Abstract P226: Transcriptome Signature Of Placentas From Diabetic Pregnancies Is Confounded By Fetal Sex.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Sarah M Kedziora ◽  
Benedikt Obermayer ◽  
Meryam Sugulle ◽  
Florian Herse ◽  
Kristin Kräker ◽  
...  

Hypertension-associated obstetric diseases like diabetes mellitus (DM) or preeclampsia occur in 25-35% of pregnancies and are related to placental dysfunction. The placenta has a unique structure and function to guarantee healthy pregnancy, fetal development, and outcome. Thus, the diabetic environment featuring inflammation, metabolic alterations, and hypoxia, is challenging with increased stress for mother and foetus. Delivery-related complications and adverse post-pregnancy outcomes, for example the increased risk for preeclampsia, are related to placental pathology in the different types of DM. Therefore, understanding disturbed placental development during pathologic pregnancy is important. We hypothesize a placental transcriptome signature present in pathologic pregnancy. We aimed to broaden our understanding of placental adaptations to various forms of diabetic pregnancy. Human placenta samples from healthy controls (n = 29), women with gestational DM (GDM, n = 12), DM type 1 (DM1, n = 17), DM type 2 (DM2, n = 3) and GDM, DM1 or DM2 superimposed by preeclampsia (n = 16) were included. We quantified gene expression by Illumina TruSeq stranded total RNA Sequencing and analyzed data by means of principal component analysis (PCA), differential expression and gene set enrichment. The samples were mainly split by fetal sex in the PCA rather than diabetic subgroups. Genes associated with the principal components were primary located on the male sex chromosome ( Xist, Uty, Usp9y, Ddx3y ) and only weakly enriched in functionally relevant gene sets. The fetal sex was identified as single main explanatory variable when the principal components were associated with clinical patient data. Placentas complicated by DM2 identified 93 and 27 significant differential expressed genes (DEG; adj. p-value < 0.05) in comparison to healthy controls and GDM, respectively. Comparison of DM1 to DM2 or GDM showed four and two significant genes. In this cohort possible effects of GDM and preeclampsia were not observed.We conclude that fetal sex is dominating placental gene expression and confounding transcriptome signatures resulting from diabetes, in settings of well controlled diabetic disease.

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2588
Author(s):  
Sebastià Galmés ◽  
Andreu Palou ◽  
Francisca Serra

Obesity is characterized by an excessive body fat percentage (BF%). Animal and cell studies have shown benefits of vitamin A (VA) on BF% and lipid metabolism, but it is still controversial in humans. Furthermore, although some genetic variants may explain heterogeneity in VA plasma levels, their role in VA metabolic response is still scarcely characterized. This study was designed as a combination of an observational study involving 158 male subjects followed by a study with a well-balanced genotype–phenotype protocol, including in the design an ex vivo intervention study performed on isolated peripheral blood mononuclear cells (PBMCs) of the 41 former males. This is a strategy to accurately identify the delivery of Precision Nutrition recommendations to targeted subjects. The study assesses the influence of rs5888 (SCARB1), rs659366 (UCP2), and rs1800629 (UCP1) variants on higher BF% associated with suboptimal VA consumption and underlines the cellular mechanisms involved by analyzing basal and retinoic acid (RA) response on PBMC gene expression. Data show that male carriers with the major allele combinations and following suboptimal-VA diet show higher BF% (adjusted ANOVA test p-value = 0.006). Genotype–BF% interaction is observed on oxidative/inflammatory gene expression and also influences lipid related gene expression in response to RA. Data indicate that under suboptimal consumption of VA, carriers of VA responsive variants and with high-BF% show a gene expression profile consistent with an impaired basal metabolic state. The results show the relevance of consuming VA within the required amounts, its impact on metabolism and energy balance, and consequently, on men’s adiposity with a clear influence of genetic variants SCARB1, UCP2 and UCP1.


2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Shamone R Gore ◽  
Jeffery Hsu ◽  
Peter Hanna ◽  
David R Van Wagoner ◽  
John Barnard ◽  
...  

