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Introduction: The COVID-19 pandemic represented one of the most significant challenges to researchers and healthcare providers. Several factors determine the disease severity, whereas none alone can explain the tremendous variability. The Single nucleotide variants (SNVs) in angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease type-2 (TMPRSS2) genes affect the virus entry and are considered possible risk factors for COVID-19. Methods: We compiled a panel of gene variants from both genes and used insilico analysis to predict their significance. We performed biological validation to assess their capacity to alter the ACE2 interaction with the virus spike protein. Subsequently, we conducted a retrospective comparative genome analysis on those variants in the Emirati patients with different disease severity (total of 96) along with 69 healthy control subjects. Results: Our results showed that the Emirati population lacks the variants that were previously reported as associated with disease severity, whereas a new variant in ACE2 "Chr X:g.15584534" was associated with disease severity specifically among female patients. In-silico analysis revealed that the new variant can determine the ACE2 gene transcription. Several cytokines (GM-CSF and IL-6) and chemokines (MCP-1/CCL2, IL-8/CXCL8, and IP-10/CXCL10) were markedly increased in COVID-19 patients with a significant correlation with disease severity. The newly reported genetic variant of ACE2 showed a positive correlation with CD40L, IL-1β, IL-2, IL-15, and IL-17A in COVID-19 patients. Conclusion: Whereas COVID-19 represents now a past pandemic, our study underscores the importance of genetic factors specific to a population, which can influence both the susceptibility to viral infections and the level of severity; subsequently expected required preparedness in different areas of the world. [ABSTRACT FROM AUTHOR]

Introduction: Frailty is the most common medical condition affecting the aging population, and its prevalence increases in the population aged 65 or more. Frailty is commonly diagnosed using the frailty index (FI) or frailty phenotype (FP) assessments. Observational studies have indicated the association of frailty with Alzheimer's disease (AD). However, the shared genetic and biological mechanism of these comorbidity has not been studied. Methods: To assess the genetic relationship between AD and frailty, we examined it at single nucleotide polymorphism (SNP), gene, and pathway levels. Results: Overall, 16 genome-wide significant loci (15 unique loci) (pmeta-analysis < 5 × 10-8) and 22 genes (21 unique genes) were identified between AD and frailty using cross-trait meta-analysis. The 8 shared loci implicated 11 genes: CLRN1-AS1, CRHR1, FERMT2, GRK4, LINC01929, LRFN2, MADD, RP11-368P15.1, RP11-166N6.2, RNA5SP459, and ZNF652 between AD and FI, and 8 shared loci between AD and FFS implicated 11 genes: AFF3, C1QTNF4, CLEC16A, FAM180B, FBXL19, GRK4, LINC01104, MAD1L1, RGS12, ZDHHC5, and ZNF521. The loci 4p16.3 (GRK4) was identified in both meta-analyses. The colocalization analysis supported the results of our meta-analysis in these loci. The gene-based analysis revealed 80 genes between AD and frailty, and 4 genes were initially identified in our meta-analyses: C1QTNF4, CRHR1, MAD1L1, and RGS12. The pathway analysis showed enrichment for lipoprotein particle plasma, amyloid fibril formation, protein kinase regulator, and tau protein binding. Conclusion: Overall, our results provide new insights into the genetics of AD and frailty, suggesting the existence of non-causal shared genetic mechanisms between these conditions. [ABSTRACT FROM AUTHOR]

IntroductionThe COVID-19 pandemic represented one of the most significant challenges to researchers and healthcare providers. Several factors determine the disease severity, whereas none alone can explain the tremendous variability. The Single nucleotide variants (SNVs) in angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease type-2 (TMPRSS2) genes affect the virus entry and are considered possible risk factors for COVID-19.MethodsWe compiled a panel of gene variants from both genes and used in-silico analysis to predict their significance. We performed biological validation to assess their capacity to alter the ACE2 interaction with the virus spike protein. Subsequently, we conducted a retrospective comparative genome analysis on those variants in the Emirati patients with different disease severity (total of 96) along with 69 healthy control subjects.ResultsOur results showed that the Emirati population lacks the variants that were previously reported as associated with disease severity, whereas a new variant in ACE2 “Chr X:g.15584534” was associated with disease severity specifically among female patients. In-silico analysis revealed that the new variant can determine the ACE2 gene transcription. Several cytokines (GM-CSF and IL-6) and chemokines (MCP-1/CCL2, IL-8/CXCL8, and IP-10/CXCL10) were markedly increased in COVID-19 patients with a significant correlation with disease severity. The newly reported genetic variant of ACE2 showed a positive correlation with CD40L, IL-1β, IL-2, IL-15, and IL-17A in COVID-19 patients.ConclusionWhereas COVID-19 represents now a past pandemic, our study underscores the importance of genetic factors specific to a population, which can influence both the susceptibility to viral infections and the level of severity; subsequently expected required preparedness in different areas of the world.

