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Gene expression profile of calcified and normal tricuspid aortic valves by RNA sequencing.

ABSTRACT: Purpose: Calcific aortic valve stenosis (AS) is a fatal disease with currently no medical therapy. Some genes were associated with AS, but the genetic architecture of the disease has yet to be discovered. The objective of this study was to combine genome-wide association studies (GWAS) and gene expression in human valve tissues to identify new susceptibility genes of AS. Methods: A meta-analysis was performed combining the results of two independent GWAS in 474 patients that underwent aortic valve replacement from Quebec city and 486 echocardiography cases from France. The controls consisted of 3,151 publically available individuals of European ancestry. Sixty-nine SNPs selected from the meta-analysis (p < 1 x 10-4) were followed-up for replication in a third cohort of 395 cases and 404 controls. Single marker and gene set association analyses were performed. The mRNA expression levels of susceptibility genes were evaluated in 19 human aortic valves with (n=9) and without (n=10) AS by RNA sequencing. Results: Single marker analysis identified 15 SNPs with p values lower than 1 x 10-6 in the meta-analysis near the FAR2 gene on chromosome 12. At the replication stage, none of these SNPs were confirmed and three other SNPs on chromosomes 2 and 5 reached p < 0.05. Gene set analysis revealed more meaningful association with the calcium signaling pathway enriched for genes mapped to disease-associated SNPs. Genes in this pathway including F2R, GNA14, HTR4, P2RX6, and TNNC1 were found differentially expressed in valves with and without AS. Conclusions: This integrative genomic study identified new AS susceptibility genes expressed in human valve tissue. Moderate but coordinated genetic association and expression patterns were observed for genes implicated in the calcium signaling pathway and may provide new therapeutic targets to treat this frequent and rising life-threatening disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55492 | GEO | 2015/12/09

SECONDARY ACCESSION(S): PRJNA239776

REPOSITORIES: GEO

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Project description:Purpose: Calcific aortic valve stenosis (AS) is a fatal disease with currently no medical therapy. Some genes were associated with AS, but the genetic architecture of the disease has yet to be discovered. The objective of this study was to combine genome-wide association studies (GWAS) and gene expression in human valve tissues to identify new susceptibility genes of AS. Methods: A meta-analysis was performed combining the results of two independent GWAS in 474 patients that underwent aortic valve replacement from Quebec city and 486 echocardiography cases from France. The controls consisted of 3,151 publically available individuals of European ancestry. Sixty-nine SNPs selected from the meta-analysis (p < 1 x 10-4) were followed-up for replication in a third cohort of 395 cases and 404 controls. Single marker and gene set association analyses were performed. The mRNA expression levels of susceptibility genes were evaluated in 19 human aortic valves with (n=9) and without (n=10) AS by RNA sequencing. Results: Single marker analysis identified 15 SNPs with p values lower than 1 x 10-6 in the meta-analysis near the FAR2 gene on chromosome 12. At the replication stage, none of these SNPs were confirmed and three other SNPs on chromosomes 2 and 5 reached p < 0.05. Gene set analysis revealed more meaningful association with the calcium signaling pathway enriched for genes mapped to disease-associated SNPs. Genes in this pathway including F2R, GNA14, HTR4, P2RX6, and TNNC1 were found differentially expressed in valves with and without AS. Conclusions: This integrative genomic study identified new AS susceptibility genes expressed in human valve tissue. Moderate but coordinated genetic association and expression patterns were observed for genes implicated in the calcium signaling pathway and may provide new therapeutic targets to treat this frequent and rising life-threatening disease. Samples of aortic valves were collected from 19 male patients undergoing aortic valve replacement surgery. RNA sequencing was performed using the Illumina Hiseq 2000. Three pairwise comparison among the two kind of valves were made.

Project description:Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure. Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.

Project description:Medical research focuses on disease-specific genes. By contrast, here we systematically examined the roles of shared genes for disease susceptibility and as therapeutic and diagnostic targets. Meta-analysis of all published disease-related genome-wide association studies (GWAS) showed that T helper (Th) cell differentiation was the most shared pathway. Expression profiling data from highly diverse CD4+ T cell-associated diseases revealed shared disease-associated genes, which were enriched for Th cell differentiation, but also metabolic and proliferative pathways. This pleiotropy suggested that altered functions of shared genes could generally increase disease susceptibility. Indeed, compared to specific genes, the shared genes were enriched for disease-associated SNPs identified by allÂ published disease-related GWAS. To examine if the shared genes induced disease-relevant pathways, we focused on transcription factors (TFs) that induced Th differentiation. Those TFs were enriched among the shared genes, as well as for disease-associated SNPs identified by GWAS, and disease-phenotypes in mice knock-out studies. Original GWAS and profiling data fromÂ patients with multiple sclerosis and allergyÂ confirmed enrichment of disease-associated SNPs in the TFs, and that the TFs were differentially expressed at early disease stages, and their targets increased in parallel with disease development. From a clinical perspective, the shared genes were significantly enriched for known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed that shared or specific genes could be used to stratify patients for individualized medicine. Our findings show that shared disease genes generally increase disease susceptibility and are important therapeutic and diagnostic targets. Patients with multiple sclerosis (MS) display variations in response to natalizumab treatment. PBMCs were collected from 8 high responders (HR) and 8 low responders (LR) to natalizumab treatment. CD4+ T cells were cultured for 48h. Cells were activated with anti-CD3 and anti-CD28 mAbs (0.5 Âµg/mL), either with natalizumab (25 Âµg/mL BiogenIdec) or without additional stimulus. Gene expression analysis was performed using SurePrint G3 Human Gene Expression 8X60K microarrays.

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Gene expression profile of calcified and normal tricuspid aortic valves by RNA sequencing.

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