Genetic Variants in PGE2 Receptors Modulate the Risk of Nephrosclerosis and Clinical Outcomes in These Patients

Abstract

Prostaglandin E2 (PGE2) is a major actor mediating renal injury. We aimed to determine genetic variability in the genes coding for its receptors (PTGER1-4) and study associations with nephrosclerosis risk and clinical outcomes. We identified 96 tag-SNPs capturing global variability in PTGER1-4 and screened 1209 nephrosclerosis patients and controls. The effect of these variants was evaluated by multivariate regression analyses. Two PTGER3 SNPs, rs11209730 and rs10399704, remained significant in a backward elimination regression model with other non-genetic variables (OR = 1.45 (1.07–1.95), p = 0.016 and OR = 0.71 (0.51–0.99), p = 0.041, respectively). In the nephrosclerosis patients, a proximal region of PTGER3 was tagged as relevant for eGFR (p values for identified SNPs ranged from 0.0003 to 0.038). Two consecutive PTGER3 SNPs, rs2284362 and rs2284363, significantly decreased systolic (p = 0.005 and p = 0.0005), diastolic (p = 0.039 and p = 0.005), and pulse pressure values (p = 0.038 and 0.014). Patients were followed for a median of 47 months (7–54) to evaluate cardiovascular (CV) risk. Cox regression analysis showed that carriers of the PTGER1rs2241360 T variant had better CV event-free survival than wild-type individuals (p = 0.029). In addition, PTGER3rs7533733 GG carriers had lower event-free survival than AA/AG patients (p = 0.011). Our results indicate that genetic variability in PGE2 receptors, particularly EP3, may be clinically relevant for nephrosclerosis and its associated CV risk.

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

“…The main function of cPLA2, the enzyme encoded by PLA2G4A , is the release of arachidonic acid from the membrane to initiate a cascade of pro-inflammatory mediators. In this regard, our group has previously reported an association between SNPs in PGE2 receptors, at the end of this cascade, with the occurrence of CV events in CKD patients ( González et al, 2021 ). In addition, cPLA2 have been shown to mediate platelet aggregation induced by homocysteinemia ( d'Emmanuele di Villa Bianca et al, 2013 ) and by high doses of digoxin in atrial fibrillation that can be behind CV mortality in these patients ( Pastori et al, 2018 ).…”

“…Categorical variables were compared with the Chi-square test, whilst quantitative variables were compared by the Mann-Whitney or Kruskal-Wallis tests depending on the number of groups. The influence of the SNPs on the risk of nephrosclerosis and other clinical variables was assessed by regression modelling, adjusting for demographics and classic risk factors, namely age, sex, body mass index, ethnicity, diabetes, blood pressure and CKD stage, as formerly described ( Valls et al, 2019 ; González et al, 2021 ). Kaplan-Meier curves for evaluating the influence of SNPs on CV events were compared with log-rank tests.…”

Influence of variability in the cyclooxygenase pathway on cardiovascular outcomes of nephrosclerosis patients

“… This same population has also been analyzed in previous studies by our group 11 , 12 . BMI body mass index, eGFR estimated glomerular filtration rate, DM diabetes mellitus, ACR albumin-to-creatinine ratio, NS not significant.…”

“… SP slow progression, AP accelerated progression. These parameters have previously been analyzed in the same patients regarding their association with other gene sets in previous studies by our group 11 , 12 . …”

“…Genetics are known to play a role in CKD onset and development 9 , 10 , accordingly, we hypothesize that the pathway leading to PGE2 synthesis and its actions may be a suitable candidate for identifying genetic variants relevant for CKD, particularly for its CV-associated impact. Indeed, we have recently shown how single nucleotide polymorphisms (SNPs) in the genes coding for PGE2 receptors 11 and phospholipase-related genes 12 are associated with CV outcomes in these patients. Our aim was therefore to identify tag-SNPs (variants that represent variability in a certain region of the gene locus) in five candidate genes of the cyclooxygenase pathway (Fig.…”