NOS2 Variants Reveal a Dual Genetic Control of Nitric Oxide Levels, Susceptibility to Plasmodium Infection, and Cerebral Malaria

Abstract

g Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E-04 < P < 7.57E-04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E-05 < P < 7.90E-04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E-4 < P < 4.33E-02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely, NOS2 cistronic variants (namely, rs6505469) operate in infected individuals to increase NO bioavailability and confer increased susceptibility to unapparent infection but protect from cerebral malaria. These findings corroborate the hypothesis that NO anti-inflammatory properties impact on different steps of malaria pathogenesis, explicitly by favoring infection susceptibility and deterring severe malaria syndromes.

Polymorphisms in the promoter region of iNOS predispose to rheumatoid arthritis in south Indian Tamils

“…(-1659C/T) and rs11080358 (-4760G/A) were reported to be associated with lower levels of plasma NO. A strong LD between these two polymorphisms (rs2779249, rs11080358) was also reported (Trovoada Mde et al (2014). One of the most reported promoter polymorphism of iNOS gene is the (CCTTT) n microsatellite repeat polymorphism.…”

Genetic variation in human drug-related genes

“…4B). This difference between populations is mainly due to a SNP in NOS2 , which occurs in the population of African ancestry with higher than average frequency (rs3730017, AF AFR =19% vs AF global =4%) and while not functionally characterized, has been associated with protection against cerebral malaria 52 . In PTGS1 , three functional-variants have allele frequencies above 0.1% in the cohort of African ancestry.…”

Nitric Oxide Protects against Infection-Induced Neuroinflammation by Preserving the Stability of the Blood-Brain Barrier

“…Exogenous GSNO protected against ECM, decreased pro-inflammatory biomarkers in the blood and vascular leakage into the brain, without affecting levels of parasitemia [ 32 , 33 ]. Polymorphisms in the gene encoding iNOS associated with malaria severity in human populations [ 34 , 35 ]. Moreover, the levels of NO in plasma correlated inversely with the incidence of severe malaria in human populations [ 35 , 36 ].…”

“…Polymorphisms in the gene encoding iNOS associated with malaria severity in human populations [ 34 , 35 ]. Moreover, the levels of NO in plasma correlated inversely with the incidence of severe malaria in human populations [ 35 , 36 ]. Accordingly, the protection against neuroinflammation observed in T .…”