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Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma.

Raby BA, Van Steen K, Lasky-Su J, Tantisira K, Kaplan F, Weiss ST - Respir. Res. (2009)

Bottom Line: In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids.This improvement was similar to that among children treated with long-term inhaled corticosteroids.IPO13 variation is associated with improved AHR in asthmatic children.

View Article: PubMed Central - HTML - PubMed

Affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. rebar@channing.harvard.edu

ABSTRACT

Background: Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20).

Methods: 10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association.

Results: Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51-2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01-0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids.

Conclusion: IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.

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Impact of IPO13 polymorphism rs2428953 on airway hyperresponsiveness. Mean log(methacholine PC20) values and SEM. Common genotype (CC) denoted by solid black lines, heterozygotes and TT homozygotes denoted by dashed red lines. Open circles denote placebo/nedocromil groups, closed circles represent budesonide groups. Vertical line at 0 months denotes time of randomization. Airway hyperresponsiveness was significantly different (p < 0.05) between the placebo/nedocromil subjects with CC genotype and all other subjects at all time points following randomization, as denoted by (*).
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Figure 2: Impact of IPO13 polymorphism rs2428953 on airway hyperresponsiveness. Mean log(methacholine PC20) values and SEM. Common genotype (CC) denoted by solid black lines, heterozygotes and TT homozygotes denoted by dashed red lines. Open circles denote placebo/nedocromil groups, closed circles represent budesonide groups. Vertical line at 0 months denotes time of randomization. Airway hyperresponsiveness was significantly different (p < 0.05) between the placebo/nedocromil subjects with CC genotype and all other subjects at all time points following randomization, as denoted by (*).

Mentions: Figure 2 illustrates the differential effects of one representative polymorphism (rs2428953) on airway responsiveness over the course of the clinical trial. As can be seen, T-allele carriers on placebo or nedocromil had improvements in PC20 values over the course of the trial that approached those observed among subjects who were treated with budesonide. In keeping with the longitudinal analysis, similar profiles were observed for the other IPO13 SNP, with carriers of the minor alleles at all loci (with the exception of rs2240447 and rs2301993) randomized to placebo or nedocromil demonstrating significantly less airways responsiveness compared to non-carriers (data not shown). From these data, we conclude that IPO13 variation influences the natural progression of methacholine PC20 among children with asthma, resulting in significantly less severe airway hyperresponsiveness, and approaching levels achieved with inhaled corticosteroid therapy. These data also suggest that the addition of inhaled corticosteroids confers no additional benefit among IPO13 carriers, though our study is underpowered to formally test that specific interaction. We also note that airway hyperresponsiveness was lowest among subjects homozygous for IPO13 variants (for example, the mean logPC20 was 1.31 among SNP rs2428953 TT homozygotes compared to 0.77 among heterozygotes), suggesting an additive genetic relationship, though the number of subjects with rare homozygous genotypes was generally too small (13 in the non-budesonide group, 2 in the budesonide group) to make formal statements regarding the significance of this observation.


Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma.

Raby BA, Van Steen K, Lasky-Su J, Tantisira K, Kaplan F, Weiss ST - Respir. Res. (2009)

Impact of IPO13 polymorphism rs2428953 on airway hyperresponsiveness. Mean log(methacholine PC20) values and SEM. Common genotype (CC) denoted by solid black lines, heterozygotes and TT homozygotes denoted by dashed red lines. Open circles denote placebo/nedocromil groups, closed circles represent budesonide groups. Vertical line at 0 months denotes time of randomization. Airway hyperresponsiveness was significantly different (p < 0.05) between the placebo/nedocromil subjects with CC genotype and all other subjects at all time points following randomization, as denoted by (*).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724419&req=5

Figure 2: Impact of IPO13 polymorphism rs2428953 on airway hyperresponsiveness. Mean log(methacholine PC20) values and SEM. Common genotype (CC) denoted by solid black lines, heterozygotes and TT homozygotes denoted by dashed red lines. Open circles denote placebo/nedocromil groups, closed circles represent budesonide groups. Vertical line at 0 months denotes time of randomization. Airway hyperresponsiveness was significantly different (p < 0.05) between the placebo/nedocromil subjects with CC genotype and all other subjects at all time points following randomization, as denoted by (*).
Mentions: Figure 2 illustrates the differential effects of one representative polymorphism (rs2428953) on airway responsiveness over the course of the clinical trial. As can be seen, T-allele carriers on placebo or nedocromil had improvements in PC20 values over the course of the trial that approached those observed among subjects who were treated with budesonide. In keeping with the longitudinal analysis, similar profiles were observed for the other IPO13 SNP, with carriers of the minor alleles at all loci (with the exception of rs2240447 and rs2301993) randomized to placebo or nedocromil demonstrating significantly less airways responsiveness compared to non-carriers (data not shown). From these data, we conclude that IPO13 variation influences the natural progression of methacholine PC20 among children with asthma, resulting in significantly less severe airway hyperresponsiveness, and approaching levels achieved with inhaled corticosteroid therapy. These data also suggest that the addition of inhaled corticosteroids confers no additional benefit among IPO13 carriers, though our study is underpowered to formally test that specific interaction. We also note that airway hyperresponsiveness was lowest among subjects homozygous for IPO13 variants (for example, the mean logPC20 was 1.31 among SNP rs2428953 TT homozygotes compared to 0.77 among heterozygotes), suggesting an additive genetic relationship, though the number of subjects with rare homozygous genotypes was generally too small (13 in the non-budesonide group, 2 in the budesonide group) to make formal statements regarding the significance of this observation.

Bottom Line: In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids.This improvement was similar to that among children treated with long-term inhaled corticosteroids.IPO13 variation is associated with improved AHR in asthmatic children.

View Article: PubMed Central - HTML - PubMed

Affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. rebar@channing.harvard.edu

ABSTRACT

Background: Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20).

Methods: 10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association.

Results: Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51-2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01-0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids.

Conclusion: IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.

Show MeSH
Related in: MedlinePlus