An association between L-arginine/asymmetric dimethyl arginine balance, obesity, and the age of asthma onset phenotype

Rationale: Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (FE_NO). Thismaybeexplained by an increase in the concentration of asymmetric dimethyl arginine (ADMA) relative to L-arginine, which can lead to greater nitric oxide synthase uncoupling. Objectives: To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function. Methods: Cross-sectional study of participants fromthe Severe Asthma Research Program, across early- (<12 yr) and late- (>12 yr) onset asthma phenotypes. Measurements and Main Results: Subjects with late-onset asthma had a higher median plasma ADMA level (0.48 μM, [interquartile range (IQR), 0.35-0.7] compared with early onset, 0.37 μM [IQR, 0.29- 0.59], P = 0.01) and lower median plasma L-arginine (late onset, 52.3 [IQR, 43-61] compared with early onset, 51 μM [IQR 39-66]; P = 0.02). The log of plasma L-arginine/ADMA was inversely correlated with BMI in the late- (r = 20.4, P = 0.0006) in contrast to the early-onset phenotype (r = 20.2, P = 0.07). Although FE_NO was inversely associated with BMI in the late-onset phenotype (P = 0.02), the relationship was lost after adjusting for L-arginine/ADMA.Also in this phenotype, a reduced L-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life. Conclusions: Inlate-onsetasthmaphenotype,plasmaratiosof L-arginine to ADMA may explain the inverse relationship of BMI to FE_NO. In addition, these lower L-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.