Apical periodontitis (AP) is a common consequence of root canal infection leading to periapical bone resorption. Microbial and host genetic factors and their interactions have been shown to play a role in AP development and progression. Variations in a few genes have been reported in association with AP; however, the lack of genome-wide studies has hindered progress in understanding the molecular mechanisms involved. Here, we report the first genome-wide association study of AP in a large and well-characterized population. Male and female adults (n = 932) presenting with deep caries and AP (cases), or deep caries without AP (controls) were included. Genotyping was performed using the Illumina Expanded Multi-Ethnic Genotyping Array (MEGA). Single-variant association testing was performed adjusting for sex and 5 principal components. Subphenotype association testing, analyses of genetically regulated gene expression, polygenic risk score, and phenome-wide association (PheWAS) analyses were also conducted. Eight loci reached near genome-wide significant association with AP (P < 5 × 10−6); gene-focused analyses replicated 3 previously reported associations (P < 8.9 × 10−5). Sex-specific and subphenotype-specific analyses revealed additional significant associations with variants genome-wide. Functionally oriented gene-based analyses revealed 8 genes significantly associated with AP (P < 5 × 10−5), and PheWAS analysis revealed 33 phecodes associated with AP risk score (P < 3.08 × 10−5). This study identified novel genes/loci contributing to AP and specific contributions to AP risk in men and women. Importantly, we identified additional systemic conditions significantly associated with AP risk. Our findings provide strong evidence for host-mediated effects on AP susceptibility. [ABSTRACT FROM AUTHOR]

Introduction: The knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules. Objective: This study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD. Methods: We analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism. Discussion: Our results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility. [ABSTRACT FROM AUTHOR]

IntroductionThe knowledge of the aetiology of Behçet disease (BD), an immune-mediated vasculitis, is limited. HLA-B, mainly HLA-B51, and HLA-A molecules are associated with disease, but the ultimate cause of this association remains obscure. There is evidence that NK cells participate in the etiopathology of BD. NK cells have activator and inhibitor surface receptors, like the KIR and the NKG2 families. Classical HLA-class I molecules (A, B and C) are keys in the activity control of the NK because they are KIR ligands. Most NKG2 receptors bind HLA-E, which presents only nonapeptides derived from the signal peptide of other class-I molecules.ObjectiveThis study investigates the contribution of the pair HLA-E and ligand, nonapeptide derived from the 3-11 sequence of the signal peptides of class I classical molecules, to the susceptibility to BD.MethodsWe analyzed the frequency of the HLA-derivated nonapeptide forms in 466 BD patients and 444 controls and an HLA-E functional dimorphism in a subgroup of patients and controls. Results: In B51 negative patients, the frequency of VMAPRTLLL was lower (70.4% versus 80.0% in controls; P=0.006, Pc=0.04, OR=0.60, 95%CI 0.41-0.86), and the frequency of VMAPRTLVL was higher (81.6% versus 71.4% in controls; P=0.004, Pc=0.03, OR=1.78, 95%CI 1.20-2.63). In homozygosity, VMAPRTLLL is protective, and VMAPRTLVL confers risk. The heterozygous condition is neutral. There were no significant differences in the distribution of the HLA-E dimorphism.DiscussionOur results explain the association of BD with diverse HLA-A molecules, reinforce the hypothesis of the involvement of the NK cells in the disease and do not suggest a significant contribution of the HLA-E polymorphism to disease susceptibility.

Coevolution at the gene level, as reflected by correlated events of gene loss or gain, can be revealed by phylogenetic profile analysis. The optimal method and metric for comparing phylogenetic profiles, especially in eukaryotic genomes, are not yet established. Here, we describe a procedure suitable for large-scale analysis, which can reveal coevolution based on the assessment of the statistical significance of correlated presence/absence transitions between gene pairs. This metric can identify coevolution in profiles with low overall similarities and is not affected by similarities lacking coevolutionary information. We applied the procedure to a large collection of 60,912 orthologous gene groups (orthogroups) in 1,264 eukaryotic genomes extracted from OrthoDB. We found significant cotransition scores for 7,825 orthogroups associated in 2,401 coevolving modules linking known and unknown genes in protein complexes and biological pathways. To demonstrate the ability of the method to predict hidden gene associations, we validated through experiments the involvement of vertebrate malate synthase-like genes in the conversion of (S)-ureidoglycolate into glyoxylate and urea, the last step of purine catabolism. This identification explains the presence of glyoxylate cycle genes in metazoa and suggests an anaplerotic role of purine degradation in early eukaryotes. [ABSTRACT FROM AUTHOR]

