scholarly journals Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jessika Nordin ◽  
Mats Pettersson ◽  
Lina Hultin Rosenberg ◽  
Argyri Mathioudaki ◽  
Åsa Karlsson ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ankylosing Spondylitis ◽  
Protein Coding ◽  
Female Population ◽  
Risk Variants ◽  
Disease Predisposition ◽  
Hla Dqa1 ◽  
Coding Variants ◽  
The Impact

ObjectivesTo further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease.MethodsHigh-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined.ResultsTwenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations.ConclusionPopulation stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.

scholarly journals Genomic and functional analysis of Romboutsia ilealis CRIBT reveals adaptation to the small intestine

2017 ◽  
Author(s):  
Jacoline Gerritsen ◽  
Bastian Hornung ◽  
Bernadette Renckens ◽  
Sacha A.F.T. van Hijum ◽  
Vitor A.P. Martins dos Santos ◽  
...  
Keyword(s):  
Amino Acids ◽  
Small Intestine ◽  
Short Chain Fatty Acids ◽  
Limited Capacity ◽  
Illumina Hiseq ◽  
Circular Chromosome ◽  
Protein Coding ◽  
Mate Pair ◽  
Simple Carbohydrates

Background. The microbiota in the small intestine relies on their capacity to rapidly import and ferment available carbohydrates to survive in a complex and highly competitive ecosystem. Understanding how these communities function requires elucidating the role of its key players, the interactions among them and with their environment/host. Methods. The genome of the gut bacterium Romboutsia ilealis CRIBT was sequenced with multiple technologies (Illumina paired end, mate pair and PacBio). The transcriptome was sequenced (Illumina HiSeq) while growing on three different carbohydrate sources and short chain fatty acids were measured via HPLC. Results. Hence, we present the complete genome of Romboutsia ilealis CRIBT, a natural inhabitant and key player of the small intestine of rats. R. ilealis CRIBT possesses a circular chromosome of 2,581,778 bp and a plasmid of 6,145 bp, carrying 2,351 and eight predicted protein coding sequences, respectively. Analysis of the genome revealed limited capacity to synthesize amino acids and vitamins, whereas multiple and partially redundant pathways for the utilization of different relatively simple carbohydrates are present. Transcriptome analysis allowed pinpointing the key components in the degradation of glucose, L-fucose and fructo-oligosaccharides. Discussion. This revealed that R. ilealis CRIBT is adapted to a nutrient-rich environment where carbohydrates, amino acids and vitamins are abundantly available and uncovered potential mechanisms for competition with mucus-degrading microbes.

scholarly journals Impact of the trace element status on the course of ankylosing spondylitis in the Orenburg Region patients

2019 ◽  
Vol 13 (4) ◽  
pp. 66-74
Author(s):  
U. A. Yakubova ◽  
O. V. Bugrova ◽  
S. I. Krasikov ◽  
N. P. Setko ◽  
R. I. Saifutdirov
Keyword(s):  
Ankylosing Spondylitis ◽  
Inflammatory Diseases ◽  
Clinical Manifestations ◽  
Atomic Absorption Spectrophotometry ◽  
Zn Deficiency ◽  
Orenburg Region ◽  
And Zn Deficiency ◽  
Trace Element Status ◽  
The Impact

The role of trace elements (TEs) and their imbalance in the physiology of bone tissue and in the development of inflammatory diseases of the joints and spine has been discussed in recent years; however, there is no evidence for the TE status of patients with ankylosing spondylitis (AS) and its possible impact on the course of the disease.Objective: to investigate the impact of the TE status of patients with AS on the course, clinical manifestations, and activity of the disease.Patients and methods. Examinations were made in 58 patients (39 men and 19 women), residents of the Orenburg Region, with a reliable diagnosis of AS, the duration of which was 16 [11; 26] years. The patients’ mean age was 38 [31; 48] years. HLA-B27 antigen was detected in 91.4% of cases. In addition to the generally accepted examination, atomic absorption spectrophotometry was used to determine the hair levels of 9 TEs: Cu, Zn, Fe, Mn, Cr, Co, Ni, Pb, and Cd in all the patients.Results and discussion. The AS patients living in the Orenburg Region showed TE imbalance manifested by Cu and Zn deficiency and Ni, Cr, and Mn accumulation in the hair. Multidirectional correlations were found between the values of these TEs and the presence of extra-axial (peripheral arthritis, dactylitis) and extra-skeletal (uveitis) manifestations of AS, its activity, and severity of functional disorders.Conclusion. The preliminary results may suggest that the emerging imbalance of TEs can affect the course of AS, maintaining and increasing its activity.

