Specific Gene Variants Research Articles

From Feeding Challenges to Oral-Motor Dyspraxia: A Comprehensive Description of 10 New Cases with CTNNB1 Syndrome.

CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-score equivalent was 43.1 ± 7.5. These findings contribute to the understanding of the CTNNB1 syndrome highlighting the oral motor phenotype, and correlating specific gene variants with clinical characteristics.

Gene-based burden scores identify rare variant associations for 28 blood biomarkers

BackgroundA relevant part of the genetic architecture of complex traits is still unknown; despite the discovery of many disease-associated common variants. Polygenic risk score (PRS) models are based on the evaluation of the additive effects attributable to common variants and have been successfully implemented to assess the genetic susceptibility for many phenotypes. In contrast, burden tests are often used to identify an enrichment of rare deleterious variants in specific genes. Both kinds of genetic contributions are typically analyzed independently. Many studies suggest that complex phenotypes are influenced by both low effect common variants and high effect rare deleterious variants. The aim of this paper is to integrate the effect of both common and rare functional variants for a more comprehensive genetic risk modeling.MethodsWe developed a framework combining gene-based scores based on the enrichment of rare functionally relevant variants with genome-wide PRS based on common variants for association analysis and prediction models. We applied our framework on UK Biobank dataset with genotyping and exome data and considered 28 blood biomarkers levels as target phenotypes. For each biomarker, an association analysis was performed on full cohort using gene-based scores (GBS). The cohort was then split into 3 subsets for PRS construction and feature selection, predictive model training, and independent evaluation, respectively. Prediction models were generated including either PRS, GBS or both (combined).ResultsAssociation analyses of the cohort were able to detect significant genes that were previously known to be associated with different biomarkers. Interestingly, the analyses also revealed heterogeneous effect sizes and directionality highlighting the complexity of the blood biomarkers regulation. However, the combined models for many biomarkers show little or no improvement in prediction accuracy compared to the PRS models.ConclusionThis study shows that rare variants play an important role in the genetic architecture of complex multifactorial traits such as blood biomarkers. However, while rare deleterious variants play a strong role at an individual level, our results indicate that classical common variant based PRS might be more informative to predict the genetic susceptibility at the population level.

Estudio de variantes genéticas en 169 pacientes de cáncer de pulmón no microcítico

IntroductionLung cancer is the leading cause of cancer death in our country. Non-small cell lung cancer (NSCLC) represents the paradigm of personalized medicine. The main objective of this study is analysing the distribution of the most frequently described clinically significant variants in NSCLC, in our environment. Material and methodsWe studied the immunohistochemical expression of TTF1, p40 and PD-L1 and the genetic variants frequency using Next-Generation Sequencing (NGS) with a panel of 52 genes, in 174 NSCLC paraffin-embedded samples in 169 patients (111 men and 52 women) from the province of Cádiz. ResultsThe immunohistochemical expression of TTF1, p40 and PD-L1 was positive in 87%, 0% and 46% in adenocarcinoma, and 0%, 100% and 41% in squamous cell carcinoma. In NGS, the most common single nucleotide variants (SNVs) were KRAS (36%), EGFR (14%), BRAF (10%), PIK3CA (8%), and MET (3%). The most frequent copy number variants (CNVs) were amplifications in NF1 (30%), EGFR (18%), CCND1 (9%), MYC (9%) and KRAS (7%). In women, SNV in EGFR are more frequent than in men (P<.0001). Adenocarcinoma is the most frequent histological type with SNV in KRAS (P=.007361) or in EGFR (P<.0001). Gene fusions were detected in 16 patients (9.47%), in 9 cases in the MET gene. ConclusionsWe detected associations, not described so far, between immunohistochemical expression and specific gene variants, which could have an impact on the treatment of NSCLC patients.

A Comprehensive Genome-Wide Investigation of the Cytochrome 71 (OsCYP71) Gene Family: Revealing the Impact of Promoter and Gene Variants (Ser33Leu) of OsCYP71P6 on Yield-Related Traits in Indica Rice (Oryza sativa L.).

