scholarly journals The Impact of Genetic Variants on PTEN Molecular Functions and Cellular Phenotypes

2019 ◽  
Vol 9 (11) ◽  
pp. a036228
Author(s):  
Nicholas Hasle ◽  
Kenneth A. Matreyek ◽  
Douglas M. Fowler
Keyword(s):  
Genetic Variants ◽  
Molecular Functions ◽  
Cellular Phenotypes ◽  
The Impact

Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

scholarly journals Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration

2018 ◽  
Vol 115 (50) ◽  
pp. E11701-E11710 ◽  
Author(s):  
Yoong Wearn Lim ◽  
Haiyin Chen-Harris ◽  
Oleg Mayba ◽  
Steve Lianoglou ◽  
Arthur Wuster ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Immunotherapy ◽  
Genetic Variants ◽  
Immune Cell ◽  
Response To Therapy ◽  
Cell Infiltration ◽  
Cancer Type ◽  
Immune Cell Infiltration ◽  
Durable Response ◽  
The Impact

Cancer immunotherapy has emerged as an effective therapy in a variety of cancers. However, a key challenge in the field is that only a subset of patients who receive immunotherapy exhibit durable response. It has been hypothesized that host genetics influences the inherent immune profiles of patients and may underlie their differential response to immunotherapy. Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor. We identified 64,094 expression quantitative trait loci (eQTLs) that associated with 18,210 genes (eGenes) across 24 human cancers. Overall, eGenes were enriched for their being involved in immune processes, suggesting that expression of immune genes can be shaped by hereditary genetic variants. We identified the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene as a pan-cancer type eGene whose expression levels stratified overall survival in a subset of patients with bladder cancer receiving anti–PD-L1 (atezolizumab) therapy. Finally, we identified 103 gene signature QTLs (gsQTLs) that were associated with predicted immune cell abundance within the tumor microenvironment. Our findings highlight the impact of germline SNPs on cancer-immune phenotypes and response to therapy; and these analyses provide a resource for integration of germline genetics as a component of personalized cancer immunotherapy.

GEMPROT: visualization of the impact on the protein of the genetic variants found on each haplotype

2018 ◽  
Vol 35 (14) ◽  
pp. 2492-2494
Author(s):  
Tania Cuppens ◽  
Thomas E Ludwig ◽  
Pascal Trouvé ◽  
Emmanuelle Genin
Keyword(s):  
Genetic Variants ◽  
Protein Sequence ◽  
Sequence Data ◽  
Protein Sequences ◽  
Supplementary Information ◽  
Analysis Tool ◽  
Functional Protein ◽  
Key Players ◽  
On Line ◽  
The Impact

Abstract Summary When analyzing sequence data, genetic variants are considered one by one, taking no account of whether or not they are found in the same individual. However, variant combinations might be key players in some diseases as variants that are neutral on their own can become deleterious when associated together. GEMPROT is a new analysis tool that allows, from a phased vcf file, to visualize the consequences of the genetic variants on the protein. At the level of an individual, the program shows the variants on each of the two protein sequences and the Pfam functional protein domains. When data on several individuals are available, GEMPROT lists the haplotypes found in the sample and can compare the haplotype distributions between different sub-groups of individuals. By offering a global visualization of the gene with the genetic variants present, GEMPROT makes it possible to better understand the impact of combinations of genetic variants on the protein sequence. Availability and implementation GEMPROT is freely available at https://github.com/TaniaCuppens/GEMPROT. An on-line version is also available at http://med-laennec.univ-brest.fr/GEMPROT/. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals The impact of genetic variants inIL1R2on cervical cancer risk among Uygur females from China: A case-control study

2018 ◽  
Vol 7 (1) ◽  
pp. e00516 ◽  
Author(s):  
Fanglin Niu ◽  
Tianchang Wang ◽  
Jing Li ◽  
Mengdan Yan ◽  
Dianzhen Li ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Risk ◽  
Genetic Variants ◽  
Case Control Study ◽  
Case Control ◽  
Cervical Cancer Risk ◽  
The Impact ◽  
Control Study

scholarly journals Genetic polymorphisms mediating behavioural and immune response to pathogens may moderate the impact of the COVID-19 pandemic: a pilot study

2020 ◽  
Author(s):  
Ravi Philip Rajkumar
Keyword(s):  
Immune Response ◽  
Pilot Study ◽  
Immune Responses ◽  
Genetic Variants ◽  
Mortality Rates ◽  
Therapeutic Strategies ◽  
Published Data ◽  
Entire World ◽  
S Allele ◽  
The Impact