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with a 2-fold increased risk of mortality and a ~5- fold increased risk of stroke. Genome wide association studies have identified a locus on chromosome 4q25 that has the strongest association with AF. The SNPs in this locus most strongly associated with AF are located in an intergenic region that is 78 to 157 kb distal to the closest gene PITX2. PITX2 is a candidate gene for AF, due to its role in left/right patterning during heart development and expression found only in the left vs. right atrium. Our lab performed RNA-seq on human atria and identified a long intergenic non-coding RNA (linc-RNA) adjacent to PITX2 that is expressed with the same left/right atrial asymmetry as PITX2. We hypothesized that there may be functional genetic variants in the 4q25 region that directly affect expression of PITX2 or the linc-RNA adjacent to PITX2. Further, we hypothesized that the linc-RNA may control in trans the expression of genes that can alter cellular electrophysiology and lead to AF susceptibility. First we used qPCR to determine whether the expression of PITX2 and this linc-RNA were correlated in 199 human left atria samples. We found the expression of these genes to be highly and positively correlated with an r2 value of 0.47 (p < .0001). We obtained genome-wide SNP information for each of these subjects using an Illumina SNP microarray. We determined the association of SNPs on chromosome 4 with the expression levels of PITX2 and the linc-RNA by performing expression QTL (eQTL) analysis. In the 4q25 region, common genetic variation was more strongly associated with expression of the linc-RNA than PITX2. Two of the strongest linc-RNA eQTL SNPs (p-value ~10-4) were associated with AF with a p-value of ~10 15. We are now starting functional studies to determine if this linc-RNA can modulate gene expression in trans by transfection of a linc-RNA expression plasmid into HEK-293 cells. We plan to determine the effects of over expression this linc-RNA on global gene expression profiles using expression arrays and RNA-seq


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1482-1482 ◽  
Author(s):  
Vincenzo Fontana ◽  
Wenche Jy ◽  
Pamela Dudkiewicz ◽  
Lawrence L. Horstman ◽  
Carlos Bidot ◽  
...  

Abstract BACKGROUND: Cell-derived microparticles (C-MP) are microvesicles released during activation and apoptosis from platelets (PMP), leukocytes (LMP), endothelial cells (EMP) and red cells (RMP). They commonly express phosphatidylserine (PS) judged by binding annexin V (AnV) and carry markers of parent cells. C-MP are involved in thrombosis, inflammation and angiogenesis. Little is known how C-MP are cleared from circulation. To test that the spleen might be involved, we investigated C-MP profiles in patients who underwent splenectomy for various causes (group A), those with hypersplenism (group B), and healthy controls with spleen (group C). MATERIAL AND METHODS: Group A (Gr A) consisted of 44 patients (18 M and 26 F, mean age 57.2 yr) with splenectomy; group B (Gr B) consisted of 25 patients (12 M and 13 F, mean age 61.6 yr) with hypersplenism. Gr A had 25 ITP, 7 myeloproliferative disorders, 4 lymphoma, 3 hemolytic anemias, 4 trauma related splenectomy, 1 unknown reason. Group B had 19 chronic hepatitis C, 2 alcoholic, 2 idiopathic and 1 autoimmune hepatitis, 1 portal vein thrombosis. Group C (Gr C) were healthy controls with spleen (n=109). Flow cytometry was used to assay C-MP. PMP were identified by CD41+, LMP by CD45+, EMP by CD31+/CD41−, and RMP by glycophorin+. Profile of C-MP and blood counts were compared among the 3 groups. RESULTS: Table 1 summarizes C-MP data among the 3 groups. Gr A and B were well matched for ages and sex. Mean values of WBC and Hgb were normal in all groups while the platelet count was low in Gr B. Mean values of LMP, EMP and RMP were significantly higher in Gr A compared to Gr B and C, but PMP were not. All species of C-MP (PMP, LMP, EMP, RMP) in Gr B were significantly lower than Gr C (healthy control) and were markedly depressed compared to Gr A (see Table 1). Correlation analysis revealed that PMP correlated with platelet count (p<0.0001) but no correlation between LMP and WBC was seen, or between RMP and Hgb. Accordingly, high LMP and RMP in Gr A cannot explain the relatively high Hgb and WBC levels in this group. DISCUSSION/COMCLUSIONS: Our data suggest that spleen sequesters and/or clears C-MP of all types (PMP, LMP, EMP, RMP). C-MP express PS (bind AnV), which is known to promote clearance from circulation. Splenectomy is known to be associated with thrombosis but its mechanism in not well elucidated. Elevated C-MP in splenectomized patients may contribute to their increased risk of thrombosis. Table 1 Gr A (Splntomy) Gr B (Hyperspln) Gr C (Control) p value (A-C) p value (B-C) Patient no. 44 25 109 PMP 13858 7073 15992 n. s. <0.0001 LMP 2043 1180 1385 <0.0001 <0.001 EMP 857 238 436 <0.001 <0.0001 RMP 2964 926 1138 <0.0001 <0.005


