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. 2022 May 2:13:817020.
doi: 10.3389/fphar.2022.817020. eCollection 2022.

Tag-SNPs in Phospholipase-Related Genes Modify the Susceptibility to Nephrosclerosis and its Associated Cardiovascular Risk

Luz M González  1 , Nicolás R Robles  2   3 , Sonia Mota-Zamorano  1   3 , José C Arévalo-Lorido  4 , José Manuel Valdivielso  5   3 , Juan López-Gómez  6 , Guillermo Gervasini  1   3
Affiliations

Tag-SNPs in Phospholipase-Related Genes Modify the Susceptibility to Nephrosclerosis and its Associated Cardiovascular Risk

Luz M González et al. Front Pharmacol. .

Abstract

Nephrosclerosis patients have a high cardiovascular (CV) risk that is very often of more concern than the renal disease itself. We aimed to determine whether variants in phospholipase-related genes, associated with atherosclerosis and CV outcomes in the general population, could constitute biomarkers of nephrosclerosis and/or its associated CV risk. We screened 1,209 nephrosclerosis patients and controls for 86 tag-SNPs that were identified in the SCARB1, PLA2G4A, and PLA2G7 gene loci. Regression models were utilized to evaluate their effect on several clinical parameters. Most notably, rs10846744 and rs838880 in SCARB1 showed significant odds ratios (OR) of 0.66 (0.51-0.87), p = 0.003 and 1.48 (1.11-1.96), p = 0.007 for nephrosclerosis risk. PLA2G4A and PLA2G7 harboured several SNPs associated with atherosclerosis measurements in the patients, namely common carotid intima media thickness (ccIMT), presence of plaques, number of plaques detected and 2-years ccIMT progression (significant p-values ranging from 0.0004 to 0.047). Eight SNPs in PLA2G4A were independent risk factors for CV events in nephrosclerosis patients. Their addition to a ROC model containing classic risk factors significantly improved its predictive power from AUC = 69.1% (61.4-76.9) to AUC = 79.1% (73.1-85.1%), p = 0.047. Finally, PLA2G4A rs932476AA and rs6683619AA genotypes were associated with lower CV event-free survival after controlling for confounding variables [49.59 (47.97-51.21) vs. 51.81 (49.93-51.78) months, p = 0.041 and 46.46 (41.00-51.92) vs. 51.17 (50.25-52.08) months, p = 0.022, respectively]. Variability in phospholipase-related genes play a relevant role in nephrosclerosis and associated atherosclerosis measurements and CV events.

Keywords: atherosclerosis; cardiovascular risk; nephrosclerosis; phospholipases; single nucleotide polymorphism.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Association between tag-SNPs in the PLA2G7 gene with atherosclerosis-related measurements. The dotted line denotes the level of statistical significance. ccIMT, common carotid intima media thickness (mm).
FIGURE 2
FIGURE 2
Association between tag-SNPs in the PLA2G4A gene with atherosclerosis-related measurements. The dotted line denotes the level of statistical significance.
FIGURE 3
FIGURE 3
Receiving Operating Curves for the risk of cardiovascular events in (A) nephrosclerosis patients and (B) the whole population of patients and controls. The blue line corresponds to the model with classic risk factors and the green line corresponds to the same model when genetic information is added. AUC, area under the curve.
FIGURE 4
FIGURE 4
Kaplan-Meier curves of the association of two PLA2G4A polymorphisms, rs932476 (A) and rs6683619 (B), with CV event-free survival.
See this image and copyright information in PMC

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