AbstractBackgroundThe COVID-19 pandemic has affected the entire world, but there are wide variations in prevalence and mortality across nations. Genetic variants which influence behavioural or immune responses to pathogens, selected for by pathogen pressure, may influence this variability. Two relevant polymorphisms in this context are the s allele of the serotonin transporter promoter (5-HTTLPR) and the G allele of the interleukin-6 gene (IL-6 rs1800795).MethodsThe frequencies of the 5-HTTLPR s allele and IL-6 rs1800795 G allele were obtained from published data. The correlations between these allele frequencies and the prevalence and mortality rates of COVID-19 were examined across 44 nations.ResultsThe IL-6 rs1800795 G allele was negatively correlated with COVID-19 prevalence (ρ = −0.466, p < 0.01) and mortality (ρ = −0.591, p<0.001) across nations. The 5-HTTLPR s allele was negatively correlated with COVID-19 mortality rates (ρ = −0.437, p = 0.023).ConclusionsThese results suggest that a significant relationship exists between genetic variants that influence behavioural and immune responses to pathogens and indices of the impact of COVID-19 across nations. Further investigation of these variants and their correlates may permit the development of better preventive or therapeutic strategies in the management of the COVID-19 pandemic.

scholarly journals Oxidative Stress Inside the Pathogenesis of Ascending Aorta Aneurysms: A Clearer Vision for Identifying Promising Biomarkers and Therapeutic Targets

2021 ◽  
Author(s):  
Carmela Balistreri ◽  
Calogera Pisano ◽  
Giovanni Ruvolo
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Genetic Variants ◽  
Complex Disease ◽  
Ascending Aorta ◽  
Oxygen Species ◽  
Aorta Aneurysm ◽  
Independent Risk Factors ◽  
The Impact ◽  
And Oxidative Stress

Ascending aorta aneurysm (AsAA) is a complex disease, currently defined an inflammatory disease. In the sporadic form, AsAA has, indeed, a complex physiopathology with a strong inflammatory basis, significantly modulated by genetic variants in innate/inflammatory genes, acting as independent risk factors and as largely evidenced in our recent studies performed during the last 10 years. Based on these premises, here, we want to revise the impact of reactive oxygen species (ROS) and oxidative stress on AsAA pathophysiology and consequently on the onset and progression of sporadic AsAA. This might consent to add other important pieces in the intricate puzzle of the pathophysiology of this disease with the translational aim to identify biomarkers and targets to apply in the complex management of AsAA, by facilitating the AsAA diagnosis currently based only on imaging evaluations, and the treatment exclusively founded on surgery approaches.

Genetic variants involved in the lipid metabolism pathway to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC trials.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 118-118
Author(s):  
Jingyuan Wang ◽  
Joshua Millstein ◽  
Fotios Loupakis ◽  
Sebastian Stintzing ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lipid Metabolism ◽  
Genetic Variants ◽  
Progression Free Survival ◽  
Snp Markers ◽  
Acid Oxidation ◽  
Metabolism Pathway ◽  
Increased Risk ◽  
In Fire ◽  
The Impact

118 Background: Antiangiogenic drug (AAD)-triggered oxygen and nutrient depletion through suppression of angiogenesis switches the glucose-dependent metabolism to lipid-dependent metabolism. Blocking fatty acid oxidation can enhance AAD-mediated anti-tumor effects in colorectal cancer. Previous reports suggested that polymorphisms of the lipid metabolism-related genes are associated with the increased risk of CRC and poor clinical outcome in CRC. Therefore, we hypothesized that genetic variants in the lipid metabolism pathway may predict first-line treatment outcome in mCRC pts. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, FIRE-3 and MAVERICC, was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 25 selected SNPs in 10 genes involved in the lipid metabolism pathway (CD36, FABP4, LPCAT1, LPCAT2, PPARG, CPT1A, ACSS2, SREBF1, FASN, ACACA) was analyzed. Those treated with FOLFIRI/ bevacizumab (bev) in FIRE-3 (n = 107) and MAVERICC (n = 163) served as discovery and validation cohorts respectively, while FIRE-3 FOLFIRI/ cetuximab (cet) (n = 129) arm was used as the control. Interaction between each SNP and treatment was evaluated in FIRE-3 (FOLFIRI/bev arm vs. FOLFIRI/cet arm). Results: In the discovery (FIRE-3 bev) cohort, pts with FASN rs4485435 any C allele (N = 21) showed significantly shorter progression-free survival (PFS) (8.69 vs 13.48 months) compared to carriers of G/G (N = 62) in both univariate (hazard ratio [HR] = 2.88; 95% confidence interval [CI]: 1.57-5.29; p = 0.00037) and multivariate (HR = 2.87; 95%CI 1.4-5.9; p = 0.00675) analyses. These data were validated in the MAVERICC bev cohort in multivariate analysis (11.17 vs 14.06 months; HR = 2.07; 95%CI: 1.15-3.74; p = 0.02). Pts carrying any T allele in PPARG rs3856806 (N = 36) showed significantly longer overall survival (OS) (Not reached vs 42 months) than carriers of C/C (n = 93) in the FIRE-3 cet cohort in both univariate (HR = 0.4; 95%CI 0.17-0.92; p = 0.03) and multivariate (HR = 0.37; 95%CI 0.15-0.93; p = 0.02) analyses, but the association was not observed in the bev cohort of MAVERICC and FIRE-3. In the comparison of bev arm vs cet arm in FIRE-3, interactions were shown with FASN rs4485435 (p = 0.017) on PFS and PPARG rs3856806 (p = 0.059) on OS. Conclusions: Our study demonstrates for the first time that FASN polymorphism could predict outcomes of bev-based treatment in mCRC patients; Meanwhile PPARG polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the lipid metabolism pathway in contributing to resistance to anti-VEGF/EGFR treatment.