2020 ◽  
Vol 6 (4) ◽  
pp. 205521732097851
Author(s):  
IS Brorson ◽  
AM Eriksson ◽  
IS Leikfoss ◽  
V Vitelli ◽  
EG Celius ◽  
...  

Background Genetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS. Objectives Analysis of the gene expression profiles of circulating CD8+ T cells of MS patients compared to healthy controls. Methods RNA from purified CD8+ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved. Results We identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients. Conclusions CD8+ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8+ T cells and subtypes of these may increase understanding of how T cells are involved in MS.


2020 ◽  
Author(s):  
Haihua Zhang ◽  
Wenbo Zhao ◽  
Bian Liu ◽  
Tao Wang ◽  
Zhifa Han ◽  
...  

Abstract Background Interleukin-6 (IL-6) signaling is associated with an increased risk of coronary artery disease (CAD) and ischemic stroke (IS). Growing evidence shows that the minor alleles of IL-6 receptor gene (IL-6R) variants rs2228145, rs7529229, and rs4129267 significantly increase soluble IL-6R levels and reduce CAD risk. However, the role of IL-6R variants in IS is largely unknown, prompting us to perform a comprehensive analysis. Methods In stage 1 of this study, we performed a meta-analysis of three genome-wide association study datasets from MEGASTROKE, UK Biobank, and the Million Veteran Program to evaluate the association of rs7529229 with IS. In stage 2, we conducted an expression quantitative trait loci analysis to examine the effects of rs7529229 on IL-6R expression in neuropathologically healthy individuals from the UK Brain Expression Consortium, GTEx project, and the eQTLGen Consortium. In stage 3, we used a tissue-specific gene expression analysis to evaluate differences in IL-6R expression across human tissues using gene expression data from GTEx. In stage 4, we conducted a case–control gene expression analysis to explore the differential expression of IL-6R in the whole blood of IS patients and healthy controls. Results We found that: (1) the rs7529229 minor allele significantly reduced the risk of developing IS (odds ratio=0.97, 95% confidence interval 0.95–0.99, P=2.30E-03); (2) the rs7529229 minor allele significantly reduced IL-6R expression in relevant tissues especially in blood vessels and whole blood; (3) IL-6R was mainly expressed in skeletal muscle and whole blood; and (4) IL-6R expression was significantly reduced in the whole blood of healthy controls compared with IS patients. Importantly, the biological senses in stages 1–4 were all convergent. Conclusions Taken together, our findings indicate that the rs7529229 minor allele decreases IL-6R expression in relevant tissues, diminishes IL-6 signaling, and eventually reduces the IS risk. Hence, IL-6R may be a potential therapeutic target for IS. Tocilizumab, a monoclonal antibody that blocks both membrane-bound and circulating IL-6R, might be effective in treating IS or lowering its risk of development, so warrants further testing in suitably powered randomized controlled trials.


2020 ◽  
Author(s):  
Lin Zhao ◽  
Yuhui Li ◽  
Zhen Zhang ◽  
Hong Guo ◽  
Jianfu Li ◽  
...  

