title: 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 Ca(2+) 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.
authors.affiliation: Department of Life Science, Sogang University, Seoul, Republic of Korea.
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Byung-Lae
authors.initials: BL
authors.lastname: Park
authors.forename: Charisse Flerida A
authors.initials: CF
authors.lastname: Pasaje
authors.forename: Yongha
authors.initials: Y
authors.lastname: Kim
authors.forename: Joon Seol
authors.initials: JS
authors.lastname: Bae
authors.forename: Jong Sook
authors.initials: JS
authors.lastname: Park
authors.forename: Soo-Taek
authors.initials: ST
authors.lastname: Uh
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Mi-Kyeong
authors.initials: MK
authors.lastname: Kim
authors.forename: Inseon S
authors.initials: IS
authors.lastname: Choi
authors.forename: Sang Heon
authors.initials: SH
authors.lastname: Cho
authors.forename: Byoung Whui
authors.initials: BW
authors.lastname: Choi
authors.forename: InSong
authors.initials: I
authors.lastname: Koh
authors.forename: Choon-Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Hyoung Doo
authors.initials: HD
authors.lastname: Shin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics*; D055963:Asthma, Aspirin-Induced / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D019295:Computational Biology; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors; D055815:Young Adult
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009124:Muscle Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; C578224:OBSCN protein, human; D017346:Protein Serine-Threonine Kinases