The rs1126616 Single Nucleotide Polymorphism of the Osteopontin Gene Is Independently Associated with Cardiovascular Events in a Chronic Kidney Disease Cohort.

Serafí Cambray,José M Valdivielso,Rajesh Kumar Galimudi,Milica Bozic,Isabel Rodríguez,Marcelino Bermúdez-López

doi:10.3390/jcm8050592

Abstract

Chronic kidney disease (CKD) is associated with a higher risk of cardiovascular events (CVE), partly due to the higher burden of atherosclerosis. Circulating Osteopontin (OPN) levels have been also shown to have a potential role in the development of atherosclerosis. Indeed, CKD patients show an increase in circulating OPN levels, but their effect of CKD-related atherosclerosis is not clear. Polymorphisms in the OPN gene (SPP1) have been studied in atheromatous disease, but reported results show conflictive findings. Thus, the main aim of the present study is to analyze the influence of SPP1 polymorphisms in CVE in CKD patients, taking into account circulating OPN levels. We followed 559 healthy controls and 2445 CKD patients without previous CVE from the National Observatory of Atherosclerosis in Nephrology study (NEFRONA study). After 48 months of follow-up 206 CVE were recorded. Genotyping for rs9138, rs1126616, rs1126772, rs11730582 and rs28357094 polymorphisms of the SPP1 gene was performed along with the measurements of plasma OPN levels. The group of patients with CVE showed higher incidence of atherosclerotic plaque (90.3% vs 64.5%; p < 0.001) and higher OPN levels (p < 0.001) at baseline. Patients with the heterozygous genotype of the rs1126616 polymorphism showed a higher hazard ratio of having a CVE, even after adjustment for multiple potential confounders. After adjustment, OPN levels were no longer associated with the incidence of CVE. We found that the rs1126616 single nucleotide polymorphism (SNP) of the SPP1 gene is independently associated with a higher incidence of CVE in a cohort of CKD patients and that it could be used to predict CVE risk.

Highlights

Chronic kidney disease (CKD) is associated with a higher risk for cardiovascular events (CVE) [1]
Cardiovascular events are one of the main complications of CKD patients, in which cardiovascular mortality is the main cause of death [33]
Among the metabolic alterations presented by CKD patients that could be involved in the excessive cardiovascular complications, changes in mineral metabolism are suggested to play a role [2,36,37]

Summary

Introduction

Chronic kidney disease (CKD) is associated with a higher risk for cardiovascular events (CVE) [1] This increased risk seems to be strongly associated with electrolyte disturbances in dialysis patients, with a higher burden of atheromatous plaque playing a paramount role in the earlier stages [2,3]. OPN is a secreted protein that contains several functional domains, including a number of integrin-interacting domains which facilitate the recruitment of inflammatory cells [6] It is upregulated in atherosclerotic settings, where it is expressed by macrophages, endothelial and vascular smooth muscle cells, and modulates the inflammatory response by recruiting multiple inflammatory cell types [7,8,9]. Several studies have related high circulating levels of OPN to adverse cardiovascular events in the general population [17] and in CKD patients [18]

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