The cytochrome P450 (CYP450) gene family plays a critical role in plant growth and developmental processes, nutrition, and detoxification of xenobiotics in plants. In the present research, a comprehensive set of 105 OsCYP71 family genes was pinpointed within the genome of indica rice. These genes were categorized into twelve distinct subfamilies, where members within the same subgroup exhibited comparable gene structures and conserved motifs. In addition, 105 OsCYP71 genes were distributed across 11 chromosomes, and 36 pairs of OsCYP71 involved in gene duplication events. Within the promoter region of OsCYP71, there exists an extensive array of cis-elements that are associated with light responsiveness, hormonal regulation, and stress-related signaling. Further, transcriptome profiling revealed that a majority of the genes exhibited responsiveness to hormones and were activated across diverse tissues and developmental stages in rice. The OsCYP71P6 gene is involved in insect resistance, senescence, and yield-related traits in rice. Hence, understanding the association between OsCYP71P6 genetic variants and yield-related traits in rice varieties could provide novel insights for rice improvement. Through the utilization of linear regression models, a total of eight promoters were identified, and a specific gene variant (Ser33Leu) within OsCYP71P6 was found to be linked to spikelet fertility. Additionally, different alleles of the OsCYP71P6 gene identified through in/dels polymorphism in 131 rice varieties were validated for their allelic effects on yield-related traits. Furthermore, the single-plant yield, spikelet number, panicle length, panicle weight, and unfilled grain per panicle for the OsCYP71P6-1 promoter insertion variant were found to contribute 20.19%, 13.65%, 5.637%, 8.79%, and 36.86% more than the deletion variant, respectively. These findings establish a robust groundwork for delving deeper into the functions of OsCYP71-family genes across a range of biological processes. Moreover, these findings provide evidence that allelic variation in the promoter and amino acid substitution of Ser33Leu in the OsCYP71P6 gene could potentially impact traits related to rice yield. Therefore, the identified promoter variants in the OsCYP71P6 gene could be harnessed to amplify rice yields.

Soluble TREM2 Concentrations in the Cerebrospinal Fluid Correlate with the Severity of Neurofibrillary Degeneration, Cognitive Impairment, and Inflammasome Activation in Alzheimer's Disease.

Individuals with specific TREM2 gene variants that encode for a Triggering Receptor Expressed on Myeloid cells 2 have a higher prevalence of Alzheimer's disease (AD). By interacting with amyloid and apolipoproteins, the TREM2 receptor regulates the number of myeloid cells, phagocytosis, and the inflammatory response. Higher TREM2 expression has been suggested to protect against AD. However, it is extremely difficult to comprehend TREM2 signaling in the context of AD. Previous results are variable and show distinct effects on diverse pathological changes in AD, differences between soluble and membrane isoform signaling, and inconsistency between animal models and humans. In addition, the relationship between TREM2 and inflammasome activation pathways is not yet entirely understood. This study aimed to determine the relationship between soluble TREM2 (sTREM2) levels in cerebrospinal fluid (CSF) and plasma samples and other indicators of AD pathology. Using the Enzyme-Linked Immunosorbent Assay (ELISA), we analyzed 98 samples of AD plasma, 35 samples of plasma from individuals with mild cognitive impairment (MCI), and 11 samples of plasma from healthy controls (HC), as well as 155 samples of AD CSF, 90 samples of MCI CSF, and 50 samples of HC CSF. CSF sTREM2 levels were significantly correlated with neurofibrillary degeneration, cognitive decline, and inflammasome activity in AD patients. In contrast to plasma sTREM2, CSF sTREM2 levels in the AD group were higher than those in the MCI and HC groups. Moreover, concentrations of sTREM2 in CSF were substantially higher in the MCI group than in the HC group, indicating that CSF sTREM2 levels could be used not only to distinguish between HC and AD patients but also as a biomarker to detect earlier changes in the MCI stage. The results indicate CSF sTREM2 levels reliably predict neurofibrillary degeneration, cognitive decline, and inflammasome activation, and also have a high diagnostic potential for distinguishing diseased from healthy individuals. To add sTREM2 to the list of required AD biomarkers, future studies will need to include a larger number of patients and utilize a standardized methodology.

Clinical significance of mutational variants in beta and alpha genes in patients with hemoglobinopathies from two large Greek centers: a complex interplay between genotype and phenotype.

