Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a ...higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10
, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10
, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10
, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10
, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10
, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors.
Accurate placenta pathology assessment is essential for managing maternal and newborn health, but the placenta's heterogeneity and temporal variability pose challenges for histology analysis. To ...address this issue, we developed the 'Histology Analysis Pipeline.PY' (HAPPY), a deep learning hierarchical method for quantifying the variability of cells and micro-anatomical tissue structures across placenta histology whole slide images. HAPPY differs from patch-based features or segmentation approaches by following an interpretable biological hierarchy, representing cells and cellular communities within tissues at a single-cell resolution across whole slide images. We present a set of quantitative metrics from healthy term placentas as a baseline for future assessments of placenta health and we show how these metrics deviate in placentas with clinically significant placental infarction. HAPPY's cell and tissue predictions closely replicate those from independent clinical experts and placental biology literature.
The pathogenesis of type 2 diabetes (T2D) might change with increasing age. Here, we used a stratification based on age of diagnosis to gain insight into the genetics and causal risk factors of T2D ...across different age-groups. We performed genome-wide association studies (GWAS) on T2D and T2D subgroups based on age of diagnosis (<50, 50-60, 60-70, and >70 years) (total of 24,986 cases). As control subjects, participants were at least 70 years of age at the end of follow-up without developing T2D (
=187,130). GWAS identified 208 independent lead single nucleotide polymorphism (SNPs) mapping to 69 loci associated with T2D (
< 1.0e-8). Among others, SNPs mapped to
and multiple independent SNPs mapped to
were more strongly associated with cases diagnosed after age 70 years than with cases diagnosed before age 50 years. Based on the different case groups, we performed two-sample Mendelian randomization. Most notably, we observed that of the investigated risk factors, the association between BMI and T2D attenuated with increasing age of diagnosis. Collectively, our results indicate that stratification of T2D based on age of diag-nosis reveals subgroup-specific genetics and causal determinants, supporting the hypothesis that the pathogenesis of T2D changes with increasing age.
Abstract
Pelvic organ prolapse is a common gynecological condition with limited understanding of its genetic background. In this work, we perform a genome-wide association meta-analysis comprising ...28,086 cases and 546,291 controls from European ancestry. We identify 19 novel genome-wide significant loci, highlighting connective tissue, urogenital and cardiometabolic as likely affected systems. Here, we prioritize many genes of potential interest and assess shared genetic and phenotypic links. Additionally, we present the first polygenic risk score, which shows similar predictive ability (Harrell C-statistic (C-stat) 0.583, standard deviation (sd) = 0.007) as five established clinical risk factors combined (number of children, body mass index, ever smoked, constipation and asthma) (C-stat = 0.588, sd = 0.007) and demonstrates a substantial incremental value in combination with these (C-stat = 0.630, sd = 0.007). These findings improve our understanding of genetic factors underlying pelvic organ prolapse and provide a solid start evaluating polygenic risk scores as a potential tool to enhance individual risk prediction.
Previous transcriptome studies of the human endometrium have revealed hundreds of simultaneously up- and down-regulated genes that are involved in endometrial receptivity. However, the overlap ...between the studies is relatively small, and we are still searching for potential diagnostic biomarkers. Here we perform a meta-analysis of endometrial-receptivity associated genes on 164 endometrial samples (76 from 'pre-receptive' and 88 from mid-secretory, 'receptive' phase endometria) using a robust rank aggregation (RRA) method, followed by enrichment analysis, and regulatory microRNA prediction. We identify a meta-signature of endometrial receptivity involving 57 mRNA genes as putative receptivity markers, where 39 of these we confirm experimentally using RNA-sequencing method in two separate datasets. The meta-signature genes highlight the importance of immune responses, the complement cascade pathway and the involvement of exosomes in mid-secretory endometrial functions. Bioinformatic prediction identifies 348 microRNAs that could regulate 30 endometrial-receptivity associated genes, and we confirm experimentally the decreased expression of 19 microRNAs with 11 corresponding up-regulated meta-signature genes in our validation experiments. The 57 identified meta-signature genes and involved pathways, together with their regulatory microRNAs could serve as promising and sought-after biomarkers of endometrial receptivity, fertility and infertility.
Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has ...further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.
The mechanisms underlying the formation of the ovarian reserve are generally well conserved, from Drosophila to mammals. Owing to this high degree of conservation, factors shown to regulate the ovarian reserve in mouse models are all potential candidates for identifying mutations associated with POI in humans.
