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- Title
Contribution of the OBSCN Nonsynonymous Variants to Aspirin Exacerbated Respiratory Disease Susceptibility in Korean Population.
- Authors
Kim, Jeong-Hyun; Park, Byung-Lae; Pasaje, Charisse Flerida A.; Kim, Yongha; Bae, Joon Seol; Park, Jong Sook; Uh, Soo-Taek; Kim, Yong-Hoon; Kim, Mi-Kyeong; Choi, Inseon S.; Cho, Sang Heon; Choi, Byoung Whui; Koh, InSong; Park, Choon-Sik; Shin, Hyoung Doo
- 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.
- Subjects
SARCOPLASMIC reticulum; OBSCURIN; CALMODULIN; CONNECTIN; SINGLE nucleotide polymorphisms; GENETIC polymorphisms; ASTHMATICS; ALLELES
- Publication
DNA & Cell Biology, 2012, Vol 31, Issue 6, p1001
- ISSN
1044-5498
- Publication type
Article
- DOI
10.1089/dna.2011.1436