Contribution of the OBSCN Nonsynonymous Variants to Aspirin Exacerbated Respiratory Disease Susceptibility in Korean Population
- Abstract
- Airway remodeling and exacerbated airway narrowing in asthma have been attributed to the regulation of intracellular Ca2+ by sarcoplasmic reticulum (SR) of the airway smooth muscle cells. The protein encoded by obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF (OBSCN) is a crucial factor in determining the SR architecture in Obscn(-/-) mice. This study genotyped a total of 55 common single-nucleotide polymorphisms (SNPs) in 592 Korean asthmatics including 163 aspirin exacerbated respiratory disease (AERD) cases and 429 aspirin-tolerant asthma (ATA) controls. Eight SNPs, including two nonsynonymous polymorphisms rs1188722C > T (Leu2116Phe) and rs1188729G > C (Cys4642Ser), and one haplotype BL2_ht1 showed statistically significant associations with AERD development (p = 0.003-0.03). Two variants, rs1188722C > T (Leu2116Phe) and rs369252C > A, also revealed nominal association with FEV1 decline by aspirin provocation in asthmatics (p = 0.03-0.04). Intriguingly, rs1188722C > T (Leu2116Phe) is a highly conserved amino acid residue among species, suggesting its functional relevance to AERD. In addition, the A allele of rs369252C > A, which was more prevalent in AERD than in ATA, was predicted as a potential branch point (BP) site for alternative splicing (BP score = 4.29). Although further functional evaluation is required, our findings suggest that OBSCN polymorphisms, in particular, highly conserved nonsynonymous Leu2116Phe variant, might contribute to aspirin hypersensitivity in asthmatics.
- All Author(s)
- J. H. Kim
; B. L. Park
; C. F. A. Pasaje
; Y. Kim
; J. S. Bae
; J. S. Park
; S. T. Uh
; Y. H. Kim
; M. K. Kim
; I. S. Choi
; S. H. Cho
; B. W. Choi
; I. Koh
; C. S. Park
; H. D. Shin
- Issued Date
- 2012
- Type
- Article
- Keyword
- obstructive pulmonary-disease; airway smooth-muscle; sarcoplasmic-reticulum; gene polymorphisms; intolerant asthma; association; diagnosis; obscurin; hypersensitivity; pathogenesis
- ISSN
- 1044-5498
- Citation Title
- DNA and Cell Biology
- Citation Volume
- 31
- Citation Number
- 6
- Citation Start Page
- 1001
- Citation End Page
- 1009
- Language(ISO)
- eng
- DOI
- 10.1089/dna.2011.1436
- URI
- http://schca-ir.schmc.ac.kr/handle/2022.oak/2306
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