scholarly journals Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

2021 ◽  
Vol 12 ◽  
Author(s):  
Ye Lu ◽  
Chiara Corradi ◽  
Manuel Gentiluomo ◽  
Evangelina López de Maturana ◽  
George E. Theodoropoulos ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Target Genes ◽  
Meta Analysis ◽  
Micro Rna ◽  
Cancer Case ◽  
Nucleotide Polymorphisms ◽  
Genetic Heritability ◽  
Genome Wide ◽  
Association Data ◽  
Meta Analyses

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case–Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07–1.17, p = 3.03 × 10−6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.

Abstract 54: Genome-Wide Association Analysis of Gene-Sodium Interactions on Blood Pressure Phenotypes: The GenSalt Study

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Changwei Li ◽  
Jiang He ◽  
James Hixson ◽  
Dongfeng Gu ◽  
Dabeeru Rao ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Sodium Intake ◽  
Meta Analysis ◽  
Snp Array ◽  
Urinary Sodium Excretion ◽  
Dietary Sodium ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Inverse Variance ◽  
Meta Analyses

Background: Elevated blood pressure (BP) is a major public health challenge. Although the heritability of BP has been long established, current findings can explain only a small proportion of the BP variability attributed to genetic factors. Recent studies indicate that gene-environmental interactions may help to identify novel BP loci. Hence, the current study aimed to identify genetic variants influencing BP regulation by conducting genome-wide gene-sodium interaction analyses among 1,906 participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Methods: GenSalt recruited 1,906 Chinese participants from 633 families. At baseline, one 24-hour and two 8-hour urine specimens were collected to measure urinary sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 868,158 autosomal single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genomewide Human SNP array 6.0 (Affymetrix, Inc, Santa Clara, CA). Mixed effects models were used to test genome-wide SNP-sodium interactions on BP, adjusting for age, gender, and body mass index. Promising findings (interaction term P <1.00х10 -6 ) from GenSalt were further evaluated for replication among Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with available data from the database of genotypes and phenotypes (dbGaP). SNP effects in GenSalt and MESA were meta-analyzed using inverse-variance weighted fixed effect models. Results: The meta-analyses identified 3 novel loci that significantly interacted with sodium to influence BP phenotypes. SNP-sodium interactions on systolic BP were identified for NEK2 variant rs10494938 at 1q32.3 (GenSalt P =2.19х10 -6 , MESA P =4.35х10 -4 , and Meta-analysis P = 3.93х10 -8 ). In addition, CASP4 variant rs1944900 at 11q22.3 interacted with sodium to influence both systolic BP (GenSalt P =1.24х10 -9 , MESA P =4.22х10 -2 , and Meta-analysis P = 1.14х10 -10 ) and mean arterial pressure (GenSalt P =1.68х10 -9 , MESA P =4.27х10 -2 , and Meta-analysis P = 1.91х10 -10 ). Furthermore, C9orf3 variant rs17679141 at 9q22.32 interacted with sodium to influence diastolic BP (GenSalt P =2.85х10 -8 , MESA P =4.55х10 -2 , and Meta-analysis P =4.61х10 -9 ). The 3 variants all physically mapped to the intronic regions of their corresponding genes. Conclusion: The current study identified 3 novel loci which may interact with dietary sodium intake to influence BP phenotypes.

scholarly journals A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

2021 ◽  
Author(s):  
Sally Mortlock ◽  
Rosari I Corona ◽  
Pik Fang Kho ◽  
Paul Pharoah ◽  
Ji-Heui Seo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Genetic Correlation ◽  
Target Genes ◽  
Meta Analysis ◽  
Causal Variant ◽  
Genome Wide ◽  
Increased Risk ◽  
Genetic Overlap ◽  
Meta Analyses ◽  
Shared Risk

Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Data from large endometriosis and EOC genome-wide association meta-analyses were used to estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and major EOC histotypes, and to identify shared susceptibility loci. We estimated a significant genetic correlation (rg) between endometriosis and clear cell (rg=0.71), endometrioid (rg=0.48) and high-grade serous (rg=0.19) ovarian cancer, all supported by Mendelian randomization analyses. A bivariate meta-analysis identified 28 loci associated with endometriosis and EOC, including two novel risk loci, and 19 with evidence for a single underlying causal variant. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlighted several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

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.

Genetic Polymorphisms and the Risk of Diabetic Foot: A Systematic Review and Meta-Analyses

2020 ◽  
pp. 153473462097759
Author(s):  
Jun Zhao ◽  
Le-Xuan Zhang ◽  
Yu-Ting Wang ◽  
Yang Li ◽  
Hong-Lin Chen, MD
Keyword(s):  
Genetic Polymorphisms ◽  
Diabetic Foot ◽  
Protective Factor ◽  
Meta Analysis ◽  
Nucleotide Polymorphisms ◽  
Asian Populations ◽  
Tnf Α ◽  
Newcastle Ottawa Scale ◽  
Meta Analyses ◽  
Relationship Of

