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

PLoS One. 2013 Aug 22;8(8):e71993. doi: 10.1371/journal.pone.0071993. eCollection 2013.

Abstract

Introduction: 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.

Materials and 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.

Discussion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Altitude Sickness / ethnology
  • Altitude Sickness / genetics*
  • Asian People / genetics
  • Case-Control Studies
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Genotype
  • Haplotypes
  • Humans
  • Hypertension, Pulmonary / ethnology
  • Hypertension, Pulmonary / genetics*
  • Japan
  • Linkage Disequilibrium
  • Male
  • Microsatellite Repeats / genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Tissue Inhibitor of Metalloproteinase-3 / genetics*
  • Young Adult

Substances

  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-3

Supplementary concepts

  • Pulmonary edema of mountaineers

Grants and funding

This study was supported in part by a Grant-in-Aid for Scientific Research (C), No. 22590853, from the Japan Society for the Promotion of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.