Hemoglobinopathies affect patients in the wider Mediterranean area consisting of 4 distinct subgroups: beta thalassemia major (TM), beta thalassemia intermedia (TI), sickle cell disease (SCD) and hemoglobin H disease (alpha thalassemia). The clinical spectrum varies from mild to severe. Complex interactions between genes and environmental factors form the clinical manifestations. There is an unmet need to clarify these multifactorial mechanisms.This is the first Greek study describing mutational alleles (HBB and HBA1/HBA2 gene variants) in 217 patients with hemoglobinopathies of two large centers in Greece (Larissa and Athens) and associating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). Thus, the complex interplay between corresponding genotypes and phenotypes was investigated.Our results are in accordance with previous national studies with limited variations, due to regional prevalence of specific gene variants, as expected. It is also a description of the prevalence of hemoglobinopathies in the Greek population. The type and prevalence of beta and alpha globin gene variants differ significantly among countries. We also confirm the well-known observation of many studies that in our beta thalassemic or SCD patients, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course, whereas the inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype.In cases in whom the genotype and phenotype did not correlate, factors like the function or modification of possible regulatory genes or additional nutritional-environmental effects should be investigated. KEY MESSAGES: • This is the first Greek study, fully molecularly defining the beta and alpha mutational alleles in 217 patients with hemoglobinopathies of two large centers in Greece and correlating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). • In the beta thalassemic or SCD patients of our cohort, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course (confirmation of a well-known previous observation). • The inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype (confirmation of a well known previous observation). • The function or modification of possible regulatory genes should be investigated in cases in whom the genotype and phenotype did not correlate.

Studies on Genetic Environment Influences on the Development of Childhood Psychiatric Disorders: A Review

This research article review the key types of genetic research design, methodology involved and emerging and established finding in relation to child and childhood psychiatric disorders, and finally genetic factors seems especially important for autism and attention deficit hyperactivity disorder. (Thapar and McGuffin, 2008)1 Twin and adoption study design are now being used to examine gene environment interplay, the effects of environment risk factors co-morbidity phenotype definition and development change Liu et al (2006)11 The ways in which specific gene variant excert risk effects at cellular and biological system are proving to highly competitive (Moffitt et al, 2005).2 Finally, molecular genetic studies also high light the importance of gene environment interply, which seems to be especially important in depression and wide anti social behavior. Liu. et al)11, owen et al 2005)12 , Moffitt, et al, (2005)2

Clinical characteristics of patients with NOD2 high risk allele variants

The nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor. NOD2 gene variants are associated with inflammatory bowel disease (IBD) as well as Blau and Yao syndromes. IBD is associated with extraintestinal manifestations, including autoinflammation, which may be the presenting symptoms. The clinical symptoms may depend on the specific gene variants. This retrospective study was undertaken to examine the clinical manifestations of patients with pathogenic NOD2 variants in our institution. This study was approved by our Institutional Review Board.From January 2020 to February 2022, we identified 203 patients that had genetic testing that included the NOD2 gene. Forty-one had high risk alleles variants (HRA) that segregated in three mutations: HRA1 c.2104C>T (n = 24); HRA2 c.3019dup (n = 11); and HRA3 c.2722G > C (n = 6).The reported age of initial symptoms ranged from 21 days to 62 years, with most patients being < 12 years of age. All three variants had clinical evidence of immune dysregulation. Common manifestations (listed respectively for the three variants) included asthma (HRA1 = 21%, HRA2 = 9%, HRA3 = 33%), reflux/gastritis (29%, 18%, 33%), irritable bowel syndrome (21%, 18%, 7%), chronic diarrhea (8%, 18%, 0%), IBD (13%, 27%, 50%), recurrent fevers (38%, 45%, 0%), cytokine storm (4%, 9%, 17%), arthralgia/arthritis (33%, 45%, 17%), skin rashes (42%, 36%, 0%), malignancy (13%, 0%, 17%), bacterial infections (38%, 36%, 67%), fungal infections (4%, 18%, 0%), other autoimmune (21%, 9%, 0%), autoinflammatory syndromes (13%, 45%, 0%). Autoinflammatory/autoimmune disorders diagnosed within the cohort included PFAPA (HRA1 = 0, HRA2 = 1, HRA3 = 0), Yao syndrome (1, 0, 0), juvenile idiopathic arthritis (1, 1, 0), SAPHO syndrome (0, 1, 0), relapsing polychondritis (0,1,0), lupus (0,1,0), Sjogren’s syndrome (0,1,0), Raynaud’s syndrome (1, 0, 0), vitiligo (0, 1, 0), type I diabetes (2, 0, 0) and hypothyroidism (2, 1, 0). Detailed information is in table 1.Our chart review demonstrates a broad spectrum of extraintestinal clinical manifestations of patients with NOD2 variants which do not always include IBD. NOD2 is important in the protection of infection and autoinflammation and its role in human disease needs to be examined further.

