan, where increased lifespan comes at the cost of reduced fertility. Support for this prediction has been obtained from various sources. However, which genes underlie this relationship is unknown. To assess it, we first analyzed the association of fertility with age at menarche and menopause, and with mortality in 3,575 married female participants of the Rotterdam Study. In addition, we conducted a candidate gene study where 1,664 single nucleotide polymorphisms (SNPs) in 25 candidate genes were analyzed in relation to number of children as a measure of fertility. SNPs that associated with fertility were analyzed for association with mortality. We observed no associations between fertility and age at menarche (p = 0.38) and menopause (p = 0.07). In contrast, fertility was associated with mortality. Women with two to three children had significantly lower mortality (hazard ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69–0.97) compared to women with no children. No such benefit was observed for women with four or more children, who had a similar mortality risk (HR, 0.93; 95% CI, 0.76–1.13) as women with no children. The analysis of candidate genes revealed four genes that influence fertility after correction for multiple testing: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHBA (p = 0.021). However, none of the independent SNPs in these genes predicted mortality. In conclusion, women who bear two to three children live longer than those who bear none or many children, but this relationship was not mediated by the candidate genes analyzed in this study

Polymorphisms in wolframin (WFS1) gene are possibly related to increased risk for mood disorders

Wolfram syndrome gene (WFS1) has been suggested to have a role in the susceptibility for mood disorders. A 26-fold increased risk for psychiatric disorders in WFS1 mutation carriers has been suggested. In this study we tested the hypothesis that the WFS1 gene is related to the risk for mood disorders. We analysed 28 single-nucleotide polymorphisms (SNPs) of the WFS1 gene in 224 unrelated patients with major depressive disorder and bipolar disorder and in 160 healthy control subjects. Patients were further stratified according to their comorbidity with anxiety disorders. We applied arrayed primer extension (APEX)-based genotyping technology followed by association and haplotype analysis. Five SNPs in the WFS1 gene were associated with major depressive disorder, and three SNPs with bipolar disorder. Haplotype analysis revealed a common GTA haplotype, formed by SNPs 684C/G, 1185C/T and 1832G/A, conferring risk for affective disorders. Specifically, for major depression the GTA haplotype has an OR of 1.59 (p=0.01) and for bipolar disorder an OR of 1.89 (p=0.03). These results support the hypothesis that the WFS1 gene is involved in the genetic predisposition for mood disorders