Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) plays an important role in host resistance to infection with a variety of organisms. Two recent reports from Gabon and Gambia identified associations of malaria disease severity with the inducible NO synthase (NOS2) promoter G-954C and short allele (<11 repeats) pentanucleotide microsatellite polymorphisms, respectively. It was postulated that there would be a correlation of these polymorphisms with malaria disease severity and with measures of NO production in our cohort of Tanzanian children with malaria. In Tanzanian children, 15% were heterozygous or homozygous for the G-954C polymorphism, and 13% had the short-allele microsatellite polymorphism. There was no significant correlation of either polymorphism with disease severity or with measures of NO production and NOS2 expression. Black and white Americans differed significantly in the frequencies of these polymorphisms. The various association of these gene polymorphisms with malaria severity in different populations underscores the complexity of host resistance to malaria.
 ...
PMID:Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria. 1055 57

Allelic frequencies of a (CCTTT)(n) pentanucleotide repeat in the NOS2A promoter region were determined in a total of 1393 unrelated individuals from five specific population groups in four continents: Africa, Europe, Asia, and the Caribbean. There were highly significant differences in allele frequencies between the ethnically diverse populations. The repeat variation may have implications for the selective pressure of malaria or other infectious diseases that may operate at the NOS2 locus.
 ...
PMID:Survey of the allelic frequency of a NOS2A promoter microsatellite in human populations: assessment of the NOS2A gene and predisposition to infectious disease. 1094 22

Several human genetic factors, including red blood cell polymorphisms (ABO blood group, sickle-cell trait, G6PD deficiency) as well as point mutations in the mannose binding protein (MBP) and in the promoter regions of both the TNF-alpha and NOS2 genes, influence the severity of disease due to infection with Plasmodium falciparum. We assessed their impact on mild P. falciparum malaria, as part of a longitudinal investigation of clinical, parasitological and immunological parameters in a cohort of 300 Gabonese schoolchildren. We found the following frequencies: blood group O (0.54), sickle-cell trait (0.23), G6PD deficiency (0.09), MBP gene mutations (0.34), TNF-alpha promoter mutations (at positions -238: 0.17 and -308: 0.22) and NOS2 promoter mutation (0.18). Blood group O or hemoglobin AA were associated with protection against higher parasitemia. Girls with normal G6PD enzyme activity were protected against clinical malaria attacks. In addition, we demonstrated for the first time that the mutation at position -238 of the gene coding for the promoter region of TNF-alpha was positively correlated with the level of the antibody response specific for epitopes of the antigens MSA-2 and RAP-1 of P. falciparum.
 ...
PMID:Human genetic factors related to susceptibility to mild malaria in Gabon. 1119 74

Several studies have focused their attention on the relationship between host genetic factors and susceptibility/resistance to severe malaria. However, there is a paucity of information concerning the role of host genetic factors in asymptomatic malaria, a form of low-grade Plasmodium falciparum infection without clinical symptoms. We investigated in this study the potential relationship between the host (human) genetic polymorphisms (glucose-6-phosphate dehydrogenase [G6PD], mannose binding lectin [MBL], tumor necrosis factor alpha [TNFalpha](-308) and (-238), and nitric oxide synthase 2 [NOS2](-954)) and the prevalence and profile of asymptomatic P. falciparum infection in 158 Gabonese schoolchildren. We found that G6PD A- heterozygous females (18 of 74) have a low prevalence of asymptomatic malaria (38.9% versus 67.3%; P = 0.03, by chi-square test). Children heterozygous for TNFalpha(-238) (25 of 156) carry high number of diverse infecting parasite genotypes (2.5 versus 1.99; variance F = 3.05). No statistically significant association was found between MBL, TNFalpha(-308), or NOS2 polymorphisms and asymptomatic malaria. Upon combining our data on asymptomatic forms with those from the literature for others forms, we conclude that G6PD A- heterozygous females are protected against all forms of P. falciparum malaria, and that the TNFalpha(-238A) allele confers protection against clinical malaria.
 ...
PMID:Human genetic polymorphisms and asymptomatic Plasmodium falciparum malaria in Gabonese schoolchildren. 1264 10

Polymorphisms in the inducible nitric oxide synthase gene (NOS2) promoter have been associated with clinical outcome from malaria. These include a CCTTT repeat (CCTTTn) 2.5 kilobases upstream from the NOS2 transcription start site, and two single nucleotide substitutions: G-->C at position -954 (G-954C), and C-->T at position -1173 (C-1173T). Although hypothesized to influence NO production in vivo, the functional relevance of (CCTTT)n and G-954C is uncertain because disease association studies have yielded inconsistent results. This study found no association between CCTTT repeat number and levels of plasma NO metabolites or peripheral blood mononuclear cell NOS activity in a cohort of asymptomatic malaria-exposed coastal Papua New Guineans 1-60 years old. This suggests that (CCTTT)n does not independently influence NOS2 transcription in vivo. Neither the G-954C nor the C-1173T polymorphisms were identified in this population, indicating the variability and complexity of selection for NOS2 promoter polymorphisms in different malaria-endemic populations.
 ...
PMID:Inducible nitric oxide synthase (NOS2) promoter CCTTT repeat polymorphism: relationship to in vivo nitric oxide production/NOS activity in an asymptomatic malaria-endemic population. 1474 Aug 70