H2A monoubiquitination: insights from human genetics and animal models.

Metazoan development arises from spatiotemporal control of gene expression, which depends on epigenetic regulators like the polycomb group proteins (PcG) that govern the chromatin landscape. PcG proteins facilitate the addition and removal of histone 2A monoubiquitination at lysine 119 (H2AK119ub1), which regulates gene expression, cell fate decisions, cell cycle progression, and DNA damage repair. Regulation of these processes by PcG proteins is necessary for proper development, as pathogenic variants in these genes are increasingly recognized to underly developmental disorders. Overlapping features of developmental syndromes associated with pathogenic variants in specific PcG genes suggest disruption of central developmental mechanisms; however, unique clinical features observed in each syndrome suggest additional non-redundant functions for each PcG gene. In this review, we describe the clinical manifestations of pathogenic PcG gene variants, review what is known about the molecular functions of these gene products during development, and interpret the clinical data to summarize the current evidence toward an understanding of the genetic and molecular mechanism.

Preeclampsia is associated with reduced renin, aldosterone, and PlGF levels, and increased sFlt-1/PlGF ratio, and specific angiotensin-converting enzyme Ins-Del gene variants

We investigated the association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism with preeclampsia (PE) in Tunisian women. ACE I/D genotyping was done by PCR in 342 pregnant women with PE and 289 healthy pregnant women. The association between ACE I/D and PE and associated features were also evaluated. Decreased active renin concentration, plasma aldosterone concentration, and placental growth factor (PlGF) were observed in PE cases, while soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio was significantly higher in the PE group. Distribution of ACE I/D alleles and genotypes were comparable between women with PE and control women. A significant difference in the frequency of the I/I genotype was seen between PE cases and control women according to the recessive model, with a trend towards association in the codominant model. Carriers of the I/I genotype had significantly higher infant birth weights compared to the I/D and the D/D genotype carriers. A dose-dependent relationship was also seen in VEGF and PlGF plasma levels and specific ACE I/D genotypes, with the lowest VEGF levels seen in the I/I genotype carriers compared to the D/D genotype carriers. Similarly, the I/I genotype carriers had the lowest PlGF levels compared to I/D and D/D genotype carriers. Furthermore, when studying the linkage between PE features, we found a positive correlation between PAC and PIGF. Our study suggests a role for ACE I/D polymorphism in the pathogenesis of PE, possibly through modulating VEGF and PlGF levels and infant birth weight, and highlights the relationship between PAC and PlGF.

Linking human Dead end 1 (DND1) variants to male infertility employing zebrafish embryos.

