title: Polymorphisms of the tissue inhibitor of metalloproteinase 3 gene are associated with resistance to high-altitude pulmonary edema (HAPE) in a Japanese population: a case control study using polymorphic microsatellite markers.
abstract: BACKGROUND
  High-altitude pulmonary edema (HAPE) is a hypoxia-induced, life-threatening, high permeability type of edema attributable to pulmonary capillary stress failure. Genome-wide association analysis is necessary to better understand how genetics influence the outcome of HAPE.
  
  
  METHODS
  DNA samples were collected from 53 subjects susceptible to HAPE (HAPE-s) and 67 elite Alpinists resistant to HAPE (HAPE-r). The genome scan was carried out using 400 polymorphic microsatellite markers throughout the whole genome in all subjects. In addition, six single nucleotide polymorphisms (SNPs) of the gene encoding the tissue inhibitor of metalloproteinase 3 (TIMP3) were genotyped by Taqman® SNP Genotyping Assays.
  
  
  RESULTS
  The results were analyzed using case-control comparisons. Whole genome scanning revealed that allele frequencies in nine markers were statistically different between HAPE-s and HAPE-r subjects. The SNP genotyping of the TIMP3 gene revealed that the derived allele C of rs130293 was associated with resistance to HAPE [odds ratio (OR) = 0.21, P = 0.0012) and recessive inheritance of the phenotype of HAPE-s (P = 0.0012). A haplotype CAC carrying allele C of rs130293 was associated with resistance to HAPE.
  
  
  CONCLUSIONS
  This genome-wide association study revealed several novel candidate genes associated with susceptibility or resistance to HAPE in a Japanese population. Among those, the minor allele C of rs130293 (C/T) in the TIMP3 gene was linked to resistance to HAPE; while, the ancestral allele T was associated with susceptibility to HAPE.
authors.affiliation: First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan ; Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Nobumitsu
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hanaoka
authors.forename: Yunden
authors.initials: Y
authors.lastname: Droma
authors.forename: Michiko
authors.initials: M
authors.lastname: Ito
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Katsuyama
authors.forename: Keishi
authors.initials: K
authors.lastname: Kubo
authors.forename: Masao
authors.initials: M
authors.lastname: Ota
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000532:Altitude Sickness / Q000208:ethnology / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006976:Hypertension, Pulmonary / Q000208:ethnology / Q000235:genetics*; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D055815:Young Adult
chemical_list: C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3