Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes

Abstract

Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or

Mechanisms of genetically-based resistance to malaria

“…Authors conclude that this causeeffect relationship might be more complex than previously thought (Levesque et al, 2010).…”

Polymorphisms in host genes encoding NOSII, C-reactive protein, and adhesion molecules thrombospondin and E-selectin are risk factors for Plasmodium falciparum malaria in India

“…NOSII large (CCTTT) n microsatellite repeats are associated with protection from disease manifestation Genotyping of the microsatellite repeat in the promoter of NOSII revealed the presence of ten alleles, (CCTTT) [7][8][9][10][11][12][13][14][15][16][17] , in both the endemic and non-endemic regions. The frequency of each microsatellite allele in the control and patient groups is shown in Fig.…”

“…4a, b. (CCTTT) 12 was the predominant allele in the controls of both regions. We, thus, categorized the repeats into small repeats of ≤12 (SR, CCTTT 7-12 ) and large repeats of ≥13 (LR, CCTTT [13][14][15][16][17] to analyze the association of the repeat polymorphism with disease susceptibility/resistance. Large repeats CCTTT 13-17 exhibited association with protection from disease manifestation in both the endemic (p < 1 × 10 −5 ) and non-endemic regions (p<1×10 −3 ) (Fig.…”

“…On the other hand, higher levels of NO are also associated with manifestation of severe malaria, particularly cerebral malaria. Several NOSII gene promoter polymorphisms, rs9282799 (C/T), rs1800482 (G/C), and microsatellite repeat (CCTTT) n , have been studied in the context of malaria severity in African and South-East Asian populations [13][14][15].…”

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

“…The NOS2 gene codes for the inducible nitric oxide synthase (iNOS) that is responsible for high-level production of NO by activated phagocytes (4). Several studies focused on NOS2 promoter polymorphisms have reported genetic association to different malaria clinical outcomes (5)(6)(7)(8)(9)(10)(11)(12), but the role of such variants in malaria infection progression and nitric oxide production appears to be complex (13). Moreover, it is unclear whether NOS2 genetic variants play a role in susceptibility to asymptomatic malaria (14,15).…”