#4434 IMPACT OF GENETIC FACTORS FOR SALT-SENSITIVE HYPERTENSION AND RENAL DAMAGE ON HOSPITALIZED COVID-19 PATIENTS
Authors: Simonini Marco , Citterio Lorena , Messaggio Elisabetta , Zagato Laura , Tresoldi Cristina , De Lorenzo Rebecca , Querini Patrizia Rovere , Manunta Paolo , Lanzani Chiara Livia 
Published: June 2023

Abstract

Background and Aims
The coronavirus SARS-CoV-2 infects patients by binding human angiotensin-converting enzyme 2. Also, the ATP1A1 subunit of the plasma membrane Na-K-pump is critical in supporting the entry of SARS-CoV-2 into cells. Targeting of the ouabain binding site on the Na-K-pump by gene silencing or low concentrations of ouabain blocks viral infection in murine model. A recent finding demonstrated a more effective antiviral activity of digoxin and ouabain against SARS-CoV-2 infection in vitro than previously approved antiviral agents such as chloroquine and remdesivir. Moreover, cardiotonic steroids can promote renal inflammation and oxidative stress through the Na-K-pump α-1 and Src kinase signaling complex in both renal epithelial and immune cells. Arterial hypertension is one of the most common comorbidities associated with COVID-19, especially in patients with severe clinical involvement and at risk of death. The aim of this study is to evaluate the genetic aspects of pathways related to hypertension and renal failure, and to Na-K-pump activity such as endogenous ouabain and RAAS system, in order to partly dissect the wide clinical spectrum of the disease in hospitalized patients infected by SARS-CoV-2, with various degrees of symptoms.

Method
We investigated the relationship between three outcomes and genetic determinants in the COVID-BioB study (ClincalTrials.gov NCT04318366), a characterization of an Italian cohort of about 500 patients, a SARS-CoV-2 positive population recruited during the first wave of pandemic at San Raffaele Scientific Institute with biological samples and clinical assessment data available in an internal biobank. Targeted DNA genotyping was performed by custom arrays on TaqMan OpenArray system (ThermoFisher) for single nucleotide polymorphisms (SNPs). The genetic variants were selected as candidate for salt-sensitive hypertension and renal failure. Associations with genetic markers and outcomes were carried out with logistic regression analysis for outcome absence/presence comparison.

Results
COVID-19 patients were all hospitalized, with mean age 67.4±13.5 (30.2% female), pneumonia 96.9%, hypertension 51.8%, coronary arterial disease 26.8%, emergency department AKI stage 1- 11.1%, AKI stage 2- 0.4%, CKD stage&gt;3 11.5%, Chronic Obstructive Pulmonary Disease 8.2%, creatinine 1.19±0.70, all at emergency department admission, in-hospital AKI 37.8%, Intensive Care unit admission 18.3%, and in-hospital death 20.6%. The main outcomes for the analysis of SNPs were in-hospital death, AKI and onset of proteinuria. The main findings for the SNP analysis concerned different genetic markers, each specific for different outcomes. A SNP in renin gene (REN), rs10900555, was associated with the in-hospital death (OR 3.84 [95%CI 1.15;12.85], P = .029). PRKG1 gene coding for the protein kinase cGMP-Dependent reported association with AKI for two different SNPs (rs1904694, OR 2.78 [95%CI 1.63;4.72], P = .0002; rs7905063, OR 2.71 [95%CI 1.72;4.23], P = .00002), with the same risk alleles previously linked to salt-sensitive hypertension. TT genotype (at risk for salt-sensitivity) in uromodulin gene (UMOD, SNP rs4293393) increases the risk of proteinuria development (OR 1.86 [95%CI 1.02;3.40], P = .044).

Conclusion
This genetic analysis, firstly reported on the COVID-BioB cohort, showed an intriguing relation between some polymorphisms previously associated with salt-sensitive hypertension and worst outcome or renal damage, during COVID-19. This genetic stratification may help to identify patients at risk AKI, and (directly or not) for death and renal damage (proteinuria) during COVID-19. Moreover, it may explain, at least in part, the debated relationship between hypertension and severity of COVID-19.