scholarly journals Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1258
Author(s):  
Juan Sainz ◽  
Francisco José García-Verdejo ◽  
Manuel Martínez-Bueno ◽  
Abhishek Kumar ◽  
José Manuel Sánchez-Maldonado ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Mononuclear Cells ◽  
Meta Analysis ◽  
Serum Levels ◽  
Peripheral Blood Mononuclear ◽  
Host Immune Responses ◽  
Genome Wide ◽  
Stimulation Of

The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, DAPK2 (p = 2.19 × 10−5) and ATG5 (p = 6.28 × 10−4) were associated with the risk of CRC. Mechanistically, the DAPK2rs11631973G allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus (p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (p = 0.0038) and serum levels of en-RAGE (p = 0.0068). ATG5rs546456T allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (p = 0.0088 and p = 0.0076, respectively), CD14+CD16− cell levels in blood (p = 0.0068) and serum levels of CCL19 and cortisol (p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses.

scholarly journals Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

2019 ◽  
Vol 78 (10) ◽  
pp. 1430-1437 ◽  
Author(s):  
Yusuke Kawamura ◽  
Hirofumi Nakaoka ◽  
Akiyoshi Nakayama ◽  
Yukinori Okada ◽  
Ken Yamamoto ◽  
...  
Keyword(s):  
Association Study ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Serum Uric Acid Level ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Significance Level ◽  
Replication Studies ◽  
Genome Wide ◽  
First Time

ObjectiveThe first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.MethodsWe carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia).ResultsThis new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10–8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three ‘gout vs AHUA GWAS’-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level.ConclusionsThis meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

scholarly journals Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich's ataxia patient cells

2020 ◽  
Vol 295 (52) ◽  
pp. 17973-17985
Author(s):  
Gabriela Vilema-Enríquez ◽  
Robert Quinlan ◽  
Peter Kilfeather ◽  
Roberta Mazzone ◽  
Saba Saqlain ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Epigenetic Modification ◽  
Fold Increase ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Peripheral Blood Mononuclear ◽  
Genome Wide ◽  
Novel Therapeutic

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

scholarly journals Inhibition of the SUV4-20 H1 histone methyltransferase increases frataxin expression in Friedreich’s ataxia patient cells

2020 ◽  
Author(s):  
G Vilema-Enríquez ◽  
R Quinlan ◽  
P Kilfeather ◽  
R Mazzone ◽  
S Saqlain ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Epigenetic Modification ◽  
Fold Increase ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Peripheral Blood Mononuclear ◽  
Genome Wide ◽  
Novel Therapeutic

AbstractThe molecular mechanisms of reduced frataxin (FXN) expression in Friedreich’s ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN-GAA-Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by approximately 1.5-fold in the reporter cell line and in several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogues were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression, and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

scholarly journals Genetic risk of clozapine-induced leukopenia and neutropenia: a genome-wide association study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jianhua Chen ◽  
Ping Yang ◽  
Qian Zhang ◽  
Ruirui Chen ◽  
Peng Wang ◽  
...  
Keyword(s):  
Association Study ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Significance Level ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

Abstract Background Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). Methods A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). Results The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10−8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10−8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. Conclusions The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.

scholarly journals Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helena R. R. Wells ◽  
Fatin N. Zainul Abidin ◽  
Maxim B. Freidin ◽  
Frances M. K. Williams ◽  
Sally J. Dawson
Keyword(s):  
Association Study ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Significance Threshold ◽  
Genome Wide ◽  
Final Sample ◽  
Close Proximity ◽  
Repressor Complex

AbstractTinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E−08), rs4900545 (p = 1.8E−08) and 14:103042287_CT_C (p = 3.50E−08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E−06.

scholarly journals Stimulation of production of prostaglandin E in gingival cells exposed to products of human blood mononuclear cells

1981 ◽  
Vol 198 (2) ◽  
pp. 391-396 ◽  
Author(s):  
S M D'Souza ◽  
D J Englis ◽  
A Clark ◽  
R G Russell
Keyword(s):  
Mononuclear Cell ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Gingival Tissue ◽  
Prostaglandin E ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Gingival Cells ◽  
Stimulation Of

1. Supernatant media from cultures of unstimulated human peripheral blood mononuclear cells contained one or more factors that increased by several hundred-fold the production of prostaglandin E by fibroblast-like cells derived from both inflamed and normal human gingival tissue. 2. This stimulation occurred in a dose-dependent manner and was completely inhibited by 14 microM-indomethacin. 3. Responsiveness to the factor declined as the age of the cell culture increased. 4. An increase in prostaglandin E production was first observed after a 2h exposure to the mononuclear cell factor(s) and could be prevented by cycloheximide. 5. Brief exposure (0.5 and 1.0 h) to mononuclear cell factor did not increase prostaglandin E production by the cells in a subsequent 72 h incubation in the absence of mononuclear cell factor. 6. Addition of arachidonate (10 microM and 15 microM) further enhanced stimulation of prostaglandin E production in response to mononuclear cell factor. 7. The stimulatory activity was resistant to digestion by trypsin, but was heat-labile, so that only 17% remained after treatment at 56 degrees C for 30 min.

scholarly journals Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaakko Laaksonen ◽  
Pashupati P. Mishra ◽  
Ilkka Seppälä ◽  
Leo-Pekka Lyytikäinen ◽  
Emma Raitoharju ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mitochondrial Dna ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Meta Analysis ◽  
Noncommunicable Diseases ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Mitochondrial Dna Variants

AbstractHigh blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

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