Is the vertebrate protein Dead end (DND1) a causative factor for human infertility and can novel in vivo assays in zebrafish help in evaluating this? Combining patient genetic data with functional in vivo assays in zebrafish reveals a possible role for DND1 in human male fertility. About 7% of the male population is affected by infertility but linking specific gene variants to the disease is challenging. The function of the DND1 protein was shown to be critical for germ cell development in several model organisms but a reliable and cost-effective method for evaluating the activity of the protein in the context of human male infertility is still missing. Exome data from 1305 men included in the Male Reproductive Genomics cohort were examined in this study. A total of 1114 of the patients showed severely impaired spermatogenesis but were otherwise healthy. Eighty-five men with intact spermatogenesis were included in the study as controls. We screened the human exome data for rare, stop-gain, frameshift, splice site, as well as missense variants in DND1. The results were validated by Sanger sequencing. Immunohistochemical techniques and, when possible, segregation analyses were performed for patients with identified DND1 variants. The amino acid exchange in the human variant was mimicked at the corresponding site of the zebrafish protein. Using different aspects of germline development in live zebrafish embryos as biological assays, we examined the activity level of these DND1 protein variants. In human exome sequencing data, we identified four heterozygous variants in DND1 (three missense and one frameshift variant) in five unrelated patients. The function of all of the variants was examined in the zebrafish and one of those was studied in more depth in this model. We demonstrate the use of zebrafish assays as a rapid and effective biological readout for evaluating the possible impact of multiple gene variants on male fertility. This in vivo approach allowed us to assess the direct impact of the variants on germ cell function in the context of the native germline. Focusing on the DND1 gene, we find that zebrafish germ cells, expressing orthologs of DND1 variants identified in infertile men, failed to arrive correctly at the position where the gonad develops and exhibited defects in cell fate maintenance. Importantly, our analysis facilitated the evaluation of single nucleotide variants, whose impact on protein function is difficult to predict, and allowed us to distinguish variants that do not affect the protein's activity from those that strongly reduce it and could thus potentially be the primary cause for the pathological condition. These aberrations in germline development resemble the testicular phenotype of azoospermic patients. The pipeline we present requires access to zebrafish embryos and to basic imaging equipment. The notion that the activity of the protein in the zebrafish-based assays is relevant for the human homolog is well supported by previous knowledge. Nevertheless, the human protein may differ in some respects from its homologue in zebrafish. Thus, the assay should be considered only one of the parameters used in defining DND1 variants as causative or non-causative for infertility. Using DND1 as an example, we have shown that the approach described in this study, relying on bridging between clinical findings and fundamental cell biology, can help to establish links between novel human disease candidate genes and fertility. In particular, the power of the approach we developed is manifested by the fact that it allows the identification of DND1 variants that arose de novo. The strategy presented here can be applied to different genes in other disease contexts. This study was funded by the German Research Foundation, Clinical Research Unit, CRU326 'Male Germ Cells'. There are no competing interests. N/A.

Basic concepts of cancer genetics and receptor tyrosine kinase inhibition for pharmacists. A narrative review.

The intent of this review is to present basic genetic concepts key to understanding oncogenesis and the role receptor tyrosine kinase (RTK) inhibition plays in the targeted treatment of many cancer types. Oncogenic signaling by RTKs can result from genetic events such as point mutations, chromosomal rearrangements, structural variation, and gene amplification in the cancer genome. The cancer pharmacogenes discussed encode RTKs that exemplify the link between gene variation, the oncogenic process, and the basis of targeted approaches to treatment. Biochemical pathways often involved in oncogenesis and affected by RTK variation are reviewed. Molecular diagnostic testing for the presence of specific gene variants, alterations, and amplifications direct therapy to indicated tyrosine kinase inhibitors and monoclonal antibody drugs. As pharmacists are integral to the selection, preparation, and monitoring of chemotherapy, it is important that they understand the genetic basis for targeted therapies as well as the underlying disease process.

Association of Potentially Damaging De Novo Gene Variants With Neurologic Outcomes in Congenital Heart Disease

Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD), but medical and sociodemographic factors explain only one-third of the variance in outcomes. To examine whether potentially damaging de novo variants (dDNVs) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD and, post hoc, whether some dDNVs or rare putative loss-of-function variants (pLOFs) in specific gene categories are associated with outcomes. This cross-sectional study was conducted from September 2017 to June 2020 in 8 US centers. Inclusion criteria were CHD, age 8 years or older, and available exome sequencing data. Individuals with pathogenic gene variants in known CHD- or neurodevelopment-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. Heterozygous for (cases) or lacking (controls) dDNVs in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNVs and/or pLOFs in 4 gene categories: chromatin modifying, constrained, high level of brain expression, and neurodevelopmental risk. Main outcomes were neurodevelopmental assessments of academic achievement, intelligence, fine motor skills, executive function, attention, memory, social cognition, language, adaptive functioning, and anxiety and depression, as well as 7 structural, diffusion, and functional brain magnetic resonance imaging metrics. The study cohort included 221 participants in the post hoc analysis and 219 in the case-control analysis (109 cases [49.8%] and 110 controls [50.2%]). Of those 219 participants (median age, 15.0 years [IQR, 10.0-21.2 years]), 120 (54.8%) were male. Cases and controls had similar primary outcomes (reading composite, spelling, and math computation on the Wide Range Achievement Test, Fourth Edition) and secondary outcomes. dDNVs and/or pLOFs in chromatin-modifying genes were associated with lower mean (SD) verbal comprehension index scores (91.4 [20.4] vs 103.4 [17.8]; P = .01), Social Responsiveness Scale, Second Edition, scores (57.3 [17.2] vs 49.4 [11.2]; P = .03), and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores (73.8 [16.4] vs 97.2 [15.7]; P = .03), as well as higher likelihood of autism spectrum disorder (28.6% vs 5.2%; P = .01). dDNVs and/or pLOFs in constrained genes were associated with lower mean (SD) scores on the Wide Range Assessment of Memory and Learning, Second Edition (immediate story memory: 9.7 [3.7] vs 10.7 [3.0]; P = .03; immediate picture memory: 7.8 [3.1] vs 9.0 [2.9]; P = .008). Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores (mean [SD], 55.5 [15.4] vs 46.6 [12.3]; P = .007). The study findings suggest neurodevelopmental outcomes are not associated with dDNVs as a group but may be worse in individuals with dDNVs and/or pLOFs in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific gene variants to brain function and structure.

