Guillermo Solache-Berrocal
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Valeria Rolle-Sóñora
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Noelia Martín-Fernández
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Serafí Cambray
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José Manuel Valdivielso
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...
Abstract
Background and Aims
Individuals with chronic kidney disease (CKD) constitute a population with an exceptionally high cardiovascular risk. Vascular calcification, a common finding in these patients, is a known contributor to cardiovascular disease and several studies suggest it has a certain genetic component. Single nucleotide polymorphisms (SNPs) associated with the extent of calcification in CKD patients could therefore be used to predict individual susceptibility to calcification and subsequent increased cardiovascular risk. We consequently searched for associations of SNPs from candidate genes of known implication in the pathogenesis of vascular calcification (encoding cytokines, extracellular matrix proteins, members of the RANK/RANKL/OPG axis and vitamin D metabolism proteins) with the extent of arterial calcium deposits in order to improve the risk prediction of cardiovascular events in CKD patients.
Method
The study was performed in 1439 individuals from the NEFRONA population, which include CKD patients (stages 2-3, 4-5, and dialysis) as well as healthy controls recruited from 81 Spanish hospitals. Individuals were genotyped with the iPLEXGOLD MassARRAY technology and Assay Design v4 software for 61 SNPs from 22 genes. A continuous vascular calcification score was calculated from the echogenicity of atherosclerotic plaques detected by ultrasonography in the carotid and femoral arteries. Among several other clinical variables, the presence of cardiovascular events during a 4-year follow up was collected. Association of SNPs with calcification extent was identified by univariate linear regression models. Multiple linear regression with backward elimination was used for the selection of an appropriate SNP-based model adjusted by age, sex and CKD stages. Finally, a Cox proportional hazard regression model was applied for the prediction of cardiovascular risk.
Results
Arterial calcification scores were higher with increasing age, male sex, and advanced CKD stages (all p<0.001), as expected. Univariate linear regression analyses of all SNPs with the arterial calcification score as dependent variable retrieved p-values <0.05 for 6 six of them (rs11568820, rs2248359, rs2296241, rs3102735, rs385564 and rs495392), which were selected for subsequent analyses. These polymorphisms were next included in a multivariate linear regression model with CKD stage, age and sex as additional independent variables. Only rs2296241 of CYP24A1 (estimate 0.36, 95% CI 0.14 to 0.58, p=0.001 for homocygous GG) and rs495392 of KL (estimate -0.39, 95% CI -0.69 to -0.09, p=0.011 for homocygous TT) remained independently associated with the extent of calcium deposits. Finally, using Cox regression models, it was determined that both the CKD stage (HR [for dialysis stage]=8.34, 95% CI 4.59 to 15.15, p<0.001) and the calcification score (HR=2.05, 95% CI 1.67 to 2.54, p<0.001) predicted the development of cardiovascular events. Considering all possible risk factors, no differences were found in the rate of development of cardiovascular events according to the genotype for the two associated polymorphisms: rs2296241 HR=1.13, 95% CI 0.87 to 1.48, p=0.36; rs495392 HR=0.80 95% CI 0.63 to 1.03, p=0.08.
Conclusions
Polymorphisms of KL and CYP24A1 genes are associated with the extent of calcification in CKD individuals although they lack the capacity to predict cardiovascular events. However, the echogenic determination of the extent of arterial calcium deposits in CKD patients seems a promising non-invasive, non-irradiating method for the scoring of calcification and even the prediction of cardiovascular events. Further genetic association studies using this technique could therefore yield valuable results.
Pedal Arterial Calcification Score Is Associated With Hemodynamic Change and Major Amputation After Revascularization in Chronic Limb-Threatening Ischemia
