#5537 GENETIC VARIABILITY IN THE PROSTAGLANDIN E2 PATHWAY IS RELATED TO SALT SENTIVITY IN TREATMENT-NAïVE HYPERTENSIVE PATIENTS
Authors: Gonzalez Luz Maria , Lanzani Chiara Livia , Simonini Marco , Citterio Lorena , Zagato Laura , Tunesi Francesca , Robles Roberto Nicolas , Gervasini Guillermo , Manunta Paolo 
Published: June 2023

Abstract

Background and Aims
Hypertensive nephropathy is a common aging-related disorder. One of the main factors that contributes to the development of hypertension is salt intake. Based on blood pressure (BP) variation after sodium intake in an acute salt load test, individuals can be grouped in: sodium sensitive (SS), sodium resistant (SR) or inverse sodium sensitivity (ISS). Prostaglandin E2 (PGE2) is the main renal metabolite of the cyclooxygenase pathway, a major actor mediating renal injury and it has also been related to renal blood flow and hemodynamic changes. Our aim was to determine common, functional variants in genes involved in the PGE2 pathway to identify associations with the sodium sensitivity phenotype of hypertensive patients, as well as with parameters of renal function and BP traits.

Method
We studied 511 treatment-naïve hypertensive patients, who were subjected to an acute salt load test and consequently stratified into 173 SR patients, 172 SS patients and 166 ISS, after they showed an increase in BP values (SS), no substantial variation (SR) or a paradoxical decrease (ISS). Renal function was established by estimated glomerular filtration rate (eGFR) using the MDRD-4 formula. All participants were screened for 216 tag-SNPs that define the variability of 12 genes of the PGE2 pathway, namely PLA2G4A, PLA2G7, SCARB1, PTGS1, PTGS2, PGTES, PTGES2, PTGES3, PTGER1, PTGER2, PTGER3 and PTGER4. Regression models were utilized to evaluate associations with clinical parameters.

Results
Using the SS group as a reference, eleven variants in genes coding for two phospholipases (PLA2G4A, PLA2G7), cyclooxygenase-1 (PGTS1) and PGE2 receptors (PTGER1 and PTGER4) were linked to the susceptibility of becoming SR or ISS patients. Seven of these variants produced protective odds ratios, whilst four of them were associated with increased risk (Table 1). Next, we analyzed BP traits in each cohort. In SR, PTGES3 rs12824563 was associated with variability in nighttime BP values (p&lt;0.001, p&lt;0.01, p&lt;0.001 and p&lt;0.05 for systolic BP, diastolic BP, mean BP and nighttime BP fall, respectively). For the SS group, two variants in PTGER3, rs61777123 and rs12410289, were also associated with the same parameters (p&lt;0.01). Finally, in the ISS group, the most significant finding was that PTGES2 rs13283456 was strongly linked to daytime and nighttime measurements (p&lt;0.001 for each parameter). Regarding renal function, we examined the 511 patients as a whole and observed that several variants affected eGFR. Most significantly, carriers of PTGER3 rs6424406 and rs1409986 were found to be associated with higher values [Mean difference vs. non carriers: 6.34 (2.42-10.26), p&lt;0.01 and 6.20 (1.76-10.64) ml/min/1,73 m2, p&lt;0.01].

Conclusion
Variability in genes that participate in the PGE2 pathway, is associated with the response of treatment-naïve hypertensive patients to salt intake. In addition, these genetic variants may also modify BP traits and eGFR values in these patients.