title: Asthma and bronchodilator responsiveness are associated with polymorphic markers of ARG1, CRHR2 and chromosome 17q21.
abstract: OBJECTIVE
  Asthma is caused by complex interactions between multiple genes. β2-Agonist is the standard rescue treatment to relieve asthma symptoms and bronchoconstriction. A genetic study for spirometric parameters helps to predict the responses to this antiasthma treatment. This study investigated the relationship between asthma and bronchodilator responsiveness (BDR) and eight asthma genes.
  
  
  METHODS
  Fifteen single-nucleotide polymorphisms in these genes were genotyped in 345 Chinese asthmatics and 464 controls. Gene-gene interactions were analysed by generalized multifactor dimensionality reduction (GMDR).
  
  
  RESULTS
  The diagnosis of asthma was associated with rs7216389 in ORMDL3 [odds ratio (OR) 0.74 and 95% confidence interval (95% CI) 0.56-0.99] and rs3756780 in ARG1 (OR 0.67, 95% CI 0.51-0.89) and BDR with rs2749935 in ARG1. However, none of these associations remained significant at 5% when adjusted for multiple testing by the Bonferroni correction or a false discovery rate. GMDR analyses revealed that rs7216389 in ORMDL3 and rs3756780 in ARG1 might interact for a risk of asthma. Individuals with high-risk genotypes had OR 1.66 (95% CI 1.24-2.23) for asthma when compared with those with low-risk genotypes. GMDR suggested a two-locus model with rs2749935 in ARG1 and rs2190242 in CRHR2 to be associated with BDR. Specifically, reversibility of forced expiratory volume in 1 s was higher in high-risk than that in low-risk patients [mean (95% CI): 10.7 (8.6-12.9) vs. 6.8 (5.9-7.6)%]; with the latter group showing higher forced expiratory volume in 1 s reversibility compared with high-risk controls [2.8 (1.4-4.3)%].
  
  
  CONCLUSIONS
  ARG1 and ORMDL3 may interact to determine the risk of asthma and ARG1 and CRHR2 to alter BDR in asthmatics. Nonetheless, this study is only hypothesis-generating as none of the single marker comparisons is significant when adjusted for multiple testing. These findings need to be confirmed in independent populations.
authors.affiliation: Department of Paediatrics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
authors.forename: Hing Yee
authors.initials: HY
authors.lastname: Sy
authors.forename: Fanny W S
authors.initials: FW
authors.lastname: Ko
authors.forename: Hong Yin
authors.initials: HY
authors.lastname: Chu
authors.forename: Iris H S
authors.initials: IH
authors.lastname: Chan
authors.forename: Gary W K
authors.initials: GW
authors.lastname: Wong
authors.forename: David S C
authors.initials: DS
authors.lastname: Hui
authors.forename: Ting Fan
authors.initials: TF
authors.lastname: Leung
mesh_terms: D000328:Adult; D001119:Arginase / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D001249:Asthma / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*
chemical_list: D001993:Bronchodilator Agents; C101531:CRF receptor type 2; D005819:Genetic Markers; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; D018019:Receptors, Corticotropin-Releasing Hormone; C574619:ARG1 protein, human; D001119:Arginase