title: Genetic effect of single-nucleotide polymorphisms in the PPARGC1B gene on airway hyperreactivity in asthmatic patients.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor gamma coactivator 1 beta (PPARGC1B) is a co-activator for intracellular receptors such as the estrogen receptor, PPAR, and glucocorticoid receptor, which are involved in asthma development.
  
  
  OBJECTIVE
  Genetic association of single-nucleotide polymorphisms (SNPs) in the PPARGC1B gene with the risk of asthma and airway hyperreactivity (AHR) was investigated, as well as the functional effects of these SNPs on PPARGC1B gene and protein expression.
  
  
  METHODS
  Direct sequencing of DNA from 24 Korean was performed to identify PPARGC1B SNPs. Genotyping was done in 264 controls and 949 asthmatics using single-base extension methods. PPARGC1B mRNA levels were measured using real-time PCR methodology. Luciferase and electrophoretic mobility shift assays (EMSA) were performed to functionally analyse PPARGC1B SNPs on promoter.
  
  
  RESULTS
  Eighteen SNPs and one insertion/deletion polymorphism were identified, and seven SNPs were genotyped. No significant difference existed in the distribution of SNPs and haplotypes between the asthmatics and controls. However, the allele frequency of -427C>T and +102525G>A;R265Q showed a significant association with log-transformed PC(20) methacholine values in the asthmatics (P=0.005-0.0004). Real-time PCR demonstrated higher PPARGC1B mRNA levels in asthmatics having -427CC allele than in those having -427TT or CT alleles (P=0.048). The ratio of the mRNA expression for each PPARGC1B exon4-mRNA compared with the wild type was similar in peripheral blood mononuclear cells carrying the +102525G>A allele. Luciferase reporter assays revealed that -427C allele caused higher promoter activity than -427T allele. EMSA demonstrated that -427C allele exhibited stronger binding activity to a nuclear protein in 293T cells than did the -427T allele.
  
  
  CONCLUSIONS
  Polymorphisms of -427C>T on the promoter and those of +102525G>A on exon 5 of the PPARGC1B gene may affect the development of AHR through the modulation of PPARGC1B gene products. The PPARGC1B genotypes may serve as genetic markers for AHR.
authors.affiliation: Genome Research Center for Allergy and Respiratory disease, Soonchunhyang University Hospital, Wonmi-gu, Bucheon, Gyeonggi-do, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Lee
authors.forename: A-S
authors.initials: AS
authors.lastname: Jang
authors.forename: S
authors.initials: S
authors.lastname: Woo Park
authors.forename: J-S
authors.initials: JS
authors.lastname: Park
authors.forename: Y K
authors.initials: YK
authors.lastname: Kim
authors.forename: S-T
authors.initials: ST
authors.lastname: Uh
authors.forename: Y H
authors.initials: YH
authors.lastname: Kim
authors.forename: I Y
authors.initials: IY
authors.lastname: Chung
authors.forename: B-L
authors.initials: BL
authors.lastname: Park
authors.forename: H D
authors.initials: HD
authors.lastname: Shin
authors.forename: C-S
authors.initials: CS
authors.lastname: Park
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001249:Asthma / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D005541:Forced Expiratory Volume; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000378:metabolism; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C455622:PPARGC1B protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors