AUTHOR=González Luz M. , Robles Nicolás R. , Mota-Zamorano Sonia , Arévalo-Lorido José C. , Valdivielso José Manuel , López-Gómez Juan , Gervasini Guillermo 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.817020

DOI=10.3389/fphar.2022.817020

ISSN=1663-9812

ABSTRACT=<p>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 <italic>SCARB1</italic>, <italic>PLA2G4A,</italic> and <italic>PLA2G7</italic> gene loci. Regression models were utilized to evaluate their effect on several clinical parameters. Most notably, rs10846744 and rs838880 in <italic>SCARB1</italic> showed significant odds ratios (OR) of 0.66 (0.51–0.87), <italic>p</italic> = 0.003 and 1.48 (1.11–1.96), <italic>p</italic> = 0.007 for nephrosclerosis risk. <italic>PLA2G4A</italic> and <italic>PLA2G7</italic> 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 <italic>p</italic>-values ranging from 0.0004 to 0.047). Eight SNPs in <italic>PLA2G4A</italic> 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%), <italic>p</italic> = 0.047. Finally, <italic>PLA2G4A</italic> 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, <italic>p</italic> = 0.041 and 46.46 (41.00–51.92) vs. 51.17 (50.25–52.08) months, <italic>p</italic> = 0.022, respectively]. Variability in phospholipase-related genes play a relevant role in nephrosclerosis and associated atherosclerosis measurements and CV events.</p>