Migration Rates on Swim Plates Vary between Escherichia coli Soil Isolates: Differences Are Associated with Variants in Metabolic Genes.

This study investigates migration phenotypes of 265 Escherichia coli soil isolates from the Buffalo River basin in Minnesota, USA. Migration rates on semisolid tryptone swim plates ranged from nonmotile to 190% of the migration rate of a highly motile E. coli K-12 strain. The nonmotile isolate, LGE0550, had mutations in flagellar and chemotaxis genes, including two IS3 elements in the flagellin-encoding gene fliC. A genome-wide association study (GWAS), associating the migration rates with genetic variants in specific genes, yielded two metabolic variants (rygD-serA and metR-metE) with previous implications in chemotaxis. As a novel way of confirming GWAS results, we used minimal medium swim plates to confirm the associations. Other variants in metabolic genes and genes that are associated with biofilm were positively or negatively associated with migration rates. A determination of growth phenotypes on Biolog EcoPlates yielded differential growth for the 10 tested isolates on d-malic acid, putrescine, and d-xylose, all of which are important in the soil environment. IMPORTANCE E. coli is a Gram-negative, facultative anaerobic bacterium whose life cycle includes extra host environments in addition to human, animal, and plant hosts. The bacterium has the genomic capability of being motile. In this context, the significance of this study is severalfold: (i) the great diversity of migration phenotypes that we observed within our isolate collection supports previous (G. NandaKafle, A. A. Christie, S. Vilain, and V. S. Brözel, Front Microbiol 9:762, 2018, https://doi.org/10.3389/fmicb.2018.00762; Y. Somorin, F. Abram, F. Brennan, and C. O'Byrne, Appl Environ Microbiol 82:4628-4640, 2016, https://doi.org/10.1128/AEM.01175-16) ideas of soil promoting phenotypic heterogeneity, (ii) such heterogeneity may facilitate bacterial growth in the many different soil niches, and (iii) such heterogeneity may enable the bacteria to interact with human, animal, and plant hosts.

The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

The Predictive Value of A, B, and C-Type Natriuretic Peptides in People at Risk of Heart Disease: Protocol for a Longitudinal Observational Study