Claudin-14 protein plays an essential role in regulating calcium ions in the kidney and ear. Two phenotypes, hearing loss and kidney stones, were reportedly associated with variations in the CLDN14 gene. This study aimed to understand CLDN14 mutations’ contribution to hearing loss and renal stone formation in a Pakistani cohort. We analyzed CLDN14 sequence variations in 100 patients, along with healthy individuals, to assess whether specific polymorphisms were associated with the disease. Also, we performed an in silico analysis using a mutation database and protein annotation. The rs219779’s genotype CT (p = 0.0020) and rs219780’s genotype AG (p = 0.0012) were significantly associated with kidney stones. We also found that a novel haplotype, “TA” associated with kidney stone formation, has moderate linkage disequilibrium. The TA haplotype was significantly correlated with a kidney stone risk formation of 3.76-fold (OR (CI 95%) = 3.76 (1.83–7.72)) and p = 0.0016 compared to other haplotypes. In silico analysis revealed that mutations associated with hearing loss were not correlated with renal stone formation but affected claudin-14 protein stability. We structurally mapped a novel TA haplotype of CLDN14 that, based on our analysis, likely contributes to the pathogenesis of renal stones.

Translesion synthesis (TLS) is a cell signaling pathway that facilitates the tolerance of replication stress. Increased TLS activity, the particularly elevated expression of TLS polymerases, has been linked to resistance to cancer chemotherapeutics and significantly altered patient outcomes. Building upon current knowledge, we found that the expression of one of these TLS polymerases (POLI) is associated with significant differences in cervical and pancreatic cancer survival. These data led us to hypothesize that POLI expression is associated with cancer survival more broadly. However, when cancers were grouped cancer type, POLI expression did not have a significant prognostic value. We presented a binary cancer random forest classifier using 396 genes that influence the prognostic characteristics of POLI in cervical and pancreatic cancer selected via graphical least absolute shrinkage and selection operator. The classifier was then used to cluster patients with bladder, breast, colorectal, head and neck, liver, lung, ovary, melanoma, stomach, and uterus cancer when high POLI expression was associated with worsened survival (Group I) or with improved survival (Group II). This approach allowed us to identify cancers where POLI expression is a significant prognostic factor for survival (p = 0.028 in Group I and p = 0.0059 in Group II). Multiple independent validation approaches, including the gene ontology enrichment analysis and visualization tool and network visualization support the classification scheme. The functions of the selected genes involving mitochondrial translational elongation, Wnt signaling pathway, and tumor necrosis factor-mediated signaling pathway support their association with TLS and replication stress. Our multidisciplinary approach provides a novel way of identifying tumors where increased TLS polymerase expression is associated with significant differences in cancer survival. [ABSTRACT FROM AUTHOR]

The recent development of a high throughput single-cell RNA sequence devises the opportunity to study entire transcriptomes in the smallest detail. It also leads to the characterization of molecules and subtypes of a cell. Cancer epigenetics induced not only from individual molecules but also from the dysfunction of the system and the coupling effect of genes. While rapid advances are being made in the development of tools for single-cell RNA-seq data analysis, few slants are noticed in the potential advantages of single-cell network construction. Here, we used network perturbation theory with significant analysis to develop a cell-specific network that provides an insight into gene–gene association based on molecular expressions in a single-cell resolution. Besides, using this method, we can characterize each cell by inspecting how genes are connected and can identify the hub genes using network degree theory. Pathway & Gene enrichment analysis of the identified cell-specific high network degree genes supported the effectiveness of this method. This method could be beneficial for personalized drug design and even therapeutics. [ABSTRACT FROM AUTHOR]

Several studies have previously assessed the association between interleukin (IL)-10 gene polymorphisms and the risk of asthma, leading to conflicting results. To resolve the incongruent outcomes yielded from different single studies, we conducted the most up-to-date meta-analysis of the IL-10 gene rs1800896, rs1800871, and rs1800872 single-nucleotide polymorphisms (SNPs) and susceptibility to asthma. A systematic literature search performed until April 2020, and the pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) were calculated to determine the association strength. Thirty articles comprising 5678 asthmatic patients and 6079 controls met the inclusion criteria. No significant association was found between rs1800872 SNP and susceptibility to asthma across all genetic models in the overall and subgroup analyses. The rs1800871 SNP had only significant association with a decreased risk of asthma in Europeans (OR 0.66, CI 0.53–0.82, P < 0.001). However, rs1800896 SNP was significantly associated with a decreased risk of asthma by dominant (OR 0.67, CI 0.50–0.90, P < 0.001) and heterozygote (OR 0.66, CI 0.49–0.88, P < 0.001) models in the overall analysis. Subgroup analyses indicated significant association of rs1800896 SNP by dominant (OR 0.45, CI 0.28–0.72, P < 0.001) and heterozygote (OR 0.43, CI 0.26–0.70, P < 0.001) models in the African population. The IL-10 rs1800896 SNP confers protection against the risk of asthma, especially in Africans. Additionally, rs1800871 SNP has a protective role against asthma in Europeans. [ABSTRACT FROM AUTHOR]