Abstract Background Ovarian cancer causes high mortality rate worldwide, and despite numerous attempts, the outcome for patients with ovarian cancer are still not well improved. Microarray based gene expressional analysis provides with valuable information for discriminating functional genes in ovarian cancer development and progression. However, due to the differences in experimental design, the results varied significantly across individual datasets. Methods In the present study, the data of gene expression in ovarian cancer was downloaded from Gene Expression Omnibus and 16 studies were included. A meta-analysis based gene expression analysis was performed to identify differentially expressed genes (DEGs). The most differentially expressed genes in our meta-analysis were selected for gene expression and gene function validation. Results A total of 972 DEGs with P -value<0.001 were identified in ovarian cancer, including 541 up-regulated genes and 431 down-regulated genes, among which 92 additional DEGs were found as gained DEGs. Top five up-and down-regulated genes were selected for the validation of gene expressional profiling. Among these genes, up-regulated CD24 , SOX17 , WFDC2 , EPCAM , INAVA , and down-regulated AOX1 were revealed to be with consistent expressional patterns in clinical patient samples of ovarian cancer. Gene functional analysis demonstrated that up-regulated WFCD2 and INAVA promoted ovarian cancer cell migration, WFDC2 enhanced cell proliferation, while down-regulated AOX1 was functional in inducing cell apoptosis of ovarian cancer. Interestingly. Conclusion Our study shed light on the molecular mechanisms underlying the development of ovarian cancer, and facilitated the understanding of novel diagnostic and therapeutic targets in ovarian cancer.


2020 ◽  
Author(s):  
Haihua Zhang ◽  
Wenbo Zhao ◽  
Bian Liu ◽  
Tao Wang ◽  
Zhifa Han ◽  
...  

Abstract BackgroundInterleukin-6 (IL-6) signaling is associated with the increased risk of coronary artery disease (CAD) and ischemic stroke (IS). Growing evidence shows that the minor allele of IL-6R rs7529229 variant could significantly increase the soluble IL-6 receptor levels and reduce CAD risk. However, it is largely unknown about the role of rs7529229 in IS, which promotes us to perform a comprehensive analysis. MethodsIn stage 1, we performed a meta-analysis of three GWAS datasets from MEGASTROKE, UK Biobank, and Million Veteran Program to evaluate the association of rs7529229 with IS. In stage 2, we conducted an expression quantitative trait loci analysis to examine the effects of rs7529229 on IL-6R expression in neuropathologically normal individuals from UK Brain Expression Consortium, GTEx project and eQTLGen Consortium. In stage 3, a tissue-specific gene expression analysis is used to evaluate the potential difference of IL-6R expression across the human tissues using gene expression data from GTEx. In stage 4, a case-control gene expression analysis is used to explore the potentially differential expression of IL-6R in IS and healthy controls in whole blood. ResultsOur results show that (1) rs7529229 minor allele could significantly reduce the risk of IS (OR=0.97, 95% CI 0.95-0.99, P=2.30E-03); (2) rs7529229 minor allele could significantly reduce IL-6R expression in relevant tissues especially in blood vessels and whole blood; (3) IL-6R is mainly expressed in skeletal muscle and whole blood; (4) expression of IL-6R is significantly reduced in healthy controls compared with IS cases in whole blood. Importantly, the biological senses in stage 1-4 are all convergent. ConclusionsCollectively, these findings indicate that rs7529229 minor allele may first reduce IL-6R expression in relevant tissues, further reduce IL-6 signaling, and eventually reduce the IS risk. Hence, IL-6R may be a potential therapeutic target, and blocking IL-6 signaling might be effective in treatment of IS.


2020 ◽  
Vol 26 ◽  
Author(s):  
Abdulqader Fadhil Abed ◽  
Yazun Bashir Jarrar ◽  
Hamzeh J Al-Ameer ◽  
Wajdy Al-Awaida ◽  
Su-Jun Lee

