Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes.
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.
Levesque
Marc C
MC
Durham VA Medical Center, Durham, NC, USA. MCL40@pitt.edu
Hobbs
Maurine R
MR
O'Loughlin
Charles W
CW
Chancellor
Jennifer A
JA
Chen
Youwei
Y
Tkachuk
Ariana N
AN
Booth
Jennifer
J
Patch
Kistie B
KB
Allgood
Sallie
S
Pole
Ann R
AR
Fernandez
Carolyn A
CA
Mwaikambo
Esther D
ED
Mutabingwa
Theonest K
TK
Fried
Michal
M
Sorensen
Bess
B
Duffy
Patrick E
PE
Granger
Donald L
DL
Anstey
Nicholas M
NM
Weinberg
J Brice
JB
D000483:Alleles; D001483:Base Sequence; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007223:Infant; D007630:Kenya; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D012720:Severity of Illness Index; D013636:Tanzania
C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II