Heart disease and stroke are major and often unheralded causes of serious morbidity and premature death in middle age. Early detection of those most at risk is an urgent unmet need for instituting preventative measures. In an earlier community study (Canterbury Health, Ageing and Life Course [CHALICE]) of healthy people aged 50 years, contrary to previous reports, low levels of the heart hormone B-type natriuretic peptide (BNP) were associated with reduced measures of heart function and higher markers of vascular risk. A specific gene variant (rs198358) was found to be an independent contributor to higher BNP levels. A closely related vascular hormone (C-type natriuretic peptide [CNP]) showed opposite associations-higher levels were correlated with higher vascular risk and reduced cardiac function. To determine whether these novel findings predict serious heart or vascular disease in later life, this proposal re-examines the same CHALICE participants 15 years later. The primary objective is to determine the predictive value of (1) low plasma concentrations of the circulating cardiac hormones (atrial natriuretic peptide [ANP] and BNP) and (2) high levels of the vascular hormone CNP at age 50 years in detecting impaired cardiac and vascular function 15 years later. Secondary objectives are to determine specific associations of individual analytes (ANP, BNP, CNP, cyclic guanosine monophosphate [cGMP]) with echo-derived changes in cardiac performance at ages 50 years and 65 years. All of the 348 participants (205/348, 58.9% female; 53/348, 15.2% Māori or Pacifica ethnicity) participating in the original CHALICE study-free of history of heart or renal disease at age 50 years and who consented to further study-will be contacted, recruited, and restudied as previously described. Data will include intervening health history, physical examination, heart function (speckle-tracking echocardiography), vascular status (carotid intimal thickness), and genetic status (genome-wide genotyping). Laboratory measures will include fasting blood sampling and routine biochemistry, ANP, BNP, CNP, their downstream effector (cGMP), and their bio-inactive products. Humoral metabolic-cardiovascular risk factors will be measured after an overnight fast. Primary outcomes will be analyzed using multiple linear regression. The study will commence in 2022 and be completed in 2024. Proving our hypothesis-that low BNP and high CNP at any age in healthy people predict premature aging of heart and blood vessels, respectively-opens the way to early detection and improved outcomes for those most at risk. Confirmation of our hypotheses would improve current methods of screening and, in appropriate cases, enable interventions aimed at increasing natriuretic hormones and reducing risk of serious cardiovascular complications using drugs already available. Such advances in detection, and from interventional corrections, have the potential to not only improve health in the community but also reduce the high costs inevitably associated with heart failure. PRR1-10.2196/37011.

Exome-based genome-wide screening of rare variants associated with the risk of polycystic ovary syndrome.

Genetic factors associated with the risk of polycystic ovary syndrome (PCOS) remain largely unknown. Here, we conducted an optimal sequence kernel association test (SKAT-O), an exome-based rare variant association study, to clarify whether rare variants in specific genes contribute to the development of PCOS. SKAT-O was performed using exome data of 44 Japanese patients with PCOS and 301 control women. We analyzed frequencies of rare probably damaging variants in the genome. Rare variants of GSTO2 were more commonly identified in the patient group than in the control group (6/44 vs. 1/301; Bonferroni-corrected p-value, 0.028), while the frequencies of variants in other genes were comparable between the two groups. The identified GSTO2 variants were predicted to affect the function, structure, stability, hydrophobicity, and/or the formation of intrinsically disordered regions of the protein. GSTO2 encodes a glutathione transferase that mediates the oxidative stress response and arsenic metabolism. Previously, common variants in GSTO2 and its paralog GSTO1 were associated with the risk of PCOS. The results indicate that there are no genes whose rare variants account for a large fraction of the etiology of PCOS, although rare damaging variants in GSTO2 may constitute a risk factor in some cases.

A Pilot Genome-Wide Association Study Identifies Novel Markers of Metabolic Syndrome in Patients with Psoriasis.

Recent studies have reported that psoriasis is associated with the development of metabolic syndrome. Genome-wide association studies have been used to discover gene variant markers that occur frequently in case group in relation to specific diseases. The aim of the present study was to investigate the variants of specific genes involved in metabolic syndrome associated with psoriasis. A total of 95 psoriasis patients were recruited and divided into two groups: one with metabolic syndrome (38 patients) and the other without (57 patients). After genotyping, imputation, and quality checking, the association between the several single nucleotide polymorphisms and metabolic syndrome in psoriasis was tested, followed by gene set enrichment analysis. We found 76 gene polymorphisms that conferred an increased risk for metabolic syndrome in patients with psoriasis. Four single nucleotide polymorphisms (rs17154774 of FRMD4A, rs77498336 of GPR116, rs75949580 and rs187682251 of MAPK4) showed the strongest association between metabolic syndrome and psoriasis. The epidermal growth factor receptor protein was located at the center of the protein interactions for the gene polymorphisms. This study identified several previously unknown polymorphisms associated with metabolic syndrome in psoriasis. These results highlight the potential for future genetic studies to elucidate the development, and ultimately prevent the onset, of metabolic syndrome in patients with psoriasis.