Abstract Background C4 photosynthesis is a key domain of plant research with outcomes ranging from crop quality improvement, biofuel production and efficient use of water and nutrients. A metabolic network model of C4 “lab organism” Setaria viridis with extensive gene-reaction associations can accelerate target identification for desired metabolic manipulations and thereafter in vivo validation. Moreover, metabolic reconstructions have also been shown to be a significant tool to investigate fundamental metabolic traits. Results A mass and charge balance genome-scale metabolic model of Setaria viridis was constructed, which was tested to be able to produce all major biomass components in phototrophic and heterotrophic conditions. Our model predicted an important role of the utilization of NH 4+ $_{4}^{+}$ and NO 3− $_{3}^{-}$ ratio in balancing charges in plants. A multi-tissue extension of the model representing C4 photosynthesis was able to utilize NADP-ME subtype of C4 carbon fixation for the production of lignocellulosic biomass in stem, providing a tool for identifying gene associations for cellulose, hemi-cellulose and lignin biosynthesis that could be potential target for improved lignocellulosic biomass production. Besides metabolic engineering, our modeling results uncovered a previously unrecognized role of the 3-PGA/triosephosphate shuttle in proton balancing. Conclusions A mass and charge balance model of Setaria viridis, a model C4 plant, provides the possibility of system-level investigation to identify metabolic characteristics based on stoichiometric constraints. This study demonstrated the use of metabolic modeling in identifying genes associated with the synthesis of particular biomass components, and elucidating new role of previously known metabolic processes.

Several studies have evaluated the association between killer-cell immunoglobulin-like receptors (KIR) genes and susceptibility risk to tuberculosis (TB) infection. Nonetheless, their outcomes have not been conclusive and consistent. Here we implemented a systematic review and meta-analysis of KIR genes association to susceptibility risk of pulmonary TB (PTB) infection to attain a clear understanding of the involvement of these genes in susceptibility to PTB infection. A systematic search was conducted in the MEDLINE/PubMed and Scopus databases to find case-control studies published before November 2020. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated to determine the association between KIR genes and risk of PTB infection. After comprehensive searching and implementing the inclusion and exclusion criteria, 10 case-control studies were included in the meta-analysis. Four KIR genes were found to have significant positive association with PTB susceptibility risk of infection, including 2DL3 (OR = 1.454, 95% CI = 1.157–1.827; P = 0.001), 2DS1 (OR = 1.481, 95% CI = 1.334–1.837; P < 0.001), 2DS4 (OR = 1.782, 95% CI = 1.273–2.495; P = 0.001) and 3DL1 (OR = 1.726, 95% CI = 1.277–2.333; P < 0.001). However, the results showed that the remaining KIR genes (2DS2-4, 2DL1, 2, 4, 3DL1-2) and two pseudogenes (2DP1 and 3DP1) did not have significant associations with risk of PTB infection. This meta-analysis provides reliable evidence that the KIR genes 2DL3, 2DS1, 2DS4, and 3DL1 may be associated with an increased risk of PTB infection. [ABSTRACT FROM AUTHOR]

Abstract Background Gene Ontology (GO) is a useful resource of controlled vocabulary that provides information about annotated genes. Based on such resource, finding the biological function is useful for biologists to come up with different hypotheses and help further investigations of an experiment. The biological function for desired genes and gene associations is picked up from a randomly chosen list or through the analysis of differential gene expression. Many tools have been developed to utilize GO knowledge and cluster genes according to relevant biological functions. The retrieved GO terms include both specific and non-specific terms, which is not user-friendly in terms of data analysis. Thus one approach is still missing, which allows navigating through different levels of GO hierarchy manually. Result We developed a tool, GOTrapper, which allows moving up or down to the very bottom of the GO hierarchy. This is performed manually by the user, based on an assigned threshold. This tool grabs the shared terms by the desired set of input genes of Homo sapiens. Here, two inputs are possible. “Within” is to find associated terms within one gene list, and “Between” is to find associated terms between two lists. The tool also provides the option to return the terms with the pre-selected evidence codes. Conclusion GOTrapper is a user-friendly Java tool that helps the user move up and down the ontology tree, which leads to new hypotheses and devising new association of the input genes. It also allows returning terms of associated genes based on selected evidence codes. This tool can be accessed and is freely available at https://github.com/BioGeneTools/GOTrapper.

To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F3 sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F0 fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F3 fish, one in the slit3 gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human SLIT3 locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of slit3 mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans.