ADDRESSING THE IMPACT OF RARE GENETIC VARIANTS IN EXTENDED/MULTIPLEX BIPOLAR FAMILIES

2019 ◽  
Vol 29 ◽  
pp. S837-S838
Author(s):  
Claudio Toma ◽  
Alexander D. Shaw ◽  
Richard J.N. Allcock ◽  
Anna Heath ◽  
Kerrie D. Pierce ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Rare Genetic Variants ◽  
The Impact

scholarly journals Neuroligin dependence of social behaviour in Caenorhabditis elegans provides a model to investigate an autism-associated gene

2020 ◽  
Author(s):  
Helena Rawsthorne ◽  
Fernando Calahorro ◽  
Emily Feist ◽  
Lindy Holden-Dye ◽  
Vincent O’Connor ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Genetic Variants ◽  
Social Behaviour ◽  
Animal Studies ◽  
Model Organism ◽  
Autism Spectrum ◽  
C Elegans ◽  
Important Regulator ◽  
Human Mutation ◽  
The Impact

Abstract Autism spectrum disorder (ASD) is characterized by a triad of behavioural impairments including social behaviour. Neuroligin, a trans-synaptic adhesion molecule, has emerged as a penetrant genetic determinant of behavioural traits that signature the neuroatypical behaviours of autism. However, the function of neuroligin in social circuitry and the impact of genetic variation to this gene is not fully understood. Indeed, in animal studies designed to model autism, there remains controversy regarding the role of neuroligin dysfunction in the expression of disrupted social behaviours. The model organism, Caenorhabditis elegans, offers an informative experimental platform to investigate the impact of genetic variants on social behaviour. In a number of paradigms, it has been shown that inter-organismal communication by chemical cues regulates C. elegans social behaviour. We utilize this social behaviour to investigate the effect of autism-associated genetic variants within the social domain of the research domain criteria. We have identified neuroligin as an important regulator of social behaviour and segregate the importance of this gene to the recognition and/or processing of social cues. We also use CRISPR/Cas9 to edit an R-C mutation that mimics a highly penetrant human mutation associated with autism. C. elegans carrying this mutation phenocopy the behavioural dysfunction of a C. elegans neuroligin null mutant, thus confirming its significance in the regulation of animal social biology. This highlights that quantitative behaviour and precision genetic intervention can be used to manipulate discrete social circuits of the worm to provide further insight into complex social behaviour.

scholarly journals The impact of genetic background and cell lineage on the level and pattern of gene expression in position effect variegation

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Sidney H. Wang ◽  
Sarah C. R. Elgin
Keyword(s):  
Genetic Variants ◽  
Genetic Background ◽  
Position Effect ◽  
Cell Lineage ◽  
Inbred Lines ◽  
Position Effect Variegation ◽  
Fourth Chromosome ◽  
Heterochromatin Formation ◽  
Effect Variegation ◽  
The Impact

Abstract Background Chromatin-based transcriptional silencing is often described as a stochastic process, largely because of the mosaic expression observed in position effect variegation (PEV), where a euchromatic reporter gene is silenced in some cells as a consequence of juxtaposition with heterochromatin. High levels of variation in PEV phenotypes are commonly observed in reporter stocks. To ascertain whether background mutations are the major contributors to this variation, we asked how much of the variation is determined by genetic variants segregating in the population, examining both the level and pattern of expression using the fruit fly, Drosophila melanogaster, as the model. Results Using selective breeding of a fourth chromosome PEV reporter line, 39C-12, we isolated two inbred lines exhibiting contrasting degrees of variegation (A1: low expression, D1: high expression). Within each inbred population, remarkable similarity is observed in the degree of variegation: 90% of the variation between the two inbred lines in the degree of silencing can be explained by genotype. Further analyses suggest that this result reflects the combined effect of multiple independent trans-acting loci. While the initial observations are based on a PEV phenotype scored in the fly eye (hsp70-white reporter), similar degrees of silencing were observed using a beta-gal reporter scored across the whole fly. Further, the pattern of variegation becomes almost identical within each inbred line; significant pigment enrichment in the same quadrant of the eye was found for both A1 and D1 lines despite different degrees of expression. Conclusions The results indicate that background genetic variants play the major role in determining the variable degrees of PEV commonly observed in laboratory stocks. Interestingly, not only does the degree of variegation become consistent in inbred lines, the patterns of variegation also appear similar. Combining these observations with the spreading model for local heterochromatin formation, we propose an augmented stochastic model to describe PEV in which the genetic background drives the overall level of silencing, working with the cell lineage-specific regulatory environment to determine the on/off probability at the reporter locus in each cell. This model acknowledges cell type-specific events in the context of broader genetic impacts on heterochromatin formation.

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