Abstract 158: PPAP2B Expression Regulates the Development of Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Paul Mueller ◽  
Liping Yang ◽  
Andrew Morris ◽  
Susan Smyth
Keyword(s):  
Gene Expression ◽  
Association Studies ◽  
Experimental Atherosclerosis ◽  
Protective Role ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
En Face ◽  
Healthy Control ◽  
Artery Disease ◽  
Human Atheroma

Coronary artery disease (CAD) is the leading cause of death in both men and women worldwide. The bioactive lipid lysophosphatidic acid (LPA) accumulates in human atheroma compared to levels in healthy control tissue. LPA can be degraded by the membrane protein lipid phosphate phosphatase 3 (LPP3), encoded by the gene PPAP2B. Noncoding polymorphisms in PPAP2B associate with CAD risk, and gene expression analysis indicates that individuals possessing the risk allele exhibit lower levels of PPAP2B mRNA in leukocytes and vascular cells. We hypothesize that decreased LPP3, as a result of low PPAP2B expression, accelerates experimental atherosclerosis. Murine models of tissue specific LPP3 knockdown were generated using the Cre-Lox system driven by either the MX-1 promoter (MX-1Δ) or the smooth muscle cell specific SM22 promoter (SM22Δ) in mice on the atherogenic LDLr -/- background. Following 12 weeks on Western diet, knockdown of LPP3 in both the MX-1Δ and the SM22Δ mice resulted in significantly more atherosclerosis by en face analysis compared to LPP3-fl/fl littermate controls. LPA content determined using LC/MS/MS tended to be higher in the proximal aortas of MX-1Δ and SM22Δ knockdown mice compared to controls. Significantly higher macrophage gene expression was observed in the MX-1Δ mice while IL-6 levels were significantly higher in the SM22Δ mice compared to controls. Finally, targeting LPP3 expression in the MX-1Δ, but not the SM22Δ, mice resulted in significantly higher circulating levels of LPA compared to controls. These results are consistent with accelerated atherosclerosis in LPP3 knockdown mice and suggest a protective role for LPP3 in CAD. Increased vascular LPA content, as a consequence of decreased LPP3 expression, may promote the infiltration of monocyte/macrophages into lesions as well as exacerbate inflammation to accelerate the development of CAD. Our findings provide mechanistic insight into the genome wide association studies that linked genetic variation in PPAP2B with risk of CAD and focus attention on the LPA/ LPP3 signaling nexus as a novel therapeutic strategy to prevent atherosclerosis.

scholarly journals Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jamie W. Robinson ◽  
Richard M. Martin ◽  
Spiridon Tsavachidis ◽  
Amy E. Howell ◽  
Caroline L. Relton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Association Studies ◽  
Tissue Expression ◽  
Tissue Type ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Causal Pathways ◽  
Genome Wide ◽  
Glioma Risk ◽  
Brain Tissues

AbstractGenome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.

scholarly journals A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome

2019 ◽  
Author(s):  
Tom G Richardson ◽  
Gibran Hemani ◽  
Tom R Gaunt ◽  
Caroline L Relton ◽  
George Davey Smith
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Complex Traits ◽  
Mendelian Randomization ◽  
Drug Repositioning ◽  
Association Studies ◽  
Thyroid Tissue ◽  
Genome Wide Association Studies ◽  
Tissue Specific ◽  
Genome Wide

AbstractBackgroundDeveloping insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. By applying the principles of Mendelian randomization, we have undertaken a systematic analysis to evaluate transcriptome-wide associations between gene expression across 48 different tissue types and 395 complex traits.ResultsOverall, we identified 100,025 gene-trait associations based on conventional genome-wide corrections (P < 5 × 10−08) that also provided evidence of genetic colocalization. These results indicated that genetic variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. We identified many examples of tissue-specific effects, such as genetically-predicted TPO, NR3C2 and SPATA13 expression only associating with thyroid disease in thyroid tissue. Additionally, FBN2 expression was associated with both cardiovascular and lung function traits, but only when analysed in heart and lung tissue respectively.We also demonstrate that conducting phenome-wide evaluations of our results can help flag adverse on-target side effects for therapeutic intervention, as well as propose drug repositioning opportunities. Moreover, we find that exploring the tissue-dependency of associations identified by genome-wide association studies (GWAS) can help elucidate the causal genes and tissues responsible for effects, as well as uncover putative novel associations.ConclusionsThe atlas of tissue-dependent associations we have constructed should prove extremely valuable to future studies investigating the genetic determinants of complex disease. The follow-up analyses we have performed in this study are merely a guide for future research. Conducting similar evaluations can be undertaken systematically at http://mrcieu.mrsoftware.org/Tissue_MR_atlas/.