Short interspersed nuclear elements (SINEs) are non-autonomous retrotransposons that are highly abundant, but not well annotated, in plant genomes. In this study, we identified 41,573 copies of SINEs in seven citrus genomes, including 11,275 full-length copies. The citrus SINEs were distributed among 12 families, with an average full-length rate of 0.27, and were dispersed throughout the chromosomes, preferentially in AT-rich areas. Approximately 18.4% of citrus SINEs were found in close proximity (≤1 kb upstream) to genes, indicating a significant enrichment of SINEs in promoter regions. Citrus SINEs promote gene and genome evolution by offering exons as well as splice sites and start and stop codons, creating novel genes and forming tandem and dispersed repeat structures. Comparative analysis of unique homologous SINE-containing loci (HSCLs) revealed chromosome rearrangements in sweet orange, pummelo, and mandarin, suggesting that unique HSCLs might be valuable for understanding chromosomal abnormalities. This study of SINEs provides us with new perspectives and new avenues by which to understand the evolution of citrus genes and genomes. [ABSTRACT FROM AUTHOR]

Background: C4 photosynthesis is a key domain of plant research with outcomes ranging from crop quality improvement, biofuel production and efficient use of water and nutrients. A metabolic network model of C4 "lab organism" Setaria viridis with extensive gene-reaction associations can accelerate target identification for desired metabolic manipulations and thereafter in vivo validation. Moreover, metabolic reconstructions have also been shown to be a significant tool to investigate fundamental metabolic traits. Results: A mass and charge balance genome-scale metabolic model of Setaria viridis was constructed, which was tested to be able to produce all major biomass components in phototrophic and heterotrophic conditions. Our model predicted an important role of the utilization of NH 4 + and NO 3 − ratio in balancing charges in plants. A multi-tissue extension of the model representing C4 photosynthesis was able to utilize NADP-ME subtype of C4 carbon fixation for the production of lignocellulosic biomass in stem, providing a tool for identifying gene associations for cellulose, hemi-cellulose and lignin biosynthesis that could be potential target for improved lignocellulosic biomass production. Besides metabolic engineering, our modeling results uncovered a previously unrecognized role of the 3-PGA/triosephosphate shuttle in proton balancing. Conclusions: A mass and charge balance model of Setaria viridis, a model C4 plant, provides the possibility of system-level investigation to identify metabolic characteristics based on stoichiometric constraints. This study demonstrated the use of metabolic modeling in identifying genes associated with the synthesis of particular biomass components, and elucidating new role of previously known metabolic processes. [ABSTRACT FROM AUTHOR]

This article introduces a novel method for selecting main effects and a set of reparameterized effects called conditional main effects (CMEs), which capture the conditional effect of a factor at a fixed level of another factor. CMEs represent interpretable, domain-specific phenomena for a wide range of applications in engineering, social sciences, and genomics. The key challenge is in incorporating the implicit grouped structure of CMEs within the variable selection procedure itself. We propose a new method, cmenet, which employs two principles called CME coupling and CME reduction to effectively navigate the selection algorithm. Simulation studies demonstrate the improved CME selection performance of cmenet over more generic selection methods. Applied to a gene association study on fly wing shape, cmenet not only yields more parsimonious models and improved predictive performance over standard two-factor interaction analysis methods, but also reveals important insights on gene activation behavior, which can be used to guide further experiments. Efficient implementations of our algorithms are available in the R package cmenet in CRAN. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

Background: Gene Ontology (GO) is a useful resource of controlled vocabulary that provides information about annotated genes. Based on such resource, finding the biological function is useful for biologists to come up with different hypotheses and help further investigations of an experiment. The biological function for desired genes and gene associations is picked up from a randomly chosen list or through the analysis of differential gene expression. Many tools have been developed to utilize GO knowledge and cluster genes according to relevant biological functions. The retrieved GO terms include both specific and non-specific terms, which is not user-friendly in terms of data analysis. Thus one approach is still missing, which allows navigating through different levels of GO hierarchy manually. Result: We developed a tool, GOTrapper, which allows moving up or down to the very bottom of the GO hierarchy. This is performed manually by the user, based on an assigned threshold. This tool grabs the shared terms by the desired set of input genes of Homo sapiens. Here, two inputs are possible. "Within" is to find associated terms within one gene list, and "Between" is to find associated terms between two lists. The tool also provides the option to return the terms with the pre-selected evidence codes. Conclusion: GOTrapper is a user-friendly Java tool that helps the user move up and down the ontology tree, which leads to new hypotheses and devising new association of the input genes. It also allows returning terms of associated genes based on selected evidence codes. This tool can be accessed and is freely available at https://github.com/BioGeneTools/GOTrapper. [ABSTRACT FROM AUTHOR]

Summary: The aim of this research was to evaluate the polymorphisms of selected genes and to find their potential effect on the occurrence of osteochondrosis in Polish Warmbloods (sport horse breeds). The study was conducted on a group of 198 horses subjected to official performance tests. Investigated joints—fetlock, hock and stifle—were X‐rayed twice, once before and again at the end of the tests (first and second examination), and on this basis the degree of disease was evaluated. Based on the results of previous research, 13 candidate genes potentially associated with the occurrence of osteochondrosis were selected and, among them, 32 polymorphisms were tested. Seven SNPs located in the MATN1,CPVL,HYAL1,XIRP2,FRZB,COL5A2 and IGF1 genes were found to be associated with occurrence of osteochondrotic lesions in different joints. These intragenic polymorphisms seem to provide valuable information about the genetic basis of osteochondrosis in sport horse breeds. [ABSTRACT FROM AUTHOR]