With the generation of genetically modified mice, much insight has been gained into the mechanisms that control the formation of the ovarian reserve and trigger the activation of primordial follicles.
Comparison with animal models is complicated by the fact that the phenotype of complete gene deletion in knockout models may not be mimicked by single gene mutations.
Recently innovative treatment for POI based on in vitro activation of the dormant primordial follicular pool has been developed.
The era of precision medicine requires the achievement of accurate risk assessment. Polygenic risk scores (PRSs) have strong potential for increasing the benefits of nationwide cancer screening ...programs. The current pool of evidence on the role of a PRS as a risk stratification model in actual practice and implementation is limited. To better understand the impact of possible method-induced variance, we constructed and validated two PRSs for cervical cancer (CC) using the Estonian Biobank female population (691 CC cases and 13,820 controls) and evaluated their utility in predicting incident cervical neoplasia (CIN), cancer, and human papillomavirus (HPV) infection using two methods (LDPred and BayesRR-RC). This study demonstrated that two genetic risk scores were significantly associated with CIN, CC, and HPV infection incidence. Independent of the method, we demonstrated that women with elevated PRS values reached the observed cumulative risk levels of CIN or CC much earlier. Our results indicated that the PRS-based discrimination rules could differ substantially when the PRSs contain similar predictive information. In summary, our analysis indicated that PRSs represent a personalized genetic component that could be an additional tool for cervical cancer risk stratification, and earlier detection of abnormalities provides invaluable information for those at high risk.
The inner uterine lining (endometrium) is a unique tissue going through remarkable changes each menstrual cycle. Endometrium has its characteristic DNA methylation profile, although not much is known ...about the endometrial methylome changes throughout the menstrual cycle. The impact of methylome changes on gene expression and thereby on the function of the tissue, including establishing receptivity to implanting embryo, is also unclear. Therefore, this study used genome-wide technologies to characterize the methylome and the correlation between DNA methylation and gene expression in endometrial biopsies collected from 17 healthy fertile-aged women from pre-receptive and receptive phase within one menstrual cycle. Our study showed that the overall methylome remains relatively stable during this stage of the menstrual cycle, with small-scale changes affecting 5% of the studied CpG sites (22,272 out of studied 437,022 CpGs, FDR < 0.05). Of differentially methylated CpG sites with the largest absolute changes in methylation level, approximately 30% correlated with gene expression measured by RNA sequencing, with negative correlations being more common in 5' UTR and positive correlations in the gene 'Body' region. According to our results, extracellular matrix organization and immune response are the pathways most affected by methylation changes during the transition from pre-receptive to receptive phase.
Accumulating data have shown the involvement of microRNAs (miRNAs) in endometriosis pathogenesis. In this study, we used a novel approach to determine the endometriotic lesion-specific miRNAs by ...high-throughput small RNA sequencing of paired samples of peritoneal endometriotic lesions and matched healthy surrounding tissues together with eutopic endometria of the same patients. We found five miRNAs specific to epithelial cells--miR-34c, miR-449a, miR-200a, miR-200b and miR-141 showing significantly higher expression in peritoneal endometriotic lesions compared to healthy peritoneal tissues. We also determined the expression levels of miR-200 family target genes E-cadherin, ZEB1 and ZEB2 and found that the expression level of E-cadherin was significantly higher in endometriotic lesions compared to healthy tissues. Further evaluation verified that studied miRNAs could be used as diagnostic markers for confirming the presence of endometrial cells in endometriotic lesion biopsy samples. Furthermore, we demonstrated that the miRNA profile of peritoneal endometriotic lesion biopsies is largely masked by the surrounding peritoneal tissue, challenging the discovery of an accurate lesion-specific miRNA profile. Taken together, our findings indicate that only particular miRNAs with a significantly higher expression in endometriotic cells can be detected from lesion biopsies, and can serve as diagnostic markers for endometriosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Broad interests reap benefits for science Adamowicz, Beth M; Chong, Derrick Ho Yan; Gutiérrez, Christopher ...
Science (American Association for the Advancement of Science),
07/2018, Letnik:
361, Številka:
6397
Journal Article
Recenzirano
We asked young scientists this question: How do broad interests benefit your science? Scientists with a variety of hobbies responded that their extracurricular activities have enhanced a wide range ...of skills, from creativity to communication to resilience. Many also mentioned the value of clearing their minds and relaxing.
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