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Genome-wide association study suggests impact of chromosome 10 rs139401390 on kidney function in patients with coronary artery disease.

ABSTRACT: Chronic kidney disease (CKD) is an independent risk factor for onset and progression of coronary artery disease (CAD). Discovery of predisposing loci for kidney function in CAD patients was performed using a genome-wide association approach. Inclusion criteria were CAD with ?50% stenosis (?1 coronary artery) and a creatinine-based estimated glomerular filtration rate (eGFR) of 30-75?ml/min/1.73?m2. An association of rs139401390 located to a region 58.8?kb upstream of renalase (RNLS) with eGFR was detected in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (n?=?499, p?=?7.88?×?10-9, mean eGFR 60.7?ml/min/1.73?m2). Direct genotyping of rs139401390A?>?G suggested increased eGFR by 12.0?ml/min/1.73?m2 per A allele (p?=?0.000004). Genome-wide replication of rs139401390A?>?G in the Coronary Artery Disease and Renal Failure (CAD-REF) registry with a mean eGFR of 47.8?ml/min/1.73?m2 (n?=?574, p?=?0.033) was only nominally significant. Comparison of rs139401390 genotypes for risk of reduced kidney function in the overall LURIC study revealed higher adjusted odds ratios (OR) for eGFR <60?ml/min/1.73?m2 for CAD patients (n?=?1992, OR?=?2.36, p?=?0.008, G/A?+?G/G vs A/A) compared to patients with/without CAD (n?=?2908, OR?=?1.97, p?=?0.014, G/A?+?G/G vs A/A). No significant risk elevation was detected in patients without CAD (n?=?948, p?=?0.571). rs139401390 may affect kidney function in CAD patients with mild reduction in eGFR.

SUBMITTER: Schmitz B

PROVIDER: S-EPMC6391429 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Genome-wide association study suggests impact of chromosome 10 rs139401390 on kidney function in patients with coronary artery disease.

Schmitz Boris B Kleber Marcus E ME Lenders Malte M Delgado Graciela E GE Engelbertz Christiane C Huang Jie J Pavenstädt Hermann H Breithardt Günter G Brand Stefan-Martin SM März Winfried W Brand Eva E

Scientific reports 20190226 1

Chronic kidney disease (CKD) is an independent risk factor for onset and progression of coronary artery disease (CAD). Discovery of predisposing loci for kidney function in CAD patients was performed using a genome-wide association approach. Inclusion criteria were CAD with ≥50% stenosis (≥1 coronary artery) and a creatinine-based estimated glomerular filtration rate (eGFR) of 30-75 ml/min/1.73 m<sup>2</sup>. An association of rs139401390 located to a region 58.8 kb upstream of renalase (RNLS) w ...[more]

PMID: 30809046

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Project description:Coronary artery disease (CAD), one of the leading causes of death globally, is influenced by both environmental and genetic risk factors. Gene-centric genome-wide association studies (GWAS) involving cases and controls have been remarkably successful in identifying genetic loci contributing to CAD. Modern in silico platforms, such as candidate gene prediction tools, permit a systematic analysis of GWAS data to identify candidate genes for complex diseases like CAD. Subsequent integration of drug-target data from drug databases with the predicted candidate genes can potentially identify novel therapeutics suitable for repositioning towards treatment of CAD.Previously, we were able to predict 264 candidate genes and 104 potential therapeutic targets for CAD using Gentrepid (http://www.gentrepid.org), a candidate gene prediction platform with two bioinformatic modules to reanalyze Wellcome Trust Case-Control Consortium GWAS data. In an expanded study, using five bioinformatic modules on the same data, Gentrepid predicted 647 candidate genes and successfully replicated 55% of the candidate genes identified by the more powerful CARDIoGRAMplusC4D consortium meta-analysis. Hence, Gentrepid was capable of enhancing lower quality genotype-phenotype data, using an independent knowledgebase of existing biological data. Here, we used our methodology to integrate drug data from three drug databases: the Therapeutic Target Database, PharmGKB and Drug Bank, with the 647 candidate gene predictions from Gentrepid. We utilized known CAD targets, the scientific literature, existing drug data and the CARDIoGRAMplusC4D meta-analysis study as benchmarks to validate Gentrepid predictions for CAD.Our analysis identified a total of 184 predicted candidate genes as novel therapeutic targets for CAD, and 981 novel therapeutics feasible for repositioning in clinical trials towards treatment of CAD. The benchmarks based on known CAD targets and the scientific literature showed that our results were significant (p < 0.05).We have demonstrated that available drugs may potentially be repositioned as novel therapeutics for the treatment of CAD. Drug repositioning can save valuable time and money spent on preclinical and phase I clinical studies.

Dataset Information

Genome-wide association study suggests impact of chromosome 10 rs139401390 on kidney function in patients with coronary artery disease.

Publications

Genome-wide association study suggests impact of chromosome 10 rs139401390 on kidney function in patients with coronary artery disease.

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