Association Between Adam33, LTs Pathway, ADRB2 Genes Polymorphisms And Childhood Asthma

Backgrounds: Asthma is a common respiratory disorder. Gene-environmental interaction plays an important role in the pathogenesis of asthma. There are more than 200 candidate genes for asthma. Polymorphisms in a disintegrin and metalloproteinase 33 (ADAM33), leukotrienes (LTs) pathway, Beta-2 adrenergic receptor (ADRB2) genes were reported to be significantly associated with asthma.Aims: To investigate the association between polymorphisms of ADAM33, LTs pathway, ADRB2 genes and the susceptibility to childhoood asthma, then to evaluate whether these polymorphisms are related to atopy, allergens and lung function indexes.Methods: 17 polymorphisms, reported to be associated with asthma previously, were slected: 11 in ADAM33, 4 in LTs pathway and 2 in ADRB2 genes. 308 children with asthma and 251 healthy controls were recruited in this study. We genotyped the 17 single-nucleotide polymorphisms (SNPs) by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF). Skin prick test was used to detect common allergens. All of the asthmatics were tested lung function and airway hyperresponsiveness (AHR) provoked by methacholine. P values of≤0.017 (corrected for multiple testing) were regarded as significant.Results: The frequencies of T allele of SNP V₂ (rs13918400), which were in ADAM33 gene, were 13.6% and 9.3% of asthma and control respectively(P=0.003). There was a significantly difference of V₂ genotypes, the genotype frequencies of CC, CT, TT in asthmatics were 73.8%, 25.2% and 1%, while in control were 83.3%, 14.6% and 2%. And the wild type CC homozygote was 73.8% in cases significantly lower than control group (83.3%), P=0.008. No significant differences were detected of alleles or genotypes in the remainder SNPs between asthma and control groups.The onset age of V₂ TT genotype was 1.33±0.58 years, earlier than the onset age of CC and CT genotypes (3.72±2.67 and 4.83±3.1 years, respectively). And the subjects with mutant allele T had higher prevalence of wheezing family history than CC genotype (P=0.002, OR=2.933, 95%CI: 1.466-5.871). The FEV1 (%pred) (Percentage of predicted FEV1) level of mutant homozygote CC was 95.91±19.57, significantly higher than GC and GG genotypes (89.74±20.92 and 84.45±20.4, respectively), P=0.007. there were no significant differences were observed in the left SNPs and gender, age, onset age, FEV1 (%pred) and LogPC20 levels in the asthmatics. Conclusions: This study demonstrated that the polymorphism V₂ may associate with childhood asthma, the carriers of mutant allele T had higher prevalence of wheezing family history and onset early.Backgrounds: The common treatment of asthma were inhaled corticosteroids (ICS), long actingβ2-adrenoceptor agonist (LABA), ICS combined LABA, and leukotriene receptor antagonist (LTRA).Genetic variability in leukotrienes biosynthetic and receptor pathway gene loci may influence cysteinyl-leukotriene production and subsequent response to leukotriene modifiers. While polymorphisms of beta-2 adrenergic receptor (ADRB2) might affect LABA responses.Aims: To investigate the association between polymorphisms of a disintegrin and metalloproteinase 33 (ADAM33), LTs pathway, ADRB2 genes and the response to ICS combined LABA in childhoood asthma.Methods: 125 asthmatics were genotyped for 17 genetic polymorphisms of genes: LTs pathway (LTA4H, LTC4S, cysLTR1), ADRB2 and ADAM33. The response to ICS combined LABA used forced expiratory volume in 1 s (FEV1) and airway hyperresponsiveness (AHR) provoked by methacholine to define the response phenotype. P values of≤0.017 (corrected for multiple testing) were regarded as significant.Results: After 12 weeks ICS combined LABA treatment, the level of FEV1 (%pred) (Percentage of predicted FEV1) was 97.49±13.98, significantly higher than the level of before treatment 86.12±18.41, P<0.001. The AHR was improved, the levels of LogPC20 of before and after treatment were 0.34±0.52 and 0.59±0.52, respectively (P=0.002).Polymorphisms of ADAM33, LTs pathway, ADRB2 genes were not associated with therapeutic response to ICS combined LABA, as reflected by improvement in predicted FEV1 (%pred) (ΔFEV1).Of the 17 genetic polymorphisms examined, rs73002 (LTC4S) was significantly associated with AHR persistent status.ΔLogPC20 (improvement in PC20) of AC/CC genotype was 0.49±0.42, significantly higher than AA genotype 0.12±0.56 (P=0.004). Compared to those with mutant alleles, the AHR of subjects with wildtype alleles at this polymorphism were not decreased (P<0.001, OR=5.035, 95%CI: 2.001-12.665), and showed a significant association with the AHR persistent state(P=0.014, OR=3.8, 95%CI: 1.274-11.336).Conclusions: Our results suggest that the 12 weeks treatment of ICS combined LABA can improve lung function and decrease AHR. SNP rs730012 is genetic predictors of response to ICS combined LABA, at least with respect to changes in AHR, in Chinese patients with asthma. These findings require replication to establish validity and clinical utility.