scholarly journals CONVERGENT AGING LOCI: PATHWAYS THAT TRANSCEND INDIVIDUAL DISEASES

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S221-S221
Author(s):  
Luke C Pilling ◽  
Luigi Ferrucci ◽  
David Melzer
Keyword(s):  
Disease Risk ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Telomere Shortening ◽  
Chronic Disease Risk ◽  
Trade Offs ◽  
Age Related ◽  
Genome Wide ◽  
Artery Disease

Abstract Thousands of loci across the genome have been identified for specific diseases in genome-wide association studies (GWAS), yet very few are associated with lifespan itself. We hypothesized that specific biological pathways transcend individual diseases and affect health and lifespan more broadly. Using the published results for the most recent GWAS for 10 key age-related diseases (including coronary artery disease, type-2 diabetes, and several cancers) we identified 22 loci with a strong genetic association with at least three of the diseases. These multi-trait aging loci include known genes affecting multiple diverse health end points, such as CDKN2A/B (9p21.3) and APOE. There are also novel multi-trait genes including SH2B3 and CASC8, likely involved in hallmark pathways of aging biology, including telomere shortening and inflammation. Several of these loci involve trade-offs between chronic disease risk and cancer.

P708Identification of 26 novel loci that confer susceptibility to early-onset coronary artery disease in a Japanese population

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Oguri ◽  
K Kato ◽  
H Horibe ◽  
T Fujimaki ◽  
J Sakuma ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Genetic Variants ◽  
Early Onset ◽  
Association Studies ◽  
Allele Frequencies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Exact Test ◽  
Genome Wide ◽  
Artery Disease

Abstract Background Early-onset coronary artery disease (CAD) has a strong genetic component. Although genome-wide association studies have identified various genes and loci significantly associated with CAD mainly in European ancestry populations, genetic variants that contribute to susceptibility to this condition in Japanese individuals remain to be identified definitively. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to early-onset CAD in Japanese. We have now performed exome-wide association studies (EWASs) in subjects with early-onset CAD and controls. Methods A total of 7256 individuals aged ≤65 years was enrolled in the study. The EWAS was conducted with 1482 subjects with CAD and 5774 controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed with Illumina Human Exome-12 DNA Analysis BeadChip or Infinium Exome-24 BeadChip arrays. The relation of allele frequencies for 31,465 SNPs that passed quality control to CAD was examined with Fisher's exact test. To compensate for multiple comparisons of allele frequencies with CAD, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. Results The relation of allele frequencies for 31,465 SNPs to CAD with the use of Fisher's exact test showed that 170 SNPs were significantly (FDR <0.05) associated with CAD. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus, and dyslipidemia revealed that 162 SNPs were significantly (P<0.05) related to CAD. A stepwise forward selection procedure was performed to examine the effects of genotypes for the 162 SNPs on CAD. The 54 SNPs were significant (P<0.05) and independent [coefficient of determination (R2), 0.0008 to 0.0297] determinants of CAD. These SNPs together accounted for 15.5% of the cause of CAD. After examination of results from previous genome-wide association studies and linkage disequilibrium of the identified SNPs, we newly identified 21 genes (RNF2, YEATS2, USP45, ITGB8, TNS3, FAM170B-AS1, PRKG1, BTRC, MKI67, STIM1, OR52E4, KIAA1551, MON2, PLUT, LINC00354, TRPM1, ADAT1, KRT27, LIPE, GFY, EIF3L) and five chromosomal regions (2p13, 4q31.2, 5q12, 13q34, 20q13.2) that were significantly associated with CAD. Gene ontology analysis showed that various biological functions were predicted in the 18 genes identified in the present study. The network analysis revealed that the 18 genes had potential direct or indirect interactions with the 30 genes previously shown to be associated with CAD or with the 228 genes identified in previous genome-wide association studies of CAD. Conclusion We have newly identified 26 loci that confer susceptibility to CAD. Determination of genotypes for the SNPs at these loci may prove informative for assessment of the genetic risk for CAD in Japanese.

scholarly journals Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease

Neurology ◽  
2010 ◽  
Vol 74 (6) ◽  
pp. 480-486 ◽  
Author(s):  
F. Zou ◽  
M. M. Carrasquillo ◽  
V. S. Pankratz ◽  
O. Belbin ◽  
K. Morgan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer Disease ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Expression Levels ◽  
Genome Wide ◽  
Gene Expression Levels
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