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

Abstract

Rationale: Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (Fe(NO)). This may be explained 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 from the 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 = -0.4, P = 0.0006) in contrast to the early-onset phenotype (r = -0.2, 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: In late-onset asthma phenotype, plasma ratios of 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.

Figure 1.

Distribution of the l-arginine/asymmetric dimethyl arginine (ADMA) ratio by body mass index categories in subjects with late- and early-onset asthma. Dashed line corresponds to the median l-arginine/ADMA for the entire study population (121.9). Bonferroni comparisons for late onset: obese to lean, P = 0.003; overweight to obese, P = 0.2; overweight to lean, P = 0.4. An outlier is identified as a black dot outside the box plots.

Figure 2.

Association between log-transformed exhaled nitric oxide and body mass index by age of asthma onset phenotype. Open circles and dashed line = early onset. Closed circles and continuous line = late onset. The interaction between BMI and age of asthma onset on the log-exhaled nitric oxide (eNO) was significant, with P = 0.03.

Figure 3.

Adjusted linear regression of FEV₁% with the log of l-arginine/asymmetric dimethyl arginine (ADMA) by age of asthma onset phenotype. Open circles and dashed line = early onset. Closed circles and continuous line = late onset. Interaction of l-arginine/ADMA and age of asthma onset on FEV₁% was significant, with P = 0.04.

Figure 4.

Adjusted linear regression of FVC with the log of l-arginine/asymmetric dimethyl arginine (ADMA) by age of asthma onset phenotype. Open circles and dashed line = early onset. Closed circles and continuous line = late onset. Interaction of l-arginine/ADMA and age of asthma onset on FVC% was significant, with P = 0.01.

Figure 5.

Adjusted linear regression of the total asthma quality of life questionnaire score with the log of l-arginine/asymmetric dimethyl arginine (ADMA) by age of asthma onset phenotype. Open circles and dashed line = early onset. Closed circles and continuous line = late onset. Interaction between the l-arginine/ADMA and age of asthma onset on Asthma Quality of Life Questionnaire (AQLQ) was not significant, with P = 0.06.

Figure 6.

Association between having an l-arginine/asymmetric dimethyl arginine (ADMA) below the median distribution with the odds of having increased respiratory symptom frequency, by age of asthma phenotype. *P < 0.001; ^†P < 0.05; ^‡P < 0.01. The interaction between l-arginine/ADMA and obesity on increased wheezing was P = 0.05, only for the late-onset phenotype.

Figure 7.

Schematic representation of l-arginine–nitric oxide (NO) metabolism and NO synthase (NOS) uncoupling by asymmetric dimethyl arginine (ADMA). ADMA is one of three methylated analogs of l-arginine occurring through posttranslational modification; however, ADMA is the only one that can competitively inhibit all NOS isoforms. ADMA is synthesized from l-arginine by protein-arginine methyltransferases (PRMT) and degraded into mono- or dimethylamine and citrulline by dimethylarginine dimethylaminohydrolase (DDAH), whose activity can be reduced in obesity and the metabolic syndrome (41). Citrulline can be subsequently recycled into l-arginine (11). By competing with l-arginine, ADMA uncouples NOS, causing electrons flowing from the NADPH (nicotinamide adenine dinucleotide phosphate reduced) reductase domain to the oxygenase domain to be diverted into molecular oxygen rather than to l-arginine (19). Under uncoupling conditions, NOS generates superoxide, which correlates with airway oxidative stress in murine ovalbumin models (9).