Identification of endophenotypes supporting outcome prediction in hemodialysis patients based on mechanistic markers of statin treatment
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PROVIDER: PRJNA860171 | ENA |
REPOSITORIES: ENA
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Project description:Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of patients taking statins experience muscle related adverse events. Myalgia, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels, is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin-associated myalgia are not clearly understood. To elucidate changes in gene expression associated with statin-induced myalgia, we compared profiles of gene expression in the biopsied skeletal muscle from statin-intolerant patients undergoing statin re-challenge versus those of statin-tolerant controls. A robust separation of statin-intolerant and statin-tolerant cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of statin intolerant patients, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals are genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myopathy were observed with increased frequency among statin-intolerant study subjects.
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Project description:Secondary hyperparathyroidism is well known complication manifested in end-stage renal disease (ESRD). Both nodular and diffuse parathyreoid hyperplasia occur in ESRD patients. Distinct molecular mechanisms involved in parathyreoid hyperplasia remain poorly understood. Microarray screening proved homogeneity of gene transcripts in hemodialysis patients as compared to transplant cohort and primary hyperparathyreoidism, therefore further studies were performed in hemodialysis patints only. Enrichment analysis conducted on 485 differentially expressed genes between nodular and diffuse parathyreoid hyperplasia revealed highly significant differences in GO terms and KEGG database in ribosome structure (p=3.70-18). Next, RT-qPCR validation of microarray analysis proved higher expression of RAN guanine nucleotide release factor (RANGRF, p<0.001), calcyclin binding protein (CACYBP, p<0.05) and exocyst complex component 8 (EXOC8, p<0.05) and lower expression of peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1, p<0.01) mRNA in nodular hyperplasia. Multivariate analysis revealed RANGRF and PIN1 expression along with parathyroid weight to be associated with nodular hyperplasia. Higher expression of genes associated with ribosomal structure and function underline extended translation mechanisms involved in parathyreoid nodular formation in long-term hemodialysis treated patients. Parathyroid tissue obtained from ESRD hyperparathyroidism patients who had undergone parathyroidectomy were used for transcriptome screening (Illumina HumanHT-12 v4.0 Expression BeadChips) and subsequently for discriminatory gene analysis, pathway mapping and gene-annotation enrichment analyses. Results were verified on enlarged group of hemodialysis patients with nodular (n=20) and diffuse (n=20) hyperplasia using RT-qPCR method.
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