scholarly journals Contribution of retrotransposition to developmental disorders

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Eugene J. Gardner ◽  
Elena Prigmore ◽  
Giuseppe Gallone ◽  
Petr Danecek ◽  
Kaitlin E. Samocha ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Selective Constraint ◽  
Protein Coding ◽  
Genome Wide ◽  
De Novo Gene ◽  
The Impact ◽  
Transcribed Sequences

Abstract Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

scholarly journals Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

2020 ◽  
Vol 13 (4) ◽  
Author(s):  
Zhe Wang ◽  
Han Chen ◽  
Traci M. Bartz ◽  
Lawrence F. Bielak ◽  
Daniel I. Chasman ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Plasma Lipid ◽  
Low Frequency ◽  
Environment Interaction ◽  
Lipid Levels ◽  
Protein Coding ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Coding Variants

Background: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. Methods: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. Results: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci ( PCSK9 , LPA , LPL , LIPG , ANGPTL4 , APOB , APOC3 , and CD300LG ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered ( P =6.65×10 −6 for the interaction test) and replicated at nominal significance level ( P =0.013) in SMC5 . Conclusions: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

scholarly journals Functional Interpretation of Genetic Variants Using Deep Learning Predicts Impact on Epigenome

2018 ◽  
Author(s):  
Gabriel E. Hoffman ◽  
Eric E. Schadt ◽  
Panos Roussos
Keyword(s):  
Deep Learning ◽  
Dna Sequence ◽  
Genetic Variants ◽  
Disease Risk ◽  
Functional Interpretation ◽  
Protein Coding ◽  
Functional Consequence ◽  
Risk Variants ◽  
Causal Variants ◽  
Coding Variants

ABSTRACTIdentifying causal variants underling disease risk and adoption of personalized medicine are currently limited by the challenge of interpreting the functional consequences of genetic variants. Predicting the functional effects of disease-associated protein-coding variants is increasingly routine. Yet the vast majority of risk variants are non-coding, and predicting the functional consequence and prioritizing variants for functional validation remains a major challenge. Here we develop a deep learning model to accurately predict locus-specific signals from four epigenetic assays using only DNA sequence as input. Given the predicted epigenetic signal from DNA sequence for the reference and alternative alleles at a given locus, we generate a score of the predicted epigenetic consequences for 438 million variants. These impact scores are assay-specific, are predictive of allele-specific transcription factor binding and are enriched for variants associated with gene expression and disease risk. Nucleotide-level functional consequence scores for non-coding variants can refine the mechanism of known causal variants, identify novel risk variants and prioritize downstream experiments.

scholarly journals The Intestinal Microbiota Interferes with the microRNA Response upon Oral Listeria Infection

mBio ◽  
2013 ◽  
Vol 4 (6) ◽  
Author(s):  
Cristel Archambaud ◽  
Odile Sismeiro ◽  
Joern Toedling ◽  
Guillaume Soubigou ◽  
Christophe Bécavin ◽  
...  
Keyword(s):  
Bacterial Infection ◽  
Intestinal Microbiota ◽  
Mirna Expression ◽  
Target Genes ◽  
Host Protein ◽  
Protein Coding ◽  
Content Type ◽  
Protein Coding Genes ◽  
The Impact

ABSTRACT The intestinal tract is the largest reservoir of microbes in the human body. The intestinal microbiota is thought to be able to modulate alterations of the gut induced by enteropathogens, thereby maintaining homeostasis. Listeria monocytogenes is the agent of listeriosis, an infection transmitted to humans upon ingestion of contaminated food. Crossing of the intestinal barrier is a critical step of the infection before dissemination into deeper organs. Here, we investigated the role of the intestinal microbiota in the regulation of host protein-coding genes and microRNA (miRNA or miR) expression during Listeria infection. We first established the intestinal miRNA signatures corresponding to the 10 most highly expressed miRNAs in the murine ileum of conventional and germfree mice, noninfected and infected with Listeria. Next, we identified 6 miRNAs whose expression decreased upon Listeria infection in conventional mice. Strikingly, five of these miRNA expression variations (in miR-143, miR-148a, miR-200b, miR-200c, and miR-378) were dependent on the presence of the microbiota. In addition, as is already known, protein-coding genes were highly affected by infection in both conventional and germfree mice. By crossing bioinformatically the predicted targets of the miRNAs to our whole-genome transcriptomic data, we revealed an miRNA-mRNA network that suggested miRNA-mediated global regulation during intestinal infection. Other recent studies have revealed an miRNA response to either bacterial pathogens or commensal bacteria. In contrast, our work provides an unprecedented insight into the impact of the intestinal microbiota on host transcriptional reprogramming during infection by a human pathogen. IMPORTANCE While the crucial role of miRNAs in regulating the host response to bacterial infection is increasingly recognized, the involvement of the intestinal microbiota in the regulation of miRNA expression has not been explored in detail. Here, we investigated the impact of the intestinal microbiota on the regulation of protein-coding genes and miRNA expression in a host infected by L. monocytogenes, a food-borne pathogen. We show that the microbiota interferes with the microRNA response upon oral Listeria infection and identify several protein-coding target genes whose expression correlates inversely with that of the miRNA. Further investigations of the regulatory networks involving miR-143, miR-148a, miR-200b, miR-200c, and miR-378 will provide new insights into the impact of the intestinal microbiota on the host upon bacterial infection.

