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Glucagon-like peptide-1 receptor and sarcoglycan delta genetic variants can affect cardiovascular risk in chronic kidney disease patients under hemodialysis.

ABSTRACT: Background:Chronic kidney disease (CKD) patients under hemodialysis show a higher risk of cardiovascular (CV) mortality and morbidity than the general population. This study aims to identify genetic markers that could explain the increased CV risk in hemodialysis. Methods:A total of 245 CKD patients under hemodialysis were recruited and followed up for 5?years to record CV events. Genetic analysis was performed using single-nucleotide polymorphisms (SNPs) genotyping by Infinium Expanded Multi-Ethnic Genotyping Array (Illumina, San Diego, CA, USA) comparing patients with and without a history of CV events [161 cardiovascular diseases (CVDs) and 84 no CVDs]. The fixation index (Fst) measure was used to identify the most differentiated SNPs, and gene ontology analysis [Protein Analysis THrough Evolutionary Relationships (PANTHER) and Ingenuity Pathway Analysis (IPA)] was applied to define the biological/pathological roles of the associated SNPs. Partitioning tree analysis interrogated the genotype-phenotype relationship between discovered genetic variants and CV phenotypes. Cox regression analysis measured the effect of these SNPs on new CV events during the follow-up (FU). Results:Fst analysis identified 3218 SNPs that were significantly different between CVD and no CVD. Gene ontology analysis identified two of these SNPs as involved in cardiovascular disease pathways (Ingenuity Pathway) and heart development (Panther) and belonging to 2 different genes: Glucagon-like peptide-1 receptor (GLP1R) and Sarcoglycan delta (SGCD). The phenotype-genotype analysis found a higher percentage of CVD patients carrying the GLP1R rs10305445 allele A (P?=?0.03) and lower percentages of CVD patients carrying the SGCD rs145292439 allele A (P?=?0.038). Moreover, SGCD rs145292439 was associated with higher levels of high-density lipoprotein (P?=?0.015). Cox analysis confirmed the increased frequency of CV events during the 5-year FU in patients carrying GLP1R rs1035445 allele A but it did not show any significant association with SGCD rs145292439. Conclusions:This study identified GLP1R rs10305445 and SCGD rs145292439 as potential genetic markers that may explain the higher risk of CVD in hemodialysis patients.

SUBMITTER: Terranegra A

PROVIDER: S-EPMC7467592 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Glucagon-like peptide-1 receptor and sarcoglycan delta genetic variants can affect cardiovascular risk in chronic kidney disease patients under hemodialysis.

Terranegra Annalisa A Arcidiacono Teresa T Macrina Lorenza L Brasacchio Caterina C Pivari Francesca F Mingione Alessandra A Tomei Sara S Mezzavilla Massimo M Silcock Lee L Cozzolino Mario M Palmieri Nicola N Conte Ferruccio F Sirtori Marcella M Rubinacci Alessandro A Soldati Laura L Vezzoli Giuseppe G

Clinical kidney journal 20200205 4

<h4>Background</h4>Chronic kidney disease (CKD) patients under hemodialysis show a higher risk of cardiovascular (CV) mortality and morbidity than the general population. This study aims to identify genetic markers that could explain the increased CV risk in hemodialysis.<h4>Methods</h4>A total of 245 CKD patients under hemodialysis were recruited and followed up for 5 years to record CV events. Genetic analysis was performed using single-nucleotide polymorphisms (SNPs) genotyping by Infinium Ex ...[more]

PMID: 32905248

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Project description:ImportanceAtherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality for patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). However, testing for albuminuria among patients with T2D is substantially underutilized in clinical practice; many patients with CKD go unrecognized. For patients with T2D at high cardiovascular risk, or with established CVD, the glucagon-like peptide-1 receptor agonists (GLP1-RA) have been shown to reduce ASCVD in cardiovascular outcome trials, while potential kidney outcomes are being explored.ObservationsA recent meta-analysis found that GLP1-RA reduced 3-point major adverse cardiovascular events by 14% [HR, 0.86 (95% CI, 0.80-0.93)] in patients with T2D. The benefits of GLP1-RA to reduce ASCVD were at least as large among people with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. GLP1-RA also conferred a 21% reduction in the composite kidney outcome [HR, 0.79 (0.73-0.87)]; however, this result was achieved largely through reduction in albuminuria. It remains uncertain whether GLP1-RA would confer similar favorable results for eGFR decline and/or progression to end-stage kidney disease. Postulated mechanisms by which GLP1-RA confer protection against CVD and CKD include blood pressure lowering, weight loss, improved glucose control, and decreasing oxidative stress. Ongoing studies in T2D and CKD include a kidney outcome trial with semaglutide (FLOW, NCT03819153) and a mechanism of action study (REMODEL, NCT04865770) examining semaglutide's effect on kidney inflammation and fibrosis. Ongoing cardiovascular outcome studies are examining an oral GLP1-RA (NCT03914326), GLP1-RA in patients without T2D (NCT03574597), and dual GIP/GLP1-RA agonists (NCT04255433); the secondary kidney outcomes of these trials will be informative.Conclusions and relevanceDespite their well-described ASCVD benefits and potential kidney protective mechanisms, GLP1-RA remain underutilized in clinical practice. This highlights the need for cardiovascular clinicians to influence and implement use of GLP1-RA in appropriate patients, including those with T2D and CKD at higher risk for ASCVD.

Dataset Information

Glucagon-like peptide-1 receptor and sarcoglycan delta genetic variants can affect cardiovascular risk in chronic kidney disease patients under hemodialysis.

Publications

Glucagon-like peptide-1 receptor and sarcoglycan delta genetic variants can affect cardiovascular risk in chronic kidney disease patients under hemodialysis.

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