Background: Oxandrolone is a synthetic testosterone analogue that is widely used among bodybuilders and athletes. However, oxandrolone causes male infertility. Recently, it was found that metformin reduces the risk of infertility associated with diabetes mellitus. Aim: This study aimed to investigate the protective effects of metformin against oxandrolone-induced infertility in male rats. Methods: Rats continuously received one of four treatments (n=7) over 14 days: control DMSO administration, oxandrolone administration, metformin administration, or co-administration of oxandrolone and metformin. Doses were equivalent to those used for human treatment. Subsequently, testicular and blood samples were collected for morphological, biochemical, and histological examination. In addition, gene expression of the testosterone synthesizing enzyme CYP11A1 was analyzed in the testes using RT-PCR. Results: Oxandrolone administration induced male infertility by significantly reducing relative weights of testes by 48%, sperm count by 82%, and serum testosterone levels by 96% (ANOVA, P value < 0.05). In addition, histological examination determined that oxandrolone caused spermatogenic arrest which was associated with 2-fold downregulation of testicular CYP11A1 gene expression. However, co-administration of metformin with oxandrolone significantly ameliorated toxicological alterations induced by oxandrolone exposure (ANOVA, P value < 0.05). Conclusion: Metformin administration protected against oxandrolone-induced infertility in male rats. Further clinical studies are needed to confirm the protective effect of metformin against oxandrolone-induced infertility among athletes.


2020 ◽  
Vol 20 (7) ◽  
pp. 518-523
Author(s):  
Rugül Köse Çinar

Objective: Neuroserpin is a serine protease inhibitor predominantly expressed in the nervous system functioning mainly in neuronal migration and axonal growth. Neuroprotective effects of neuroserpin were shown in animal models of stroke, brain, and spinal cord injury. Postmortem studies confirmed the involvement of neuroserpin in Alzheimer’s disease. Since altered adult neurogenesis was postulated as an aetiological mechanism for bipolar disorder, the possible effect of neuroserpin gene expression in the disorder was evaluated. Methods: Neuroserpin mRNA expression levels were examined in the peripheral blood of bipolar disorder type I manic and euthymic patients and healthy controls using the polymerase chain reaction method. The sample comprised of 60 physically healthy, middle-aged men as participants who had no substance use disorder. Results: The gene expression levels of neuroserpin were found lower in the bipolar disorder patients than the healthy controls (p=0.000). The neuroserpin levels did not differ between mania and euthymia (both 96% down-regulated compared to the controls). Conclusion: Since we detected differences between the patients and the controls, not the disease states, the dysregulation in the neuroserpin gene could be interpreted as a result of the disease itself.


2020 ◽  
Author(s):  
Dr. Animesh Ray ◽  
Dr. Komal Singh ◽  
Souvick Chattopadhyay ◽  
Farha Mehdi ◽  
Dr. Gaurav Batra ◽  
...  

BACKGROUND Seroprevalence of IgG antibodies against SARS-CoV-2 is an important tool to estimate the true extent of infection in a population. However, seroprevalence studies have been scarce in South East Asia including India, which, as of now, carries the third largest burden of confirmed cases in the world. The present study aimed to estimate the seroprevalence of anti-SARS-CoV-2 IgG antibody among hospitalized patients at one of the largest government hospital in India OBJECTIVE The primary objective of this study is to estimate the seroprevalence of SARS-CoV-2 antibody among patients admitted to the Medicine ward and ICU METHODS This cross-sectional study, conducted at a tertiary care hospital in North India, recruited consecutive patients who were negative for SARS-CoV-2 by RT-PCR or CB-NAAT. Anti-SARS-CoV-2 IgG antibody levels targeting recombinant spike receptor-binding domain (RBD) protein of SARS CoV-2 were estimated in serum sample by the ELISA method RESULTS A total of 212 hospitalized patients were recruited in the study with mean age (±SD) of 41.2 (±15.4) years and 55% male population. Positive serology against SARS CoV-2 was detected in 19.8%patients(95% CI 14.7-25.8). Residency in Delhi conferred a higher frequency of seropositivity 26.5% (95% CI 19.3-34.7) as compared to that of other states 8% (95% CI 3.0-16.4) with p-value 0.001. No particular age groups or socio-economic strata showed a higher proportion of seropositivity CONCLUSIONS Around, one-fifth of hospitalized patients, who were not diagnosed with COVID-19 before, demonstrated seropositivity against SARS-CoV-2. While there was no significant difference in the different age groups and socio-economic classes; residence in Delhi was associated with increased risk (relative risk of 3.62, 95% CI 1.59-8.21)


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