title: NOS2 variants reveal a dual genetic control of nitric oxide levels, susceptibility to Plasmodium infection, and cerebral malaria.
abstract: 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.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Maria de Jesus
authors.initials: Mde J
authors.lastname: Trovoada
authors.forename: Madalena
authors.initials: M
authors.lastname: Martins
authors.forename: Riadh
authors.initials: R
authors.lastname: Ben Mansour
authors.forename: Maria do Rosário
authors.initials: Mdo R
authors.lastname: Sambo
authors.forename: Ana B
authors.initials: AB
authors.lastname: Fernandes
authors.forename: Lígia
authors.initials: L
authors.lastname: Antunes Gonçalves
authors.forename: Artur
authors.initials: A
authors.lastname: Borja
authors.forename: Roni
authors.initials: R
authors.lastname: Moya
authors.forename: Paulo
authors.initials: P
authors.lastname: Almeida
authors.forename: João
authors.initials: J
authors.lastname: Costa
authors.forename: Isabel
authors.initials: I
authors.lastname: Marques
authors.forename: M Paula
authors.initials: MP
authors.lastname: Macedo
authors.forename: António
authors.initials: A
authors.lastname: Coutinho
authors.forename: David L
authors.initials: DL
authors.lastname: Narum
authors.forename: Carlos
authors.initials: C
authors.lastname: Penha-Gonçalves
mesh_terms: D000483:Alleles; D015415:Biomarkers / Q000097:blood; D006801:Humans; D008288:Malaria / Q000097:blood / Q000235:genetics*; D016779:Malaria, Cerebral / Q000097:blood / Q000235:genetics*; D009569:Nitric Oxide / Q000097:blood*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D010961:Plasmodium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D015415:Biomarkers; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II