Endothelial Nitric Oxide Synthase G894T Polymorphism Associates with Disease Severity in Puumala Hantavirus Infection

Abstract

IntroductionHantavirus infections are characterized by both activation and dysfunction of the endothelial cells. The underlying mechanisms of the disease pathogenesis are not fully understood. Here we tested the hypothesis whether the polymorphisms of endothelial nitric oxide synthase, eNOS G894T, and inducible nitric oxide synthase, iNOS G2087A, are associated with the severity of acute Puumala hantavirus (PUUV) infection.Patients and MethodsHospitalized patients (n = 172) with serologically verified PUUV infection were examined. Clinical and laboratory variables reflecting disease severity were determined. The polymorphisms of eNOS G894T (Glu298Asp, rs1799983) and iNOS G2087A (Ser608Leu, rs2297518) were genotyped.ResultsThe rare eNOS G894T genotype was associated with the severity of acute kidney injury (AKI). The non-carriers of G-allele (TT-homozygotes) had higher maximum level of serum creatinine than the carriers of G-allele (GT-heterozygotes and GG-homozygotes; median 326, range 102–1041 vs. median 175, range 51–1499 μmol/l; p = 0.018, respectively). The length of hospital stay was longer in the non-carriers of G-allele than in G-allele carriers (median 8, range 3–14 vs. median 6, range 2–15 days; p = 0.032). The rare A-allele carriers (i.e. AA-homozygotes and GA-heterozygotes) of iNOS G2087A had lower minimum systolic and diastolic blood pressure than the non-carriers of A-allele (median 110, range 74–170 vs.116, range 86–162 mmHg, p = 0.019, and median 68, range 40–90 vs. 72, range 48–100 mmHg; p = 0.003, respectively).ConclusionsPatients with the TT-homozygous genotype of eNOS G894T had more severe PUUV-induced AKI than the other genotypes. The eNOS G894T polymorphism may play role in the endothelial dysfunction observed during acute PUUV infection.

Glucosuria Predicts the Severity of Puumala Hantavirus Infection

“…In addition, inflammation and cytokine release influence kidney function by decreasing renal tissue perfusion and glomerular filtration rate, decreasing the expression of SGLT2, SGLT3, and GLUT 2, and increasing fractional glucose excretion 28 . Several different cytokines are also known to influence the severity of PUUV infection 29, 30, 31. As in a case of glucosuria in experimental animal study, 16 glucosuria in our study is most likely a marker of a more severe tubular injury in patients with PUUV infection.…”

Monocyte subset redistribution from blood to kidneys in patients with Puumala virus caused hemorrhagic fever with renal syndrome

“…This disparity in disease severity may be attributed to, differences in host genetic factors or distinct PUUV strains circulating in Northern Sweden and Central Finland [ 36 ]. Certain HLA-B and HLA-DR haplotypes have been associated with more severe disease following infection with old and new world hantaviruses, and polymorphisms in the TNF, VE-cadherin, integrin and endothelial nitric oxide synthase genes have been associated with increased risk of severe disease in HFRS [ 37 – 39 ]. Although highly speculative, the apparent increase in monocyte and DC frequencies towards the Finnish PUUV strain as opposed to the one circulating in Northern Sweden could also be attributed to the different strains.…”

Coagulopathy in Acute Puumala Hantavirus Infection

“…Host genetic factors influence the clinical outcome of PUUV infection [ 5 , 6 ]. The eNOS gene polymorphism G894T (Glu298Asp) has been reported to associate with clinically severe NE [ 21 ]. This eNOS polymorphism (G894T) results in decreased enzymatic activity and decreased basal NO synthesis and release in blood vessels [ 89 , 90 ].…”

“…In the kidney, NO produced by mesangial and tubular cells is a significant regulator and protector of renal blood flow, glomerular filtration rate, and tubular function [ 91 ]. Those subjects who were TT-homozygous for the eNOS G894T gene variant were more susceptible to severe AKI, hemoconcentration, a higher blood leukocyte count and a longer hospital stay when compared with the other genotypes [ 21 ]. This gene variant may play some role in the endothelial and kidney dysfunction during NE, possibly via reduced constitutive NO formation.…”

“…Hantaviruses infect and replicate in the endothelial cells of human capillaries, which ultimately disrupts the balance of regulated hemostasis [ 4 , 16 , 17 , 18 ]. Activated platelets and endothelial dysfunction are thus involved in the disease pathogenesis [ 11 , 18 , 19 , 20 , 21 , 22 ].…”