The production of nitrogen monoxide (NO(*)) contributes to defence mechanisms of the immune system to fight infectious agents like bacteria and protozoa. The respective gene producing the NO(*) has to be carefully regulated so that an overwhelming response kills the pathogen but does not harm the host. A strong increase in the NO(*) production for efficient anti-microbial activity is achieved by the transcriptional up-regulation of the nitric oxide synthase 2 gene (NOS2 or inducible nitric oxide synthase, iNOS), which is regulated by a number of transcription factors that are vital in the regulation of many genes involved in the immune response. Binding sites for members of the nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP1) families have been detected and seem to fulfil their function in vitro. Genetic variants of the iNOS genes have been identified that are linked to NO(*) production and to the outcome of malaria in humans.
 ...
PMID:Regulation of nitrogen monoxide production in human malaria. 1496 67

The killing of blood-stage malaria parasites in vivo has been attributed to reactive intermediates of oxygen (ROI) and of nitrogen (RNI). However, in the case of the latter, this contention is challenged by recent observations that parasitemia was not exacerbated in nitric oxide synthase (NOS) knockout (KO) (NOS2-/- or NOS3-/-) mice or in mice treated with NOS inhibitors. We now report that the time course shows that Plasmodium chabaudi parasitemia in NADPH oxidase KO (p47phox-/-) mice also was not exacerbated, suggesting a minimal role for ROI-mediated killing of blood-stage parasites. It is possible that the production of protective antibodies during malaria may mask the function of ROI and/or RNI. However, parasitemia in B-cell-deficient JH-/- x NOS2-/- or JH-/- x p47phox-/- mice was not exacerbated. In contrast, the magnitude of peak parasitemia was significantly enhanced in p47phox-/- mice treated with the xanthine oxidase inhibitor allopurinol, but the duration of patent parasitemia was not prolonged. Whereas the time course of parasitemia in NOS2-/- x p47phox-/- mice was nearly identical to that seen in normal control mice, allopurinol treatment of these double-KO mice also enhanced the magnitude of peak parasitemia. Thus, ROI generated via the xanthine oxidase pathway contribute to the control of ascending P. chabaudi parasitemia during acute malaria but alone are insufficient to suppress parasitemia to subpatent levels. Together, these results indicate that ROI or RNI can contribute to, but are not essential for, the suppression of parasitemia during blood-stage malaria.
 ...
PMID:Suppression of Plasmodium chabaudi parasitemia is independent of the action of reactive oxygen intermediates and/or nitric oxide. 1550 65

Malaria causes more than one million deaths annually, worldwide. Understanding the genetic defenses against this disease is an important challenge for science. We know that the long-term presence of endemic malaria has led to a prevalence of the beta degrees 39 heterozygous thalassemia mutation in the two islands of Corsica and Sardinia. The populations of both islands are isolated, which could make it easier to find other genetic traits selected by disease pressure. We chose to investigate genes implicated in the primary defenses against Plasmodium falciparum: oxidative metabolism and the immune response. We indeed selected genes coding for nitric oxide synthase 2 (NOS2 promoter, polymorphisms NOS2(AAAT) I/D and NOS2(CCTTT)n) and genes coding for tumor necrosis factor-alpha (TNFA 3'UTR, polymorphisms TNFd(GA)n and TNFe(GA)n). Some associations of TNFA alleles or haplotypes were found either with or without the beta degrees 39 mutation, suggesting a complex link originally between TNF-alpha and resistance or susceptibility to infection.
 ...
PMID:TNFA locus is associated with beta degrees 39 thalassemia in Corsica and Sardinia. 1910 26

Malaria is perhaps the most important parasitic infection and strongest known force for selection in the recent evolutionary history of the human genome. Genetically-determined resistance to malaria has been well-documented in some populations, mainly from Africa. The disease is also endemic in South Asia, the world's second most populous region, where resistance to malaria has also been observed, for example in Nepal. The biological basis of this resistance, however, remains unclear. We have therefore investigated whether known African resistance alleles also confer resistance in Asia. We typed seven single nucleotide polymorphisms (SNPs) from the genes HBB, FY, G6PD, TNFSF5, TNF, NOS2 and FCGR2A in 928 healthy individuals from Nepal. Five loci were found to be fixed for the non-resistant allele (HBB, FY, G6PD, TNFSF5 and NOS2). The remaining two (rs1800629 and rs1801274) showed the presence of the resistant allele at a frequency of 93% and 27% in TNF and FCGR2A, respectively. However, the frequencies of these alleles did not differ significantly between highland (susceptible) and lowland (resistant) populations. The observed differences in allele and genotype frequencies in Nepalese populations therefore seem to reflect demographic processes or other selective forces in the Himalayan region, rather than malaria selection pressure actin on these alleles.
 ...
PMID:Nepalese populations show no association between the distribution of malaria and protective alleles. 1946 87

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 C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described.
 ...
PMID:Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes. 1985 40


1 2 Next >>