A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children

Hobbs, Maurine R.; Udhayakumar, Venkatachalam; Levesque, Marc C.; Booth, Jennifer; Roberts, Jacquelin M.; Tkachuk, Ariana N.; Pole, Ann; Coon, Hilary; Kariuki, Simon; Nahlen, Bernard L.; Mwaikambo, Esther D.; Lal, Altaf L; Granger, Donald L.; Anstey, Nicholas M.; Weinberg, J. Brice

doi:10.1016/s0140-6736(02)11474-7

Cited by 168 publications

(169 citation statements)

References 32 publications

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“…The polymorphism at 7 1173 in the promoter region is significantly associated with increased NOS2 expression and NO synthesis, increased urine and plasma NO metabolite concentration, and protection from symptomatic malaria in Tanzanian children and from severe malarial anaemia in Kenyan children. However, the risk of parasitemia was not significantly different in wild-type or 7 1173 C?T individuals (11). These findings may be partially reconciled by differences in population genetic backgrounds (12) and by the possibility that these polymorphisms are in linkage disequilibrium with another (unidentified) polymorphism(s) in the NOS2 gene (11).…”

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confidence: 92%

“…However, the risk of parasitemia was not significantly different in wild-type or 7 1173 C?T individuals (11). These findings may be partially reconciled by differences in population genetic backgrounds (12) and by the possibility that these polymorphisms are in linkage disequilibrium with another (unidentified) polymorphism(s) in the NOS2 gene (11).…”

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confidence: 92%

“…NO limits production of proinflammatory cytokines, proteins that stimulate immune responses and that may contribute to tissue damage in malaria (11). Enhanced NO biosynthesis in activated endothelium and local macrophages decreases the expression of the cytokine-inducible endothelial adhesion molecules, preventing the parasite infected red cells from sticking to blood vessel walls and causing the restricted blood flow associated with cerebral malaria (11). NO kills P. falciparum in the liver, where the parasite gets a foothold and begins to multiply; human monocytes also kill the parasite through a mechanism involving NO (6).…”

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confidence: 99%

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Visca³

2004

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Is There an Answer? ‐ Coordinated by Frank Vella

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2004

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“…Moreover, its putative involvement in complex genetic disorders may go beyond autoimmune demyelination. Linkage in a subset of type I diabetes pedigrees (HLA-DR3/4 positives) 12 and genetic associations with diabetic renopathy, 13 dementia with Lewy bodies, 14 coronary artery disease, 15 malaria 16,17 and Parkinson's disease 18,19 have been reported. We previously reported a NOS2A exon 10 single-nucleotide polymorphism (SNP, C/T, D346D) being associated with disease susceptibility in two independent MS datasets.…”

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confidence: 99%

Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis

et al. 2008

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Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Variation in the major histocompatibility complex on chromosome 6p21, specifically the HLA-DRB1*15 haplotype, is the strongest genetic factor for MS, yet it is estimated to account for only a portion of risk for the disease. Previous evidence has implicated the nitric oxide synthase gene (NOS2A) encoding inducible NOS on chromosome 17q11 as a potential MS susceptibility gene. To determine whether variation in the NOS2A gene contributes to MS risk, we investigated a total of 50 polymorphisms within or flanking the locus for evidence of association using a comprehensive analytical strategy. A total of 6265 members from 1858 well-characterized MS families were utilized. No evidence for overtransmission of any individual single-nucleotide polymorphism allele or haplotype to the MS-affected individuals was observed. Furthermore, different transmission rates were not observed in either DRB1*15-positive or DRB1*15-negative family subgroups, or when extreme clinical outcomes characterizing disease progression were examined. The very largest study of NOS2A variation in MS, to date, excludes even a modest role for this locus in susceptibility.

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“…6 microsatellite alleles have been associated with human disease. 37,38,[40][41][42][43][44] In vitro data have defined a functional effect for some SNP alleles 38,44 and possibly also for certain NOS2A À2.6 microsatellite alleles. 41 The haplotypic relationship between these stable and unstable markers and population-specific patterns of LD at this locus are unknown.…”

Section: Introductionmentioning

confidence: 99%

Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations

et al. 2003

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The density of genetic markers required for successful association mapping of complex diseases depends on linkage disequilibrium (LD) between non-functional markers and functional variants. The haplotypic relationship between stable markers and potentially unstable but highly informative markers (e.g. microsatellites) indicates that LD might be maintained over considerable genetic distance in non-African populations, supporting the use of such 'mixed marker haplotypes' in LD-based mapping, and allowing inferences to be drawn about human origins. We investigated sequence variation in the proximal 2.6 kb of the inducible nitric oxide synthase (NOS2A) promoter and the relationship between SNP haplotypes and a pentanucleotide microsatellite (the 'NOS2A À2.6 microsatellite') in Gambians and UK Caucasians. UK Caucasians exhibited a subset of sequence diversity observed in Gambians, sharing four of 11 SNPs and a similar haplotypic structure. Five SNPs were found in the sequence of interspersed repetitive DNA elements. In both populations, there was dramatic loss of LD between SNP haplotypes and microsatellite alleles across a very short physical distance, suggesting a high intrinsic mutation rate of the NOS2A À2.6 microsatellite, the SNP haplotypes are relatively ancient, or that this was a region of frequent recombination. Understanding locus-and population-specific LD is essential when designing and interpreting genetic association studies.

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A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children

Cited by 168 publications

References 32 publications

Is There an Answer? ‐ Coordinated by Frank Vella

Is There an Answer? ‐ Coordinated by Frank Vella

Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis

Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations

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