The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression

Alzheimer's disease (AD) is a progressive and irreversible brain disorder, which can occur either sporadically, due to a complex combination of environmental, genetic, and epigenetic factors, or because of rare genetic variants in specific genes (familial AD, or fAD). A key hallmark of AD is the accumulation of amyloid beta (Aβ) and Tau hyperphosphorylated tangles in the brain, but the underlying pathomechanisms and interdependencies remain poorly understood. Here, we identify and characterise gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 (PSEN1) gene. We do this by comparing the transcriptomes of glutamatergic forebrain neurons derived from fAD-mutant human induced pluripotent stem cells (hiPSCs) and their individual isogenic controls generated via precision CRISPR/Cas9 genome editing. Our analysis of Poly(A) RNA-seq data detects 1111 differentially expressed coding and non-coding genes significantly altered in fAD. Functional characterisation and pathway analysis of these genes reveal profound expression changes in constituents of the extracellular matrix, important to maintain the morphology, structural integrity, and plasticity of neurons, and in genes involved in calcium homeostasis and mitochondrial oxidative stress. Furthermore, by analysing total RNA-seq data we reveal that 30 out of 31 differentially expressed circular RNA genes are significantly upregulated in the fAD lines, and that these may contribute to the observed protein-coding gene expression changes. The results presented in this study contribute to a better understanding of the cellular mechanisms impacted in AD neurons, ultimately leading to neuronal damage and death.

GENETIC VARIANTS AND SERUM PROFILES OF CYTOKINES IN COVID-19 SEVERITY.

Background: Patients with severe coronavirus disease 2019 (COVID-19) are at an increased risk of acute respiratory distress syndrome and mortality. This is due to the increased levels of pro-inflammatory cytokines that amplify downstream pathways that are controlled by immune regulators. Objective: This study aimed to investigate the association between cytokine genetic variants, cytokine serum levels/profiles, and disease severity in critically and noncritically ill COVID-19 patients. Methods: This cross-sectional study recruited 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 from six collection sites across the United Arab Emirates. Medical files were accessed to retrieve clinical data. Blood samples were collected from all participants. Patients were divided into two clinical groups, noncritical (n = 453) and critical (n = 193), according to World Health Organization classification guidelines for COVID-19 patients. Cytokine analyses were conducted on serum of a subset of the cohort, specifically on 426 participants (noncritical, 264; critical, 162). Candidate gene analyses of 33 cytokine-related genes (2,836 variants) were extracted from a genome-wide association study to identify genetic variants with pleiotropic effects on a specific cytokine and the severity of COVID-19 disease. Results: Age, body mass index (BMI), and pre-existing medical conditions were found to be significant risk factors that contribute to COVID-19 disease severity. After correcting for age, sex, and BMI, IP-10 ( P < 0.001), IFN ( P = 0.001), IL-6 ( P < 0.001), and CXCL-16 ( P < 0.001) serum levels were significantly higher among critical COVID-19 cases, when compared with noncritically ill patients. To investigate if the genetic variants involved in the serum cytokine levels are associated with COVID-19 severity, we studied several genes. Single nucleotide polymorphisms in IL6 (rs1554606; odd ratio (OR) G = 0.67 [0.66, 0.68]; P = 0.017), IFNG (rs2069718; OR G = 0.63 [0.62, 0.64]; P = 0.001), MIP (rs799187; OR A = 1.69 [1.66, 1.72]; P = 0.034), and CXCL16 (rs8071286; OR A = 1.42 [1.41, 1.44]; P = 0.018) were found to be associated with critically ill patients. Polymorphisms in the CXCL10 , CCL2 , IL1 , CCL7 , and TNF genes were not associated with the COVID-19 critical phenotype. The genotypes of IL-6 (gene, IL6 [7p15.3]) and CXCL-16 (gene, CXCL16 [17p13.2]) were significantly associated with the serum levels of the respective cytokine in critical cases of COVID-19. Conclusion: Data obtained from measuring cytokine levels and genetic variant analyses suggest that IL-6 and CXCL-16 could potentially be used as potential biomarkers for monitoring disease progression of COVID-19 patients. The findings in this study suggest that specific cytokine gene variants correlate with serum levels of the specific cytokine. These genetic variants could be of assistance in the early identification of high-risk patients on admission to the clinic to improve the management of COVID-19 patients and other infectious diseases.