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.

Normative values for exhaled breath condensate pH and its relationship to exhaled nitric oxide in healthy African Americans.

BACKGROUND: Exhaled breath condensate (EBC) pH and exhaled nitric oxide (FeNO) have been proposed as markers of asthma severity. EBC pH values below 6.5 have been associated with asthma exacerbations. Protonation of airway nitrite occurs at low pH and may contribute to FeNO. OBJECTIVE: To establish normative EBC pH values and to determine the contribution of EBC pH to FeNO in healthy African Americans. METHODS: Two hundred seventy healthy African American subjects without asthma between 18 and 40 years old were evaluated. Subjects had simultaneous measurement of EBC pH, EBC nitrite, nitrate, and FeNO. RESULTS: The median EBC pH was 8.14 (interquartile range, 7.83-8.28). Of subjects, 11.9% had an EBC pH < or = 6.5. In subjects with EBC pH values below 6.5, there was an inverse correlation between EBC pH and FeNO (r(2) = 0.158; P = .0245; n = 32). In the entire cohort, there was a direct correlation between EBC pH and EBC nitrite (r(2) = 0.163; P < .0001), but there was no correlation between EBC nitrite and FeNO. In multivariate analyses, EBC pH and nitrite did not contribute significantly to FeNO variation while controlling for other confounders of FeNO. CONCLUSION: There was an increased prevalence (11.9%) of low EBC pH (less than 6.5) in healthy African American subjects compared with white subjects (<5%). EBC pH and nitrite were directly correlated, but there was no correlation between EBC nitrite and FeNO. FeNO correlated with EBC pH at pH values less than 6.5 in univariate but not multivariate analyses. This suggests that EBC pH and nitrite are not significant determinants of FeNO in healthy subjects.

Determinants of exhaled nitric oxide levels in healthy, nonsmoking African American adults.

BACKGROUND: Asthma is a significant cause of morbidity and mortality for African Americans. Fraction of exhaled nitric oxide (FeNO) levels are increased in patients with asthma, and airway levels of nitric oxide metabolites regulate airway inflammation and airway diameter. More needs to be known about the factors that regulate FeNO. There is a need for FeNO reference values for African Americans. OBJECTIVE: We sought to establish reference values and identify factors associated with FeNO levels in healthy African American adults. METHODS: FeNO levels were measured in 895 healthy, nonsmoking African Americans between the ages of 18 and 40 years. FeNO measurements were repeated in 84 subjects. Factors potentially associated with FeNO were measured, including blood pressure, height, weight, and serum total IgE, eosinophil cationic protein, C-reactive protein, and nitrate levels. Data on respiratory symptoms, including upper respiratory tract infection (URI) symptoms, were collected. Univariate and multivariate analyses of the relationship between these variables and FeNO levels were performed. RESULTS: In healthy, nonsmoking African Americans FeNO levels were stable during repeated measurements (intraclass correlation coefficient, 0.81). Sex (P < .0001), serum total IgE levels (P < .0001), and current URI symptoms (P = .0002) contributed significantly to FeNO variability but together accounted for less than 50% of the variation in FeNO levels. CONCLUSION: The high correlation between repeated measurements of FeNO and the low correlation coefficients of known factors associated with FeNO suggest that other factors might contribute substantially to variability of FeNO levels in African Americans.