Background: The development, evolution and rupture of intracranial aneurysms are in part related to genetic factors. The role of collagen type-I a2 genetic polymorphisms has not been clarified yet. Material and methods: A meta-analysis was realized by means of a genotype model-fitting process (allele contrast, recessive, dominant, additive and co-dominant), and a model-free approach using the generalized odds ratio. The latter was assessed in association to the degree of dominance (h-index). Results: No statistically significant association was documented between EX28 G>C collagen type-I a2 variant and intracranial aneurysms (generalized odds ratio = 1.23, 95% confidence interval = 0.57, 2.63). Significant associations between INT46 T>G collagen type I a2 variant and intracranial aneurysms were documented in three models, the dominant [0.52 (0.38, 069)], the co-dominant [0.50 (0.32, 0.78)] and the allele contrast models [0.63 (0.49, 0.82)]. The generalized odds ratio was estimated to be as high as 1.94 (1.23, 3.06). The degree of dominance (h-index = −1.54) indicated that the TG genotype was characterized by lower risk of developing intracranial aneurysms compared to the TT genotype. Conclusions: The available literature data demonstrated that there is no association of collagen type-(2a) and intracranial aneurysms, through EX28 G>C (rs42524) polymorphism according to the model-fitting process and the model-free approach. Regarding the INT46 T>G (rs2621215) polymorphisms, the latter models indicated that there could be a protective effect of the G-allele against the development of intracranial aneurysms. However, the majority of studies are from East Asia, therefore the results are applicable primarily to that patient population. [ABSTRACT FROM AUTHOR]

Aquagenic keratoderma has been described as a transient condition affecting predominantly young females and defined clinically by the appearance of palmar hyper-wrinkling accentuated after immersion in water. We present two new cases with aquagenic palmoplantar acrokeratoderma - a child and a young male. A significant clinical improvement was achieved after topical treatment with aluminum salts. Aquagenic palmar keratoderma may be a clue to cystic fibrosis in adolescents and young adults. We developed a new hypothesis on its pathogenesis.

Prolificacy data of Romanov sheep breed were retrieved from Sekhra Station (Jordan) through five parities. The data were used for studying the effect of Fecundity (FecB), Growth Differentiation Factor 9 (GDF9) and Prolactin genes on the prolificacy of Romanov ewes. GDF9, FecB and Prolactin genes genotypes were investigated in Romanov ewes by using the PCRRFLP technique. The Mixed Model of SAS software was used for analyzing the data. The different gene genotypes and the parity were inserted in the Model as fixed effects while the dams were inserted as Random. Fecundity gene was observed to be monomorphic, the wild type genotype of Fecundity gene was found in the Romanov ewes. Prolactin and GDF9 genes were observed to be polymorphic in Romanov. The results revealed non-significant differences in the prolificacy of the ewes that carry AA and BB of Prolactin gene genotypes. The GDF9 gene genotypes showed significant (P≤0.0001) differences in prolificacy. The homozygous MM genotype ewes produced 0.792 more lambs born per lambing than the heterozygous NM genotype. Selection based on GDF9 mutation may help in improving the prolificacy of Romanov sheep. [ABSTRACT FROM AUTHOR]

Communication disorders have complex genetic origins, with constellations of relevant gene markers that vary across individuals. Some genetic variants are present in healthy individuals as well as those affected by developmental disorders. Growing evidence suggests that some variants may increase susceptibility to these disorders in the presence of other pathogenic gene mutations. In the current study, we describe eight children with specific language impairment and four of these children had a copy number variant in one of these potential susceptibility regions on chromosome 15. Three of these four children also had variants in other genes previously associated with language impairment. Our data support the theory that 15q11.2 is a susceptibility region for developmental disorders, specifically language impairment.