scholarly journals Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

2021 ◽  
Author(s):  
Xiaoming Jia ◽  
Fernando S. Goes ◽  
Adam E. Locke ◽  
Duncan Palmer ◽  
Weiqing Wang ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Meta Analysis ◽  
Common Variant ◽  
European Ancestry ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Protein Coding ◽  
Significant Enrichment ◽  
Coding Variants

AbstractBipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

scholarly journals Follicular fluid metabolome and cytokinome profiles in poor ovarian responders and the impact of dehydroepiandrosterone supplementation

2020 ◽  
Author(s):  
Veronique Viardot-Foucault ◽  
Jieliang Zhou ◽  
Dexi Bi ◽  
Yoshihiko Takinami ◽  
Heng Hao Tan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Follicular Fluid ◽  
Lower Number ◽  
Vitro Fertilization ◽  
Future Studies ◽  
Poor Ovarian Responders ◽  
The Impact

AbstractPoor ovarian responders (POR) are women undergoing in-vitro fertilization who respond poorly to ovarian stimulation, resulting in the retrieval of lower number of oocytes, and subsequently lower pregnancy rates. The follicular fluid (FF) provides a crucial microenvironment for the proper development of follicles and oocytes. Conversely, dysregulated FF metabolome and cytokinome could have detrimental effects on oocytes in POR. Androgens such as dehydroepiandrosterone (DHEA) have been proposed to alter the POR follicular microenvironment but its effects on the FF metabolome and cytokine profiles is unknown. In this study, untargeted LC-MS/MS metabolomics was performed on FF of POR patients with DHEA supplementation (DHEA+) and without (DHEA-) in a randomized clinical trial (N=52). Untargeted metabolomics identified 118 FF metabolites of diverse chemistries, which included lipids, steroids, amino acids, hormones, among others. FF metabolomes were different between DHEA+ and DHEA- groups. Specifically, glycerophosphocholine, linoleic acid, progesterone, and valine were significantly lower in DHEA+ relative to DHEA-. Among cytokines, MCP1, IFNγ, LIF and VEGF-D were significantly lower in DHEA+ relative to DHEA. Collectively, our data suggest a role of DHEA on these metabolic and cytokines pathways, and these FF metabolites could be used to guide future studies in DHEA supplementation regimen.

scholarly journals The emerging role of the first 17 amino acids of huntingtin in Huntington’s disease

2015 ◽  
Vol 6 (1) ◽  
pp. 33-46 ◽  
Author(s):  
James R. Arndt ◽  
Maxmore Chaibva ◽  
Justin Legleiter
Keyword(s):  
Amino Acids ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Aggregate Stability ◽  
Biochemical Properties ◽  
Critical Threshold ◽  
N Terminus ◽  
The Impact ◽  
Polyq Domain

AbstractHuntington’s disease (HD) is caused by a polyglutamine (polyQ) domain that is expanded beyond a critical threshold near the N-terminus of the huntingtin (htt) protein, directly leading to htt aggregation. While full-length htt is a large (on the order of ∼350 kDa) protein, it is proteolyzed into a variety of N-terminal fragments that accumulate in oligomers, fibrils, and larger aggregates. It is clear that polyQ length is a key determinant of htt aggregation and toxicity. However, the flanking sequences around the polyQ domain, such as the first 17 amino acids on the N terminus (Nt17), influence aggregation, aggregate stability, influence other important biochemical properties of the protein and ultimately its role in pathogenesis. Here, we review the impact of Nt17 on htt aggregation mechanisms and kinetics, structural properties of Nt17 in both monomeric and aggregate forms, the potential role of posttranslational modifications (PTMs) that occur in Nt17 in HD, and the function of Nt17 as a membrane targeting domain.

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