Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.

OBJECTIVE: To determine the relationship between allelic variations in genes involved in fluticasone propionate (FP) metabolism and asthma control among children with asthma managed with inhaled FP. STUDY DESIGN: The relationship between variability in asthma control scores and genetic variation in drug metabolism was assessed by genotyping 9 single nucleotide polymorphisms in the CYP3A4, CYP3A5, and CYP3A7 genes. Genotype information was compared with asthma control scores (0=well controlled to 15=poorly controlled), determined using a questionnaire modified from the National Heart Lung and Blood Institute's Expert Panel 3 guidelines. RESULTS: Our study cohort comprised 734 children with asthma (mean age, 8.8±4.3 years) and was predominantly male (61%) and non-Hispanic white (53%). More than one-half of the children (56%; n=413) were receiving an inhaled glucocorticoid daily, with FP the most frequently prescribed agent (65%). Among the children receiving daily FP, single nucleotide polymorphisms in CYP3A5 and CYP3A7 were not associated with asthma control scores. In contrast, asthma control scores were significantly improved in the 20 children (7%) with the CYP3A4*22 allele (median, 3; range, 0-6) compared with the 201 children without the CYP3A4*22 allele (median, 4; range, 0-15; P=.02). The presence of CYP3A4*22 was associated with improved asthma control scores by 2.1 points (95% CI, 0.5-3.8). CONCLUSION: The presence of CYP3A4*22, which is associated with decreased hepatic CYP3A4 expression and activity, was accompanied by improved asthma control in the FP-treated children. Decreased CYP3A4 activity may improve asthma control with inhaled FP.

Altered leaf morphology, leaf resource dilution and defense chemistry induction in frost-defoliated aspen (Populus tremuloides).

In May 2007, a widespread frost event defoliated much of Utah's high elevation aspen. About 5 weeks later, the frost-defoliated aspen produced a second leaf flush. The objective of this study was to characterize changes in leaf morphology and function in re-flush leaves following frost defoliation. Leaf size and thickness, photosynthesis, carbohydrate and nutrient status, and defense chemistry (phenolic glycosides and condensed tannins) were measured in first and second flush leaves. The second flush leaves produced two different morphological responses depending on frost damage severity. Severe frost damage was characterized by patchy canopy re-flushing with leaves that were on average four times larger than the first flush leaves. Moderate frost damage produced full canopy flushes with second flush leaves that were typically smaller than the first flush leaves. The second flush leaves tended to be thicker, and had significantly lower nutrient and sucrose concentrations, but had equal or higher rates of photosynthesis. These leaves showed a general pattern of defense chemistry induction with phenolic glycosides and condensed tannins increasing two- to threefold. Some of the changes in leaf morphology and defense chemistry observed in second flush leaves in 2007 persisted in leaves produced in the following year. We hypothesize that defense chemistry induction following abiotic defoliation serves as insurance against secondary defoliation events by herbivores that may further deplete nutrient and carbohydrate leaf resources below threshold points that are critical for physiological function. Resource dilution and allocation to secondary defense may place constraints on growth capacity.