Background: In-stent restenosis occurs in 10-30% of patients following bare metal stent (BMS) implantation and has various risk factors. Mannose-binding lectin (MBL) is known to have effect on the progression of atherosclerosis. Single nucleotide polymorphisms (SNP) of the MBL2 gene intron 1 (codon 52, 54, 57) are known to modulate the bioavailability of the MBL protein. Our aim was to identify the association of these polymorphisms of the MBL gene in the occurrence of in-stent restenosis after coronary artery bare metal stent implantation.Methods: In a non-randomized prospective study venous blood samples were collected after recoronarography from 225 patients with prior BMS implantation. Patients were assigned to diffuse restenosis group and control group based on the result of the coronarography. MBL genotypes were determined using quantitative real-time PCR. Proportion of different genotypes was compared and adjusted with traditional risk factors using multivariate logistic regression.Results: Average follow-up time was 1.0 (+ - 1.4) year in the diffuse restenosis group (N = 117) and 2.7 (+ - 2.5) years in the control group (N = 108). The age, gender distribution and risk status was not different between study groups. Proportion of the MBL variant genotype was 26.8% (29 vs. 79 normal homozygous) in the control group and 39.3% (46 vs. 71 normal homozygous) in the restenosis group (p = 0.04). In multivariate analysis the mutant allele was an independent risk factor (OR = 1.96, p = 0.03) of in-stent restenosis.Conclusions: MBL polymorphisms are associated with higher incidence of development of coronary in-stent restenosis. The attenuated protein function in the mutant allelic genotype may represent the underlying mechanism. [ABSTRACT FROM AUTHOR]

GABAA receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarize the evidence that variations in genes encoding GABAA receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GABAA receptor. In addition to outlining the evidence for the involvement of specific subtypes in addiction, we summarize the particular contributions of these isoforms in control over the functioning of brain circuits, especially the mesolimbic system, and make a first attempt to bring together evidence from several fields to understanding potential involvement of GABAA receptor subtypes in addictive behaviour. While the weight of the published literature is on alcohol dependency, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour. [ABSTRACT FROM AUTHOR]

Psoriasis is a complex genetic disease, which has previously been associated with numerous single nucleotide polymorphisms (SNPs) that are implicated in various processes, including skin barrier functions and in the regulation of inflammatory and immune responses. The present study aimed to investigate the genotypic and allelic frequencies of 32 SNPs at 24 genetic loci, and their association with psoriasis in a Mexican population. These SNPs, which were associated with psoriasis in previous studies, included the following genes: Major histocompatibility complex class I-C (HLA-C), interleukin (IL)-12B, IL-23R, IL-23A, IL-28RA, tumor necrosis factor (TNF)-α, ring finger protein-114 (RNF114), cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1, late cornified envelope 3B/3C, signal transducer and activator of transcription 4, LINC01185, interferon induced with helicase C domain 1, IL-13, TNF-α-induced protein 3 (TNFAIP3), TNFAIP3 interacting protein 1, endoplasmic reticulum aminopeptidase 1, TNF receptor-associated factor interacting protein 2, Leptin, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha, F-box and leucine-rich repeat protein 19, nitric oxide synthase 2, cluster of differentiation 40, nuclear receptor coactivator 5, and ADAM metallopeptidase domain 33. A total of 32 male and 14 female subjects with a clinical diagnosis of chronic plaque psoriasis, as well as 103 control subjects, were analyzed. Molecular analyses were performed using TaqMan® assays in a TaqMan® OpenArray® Genotyping system. Results were analyzed using the Golden Helix SNP and Variation Suite 7 program. Of the 32 SNPs, six were associated with an increased risk of developing psoriasis, including: HLA-C rs10484554 [allele T: odds ratio (OR) 3.51], IL-12B rs3212227 (allele T: OR 1.88), IL-12B rs3213094 (allele C: OR 1.94), HLA complex group 27 rs1265181 (allele C: OR 2.83), annexin A6 rs17728338 (allele A: OR 2.41), and RNF114 rs6125829 (allele G: OR 1.98). Fisher's exact test detected statistical significance; however, following false discovery rate and Bonferroni correction, this association was no longer significant (threshold for genome-wide significance, P<1.56x10-3). SNPs that were associated with an increased risk of psoriasis in the present study have previously been associated with psoriasis in European, American, and Asian populations. In order to establish genome-wide significance, future studies must analyze a greater sample size. To the best of our knowledge, the present pilot study is the first to investigate the association between these 32 SNPs and psoriasis in a Mexican Mestizo population. [ABSTRACT FROM AUTHOR]

Aims and objectives. The aim of this discussion paper is to enable nurses to understand how deoxyribonucleic acid analysis can be predictive for some diseases and not predictive for others. This will facilitate nurses to interpret genomic test results and explain them to patients. Background. Advances in technology mean that genetic testing is now commonly performed by sequencing the majority of an individual's genome or exome. This results in a huge amount of data, some of which can be used to predict or diagnose disease. Design. This is a discussion paper. Methods. This paper emerged from multiple discussions between the three authors over many months, culminating in a writing workshop to prepare this text. Results. The results of DNA analysis can be used to diagnose or predict rare diseases that are caused by a mutation in a single gene. However, while there are a number of genetic factors that contribute to common diseases, the ability to predict whether an individual will develop that condition is limited by the overall heritability of the condition. Environmental factors (such as lifestyle) are likely to be more useful in predicting common disease than genomic testing. Genomic tests may be of use to inform management of diseases in specific situations. Conclusions. Genomic testing will be of use in diagnosing disorders due to single gene mutations, but the use of genomic testing to predict the chance of a patient being affected in the future by a common disease is unlikely to be a realistic option within a health service setting. Relevance to clinical practice. Nurses will increasingly be involved in the use of genomic tests in mainstream patient care. However, they need to understand and be able to explain to patients the practical applications of and limitations of such tests. [ABSTRACT FROM AUTHOR]