Background Diabetic foot (DF) is a dangerous complication of diabetes. The aim of the study was to synthesize all the published single nucleotide polymorphisms (SNPs) of DF to objectively evaluate the relationship of SNPs and DF risks. Methods The HuGE database and CNKI were searched for eligible publications on genetic polymorphisms and the risk of DF systematically. The quality of literatures was evaluated by the Newcastle-Ottawa scale. Pooled odds ratios with a 95% confidence interval for SNPs were evaluated through 3 genetic models. Results Citing 29 different polymorphisms from 24 articles and the study met our selection criteria. There were 24 polymorphisms summarized systematically, and 5 merged polymorphisms for a meta-analysis: 9 positively associated with DF: HIF-1α rs11549465, TNF-α rs1800629, TLR-9 rs5743836, FIB rs6056, HSP70-2437C/T, VDR rs2228570, LOX rs1800449, ITLN1 rs2274907, and OPG rs2073617, but OPG rs3134069 was not a risk factor in DF; 6 negatively associated with DF: VEGF rs833061 and rs2010963, MCP-1 rs1024611, SDF-1 rs1801157, SIRT1 rs12778366, and OPG rs2073617. In addition, 13 polymorphisms were not associated with DF: MMP-9 rs3918242, eNOS rs1799983, VEGF rs3025039, -7C/T, rs1570360, rs13207351, and rs699947, IL-6 rs1800795, HIF-1α rs11549467, TNF-α rs361525, TLR-2 rs3804100, SIRT1 rs3758391, and TIMP-1 rs2070584. Conclusions The study provided some evidence for SNPs to the development of diabetic foot. The meta-analysis showed that rs1024611 of MCP-1 may be regarded as a protective factor, especially in Asian populations. Other loci indicated inconsistent results.

scholarly journals Meta-Analyses of Genome-Wide Association Data Hold New Promise for Addiction Genetics

2016 ◽  
Vol 77 (5) ◽  
pp. 676-680 ◽  
Author(s):  
Arpana Agrawal ◽  
Howard J. Edenberg ◽  
Joel Gelernter
Keyword(s):  
Genome Wide Association ◽  
Genome Wide ◽  
Association Data ◽  
Meta Analyses

scholarly journals Genome-Wide Association study Identifies a Novel Association Between a Cardiovascular Gene Polymorphism and Superior Athletic Performance

2020 ◽  
Author(s):  
Mohamed Elrayess ◽  
Fatima Al-Khelaifi ◽  
Noha Yousri ◽  
Omar Al-Bagha
Keyword(s):  
Athletic Performance ◽  
Genome Wide Association Study ◽  
Endurance Athlete ◽  
Meta Analysis ◽  
Significant Snps ◽  
Nucleotide Polymorphisms ◽  
Replication Studies ◽  
Genome Wide ◽  
Small Effect Size ◽  
Metabolomics Analysis

Research into the genetic predisposition to superior athletic performance has been a hindered by the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. Results: The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high (n=662) and low/moderate (n=134) aerobic component. Validation of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (MYBPC3; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status (P=1.43E-08, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO2max than carriers of the AA+AG (P = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82x10-05) including the testosterone precursor androstenediol (3beta, 17beta) disulfate. Conclusion: This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted.

scholarly journals Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Alison P. Klein ◽  
Brian M. Wolpin ◽  
Harvey A. Risch ◽  
Rachael Z. Stolzenberg-Solomon ◽  
Evelina Mocci ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Meta Analysis ◽  
Susceptibility Loci ◽  
Genome Wide

Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes

Circulation ◽  
2016 ◽  
Vol 133 (suppl_1) ◽  
Author(s):  
James S Floyd ◽  
Colleen Sitlani ◽  
Christy L Avery ◽  
Eric A Whitsel ◽  
Leslie Lange ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Qt Interval ◽  
Association Studies ◽  
Meta Analysis ◽  
Small Sample ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Meta Analyses

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P < 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

scholarly journals EGFR Polymorphism and Survival of NSCLC Patients Treated with TKIs: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Vladimir Jurisic ◽  
Vladimir Vukovic ◽  
Jasmina Obradovic ◽  
Lyudmila F. Gulyaeva ◽  
Nikolay E. Kushlinskii ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Association Studies ◽  
Meta Analysis ◽  
Growth Factor Receptor ◽  
Fixed Effect Model ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Ca Repeat ◽  
Meta Analyses ◽  
Nsclc Patients

Tyrosine kinase inhibitor- (TKI-) based therapy revolutionized the overall survival and the quality of life in non-small-cell lung cancer (NSCLC) patients that have epidermal growth factor receptor (EGFR) mutations. However, EGFR is a highly polymorphic and mutation-prone gene, with over 1200 single nucleotide polymorphisms (SNPs). Since the role of EFGR polymorphism on the treatment outcome is still a matter of debate, this research analyzed the available literature data, according to the PRISMA guidelines for meta-analyses. Research includes PubMed, Scopus, ISI Web of Science, and 14 of genome-wide association studies (GWAS) electronic databases in order to provide quantitative assessment of the association between ten investigated EGFR SNPs and the survival of NSCLC patients. The pooled HR and their 95% CI for OS and PFS for different EGFR polymorphisms using a random or fixed effect model based on the calculated heterogeneity between the studies was applied. The longest and the shortest median OSs were reported for the homozygous wild genotype and a variant allele carriers for rs712829 (-216G>T), respectively. Quantitative synthesis in our study shows that out of ten investigated EGFR SNPs (rs11543848, rs11568315, rs11977388, rs2075102, rs2227983, rs2293347, rs4947492, rs712829, rs712830, and rs7809028), only four, namely, rs712829 (-216G>T), rs11568315 (CA repeat), rs2293347 (D994D), and rs4947492, have been reported to affect the outcome of TKI-based NSCLC treatment. Of these, only -216G>T and variable CA repeat polymorphisms have been confirmed by meta-analysis of available data to significantly affect OS and PFS in gefitinib- or erlotinib-treated NSCLC patients.

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