Sepsis is a major cause of neonatal morbidity and mortality, especially in vulnerable preterm populations. Immature immune defenses, and environmental and maternal factors contribute to this risk, with as many as a third of very preterm infants experiencing sepsis during their stay in the neonatal intensive care unit (NICU). Epidemiologic and twin studies have suggested that there is a genetic contribution to sepsis predilection. Several investigators have conducted candidate gene association studies on variants of specific interest and potential functional significance in neonatal sepsis. In this review, we describe details of studies that have evaluated genetic susceptibility in neonatal sepsis, and summarize findings from a review of candidate gene association studies. [ABSTRACT FROM AUTHOR]

Communication disorders have complex genetic origins, with constellations of relevant gene markers that vary across individuals. Some genetic variants are present in healthy individuals as well as those affected by developmental disorders. Growing evidence suggests that some variants may increase susceptibility to these disorders in the presence of other pathogenic gene mutations. In the current study, we describe eight children with specific language impairment and four of these children had a copy number variant in one of these potential susceptibility regions on chromosome 15. Three of these four children also had variants in other genes previously associated with language impairment. Our data support the theory that 15q11.2 is a susceptibility region for developmental disorders, specifically language impairment. [ABSTRACT FROM AUTHOR]

Objectives To examine the associations of five GWAS-identified genes with carotid intima-media thickness (IMT) in a biracial sample from the Bogalusa Heart Study, and evaluate their participation in gene-smoking interactions. Methods Far wall IMTs of common carotid arteries were measured using high-resolution B-mode ultrasound. Both the gene-smoking interactions and single-marker associations were evaluated by linear models of carotid IMT levels, while the gene-based analyses were assessed through the truncated product method. A Bonferroni multiple testing correction was applied. Results Marker rs7840785 ( PINX1 ) was significantly associated with right carotid IMT (p = 0.0003) using all participants; mean levels for the CC, TC, and TT genotypes were 0.74 (0.73 to 0.75), 0.76 (0.75 to 0.78), and 0.78 (0.75, 0.81), respectively. Similar trends were observed in blacks (p = 0.0031) and whites (p = 0.0118). Marker rs7844465 ( ZHX2 ) was significantly associated with left carotid IMT in whites (p = 0.0005); mean IMT levels for the GG, TG, and TT genotypes were 0.73 (0.71 to 0.74), 0.75 (0.74 to 0.77) and 0.78 (0.75 to 0.81), respectively. Marker rs6841473 ( EDNRA ) modified the association between smoking and left carotid IMT in blacks (p = 2.79 × 10 − 5 ). In addition, gene-based analysis demonstrated that EDNRA and ZHX2 were associated with left carotid IMT in the white and overall participants, respectively, while PINX1 was associated with right carotid IMT in both blacks and whites. Conclusion We identified two novel markers that were associated with IMT in both blacks and whites. One gene-smoking interaction was identified in blacks only. Three genes showed gene-based associations with IMT levels. However, genetic markers with small effects may have been missed due to the limited number of black participants. [ABSTRACT FROM AUTHOR]

Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine involved in the pathogenesis of spontaneous preterm birth (SPTB). We examined whether the MCP- 1 G-2518A polymorphism is associated with the risk of SPTB in a Chinese population. The MCP- 1 G-2518A polymorphism was genotyped in 569 preterm singleton neonates and in 673 term neonates using polymerase chain reaction-restriction fragment length polymorphism analysis. The distribution of the MCP- 1 G-2518A genotype and the allele frequencies between the SPTB patients and the controls were not significantly different in the overall sample. However, we found that the AA genotype was associated with significantly increased susceptibility to very SPTB (<32 weeks) [odds ratio (OR) 2.07; 95 % confidence interval (CI), 1.27-3.36; P = 0.005) and extremely SPTB (<28 weeks) (OR 2.74; 95 % CI, 1.10-6.72; P = 0.014) compared with −2518G-positive genotypes (GG + GA genotypes). When extremely preterm neonates and very preterm neonates were combined, the AA genotype was also significantly associated with increased susceptibility to SPTB (OR 2.23; 95 % CI, 1.40-3.54; P < 0.001). The MCP- 1 G-2518A polymorphism was not associated with increased susceptibility to SPTB in patients with premature rupture of the membranes (PROM) or in those without PROM. Our findings suggest that the MCP- 1 G-2518A polymorphism may plays a role in mediating the susceptibility to SPTB in the Chinese population. Knowledge of genetic factors contributing to the pathogenesis of SPTB may have implications for screening and treatment of this disorder. [ABSTRACT FROM AUTHOR]