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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.

Kobayashi N, Hanaoka M, Droma Y, Ito M, Katsuyama Y, Kubo K, Ota M - PLoS ONE (2013)

Bottom Line: A haplotype CAC carrying allele C of rs130293 was associated with resistance to HAPE.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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Linkage disequilibrium (LD) plot of six SNPs of the TIMP3 gene.LD plots were prepared from both subject groups; D’ values that correspond to SNP pairs are expressed as percentages and are shown within the respective squares. Higher D’ values are indicated with a brighter red color. These six SNPs constitute two haplotype blocks that span 11 kb and 7 kb of the TIMP3 gene.
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pone-0071993-g001: Linkage disequilibrium (LD) plot of six SNPs of the TIMP3 gene.LD plots were prepared from both subject groups; D’ values that correspond to SNP pairs are expressed as percentages and are shown within the respective squares. Higher D’ values are indicated with a brighter red color. These six SNPs constitute two haplotype blocks that span 11 kb and 7 kb of the TIMP3 gene.

Mentions: These six SNPs in TIMP3 constructed two haplotype blocks in Japanese HAPE-s and HAPE-r subjects according to the D’ values of pair-wise LD (Figure 1). Block 1 was composed of three SNPs (rs738992, rs130287, and rs130293) within a span of 11 kb and block 2 was composed of two SNPs (rs2071947 and rs9862) within a span of 7 kb of the TIMP3 gene (Figure 1). We identified four common haplotypes with a frequency of more than 0.05 in block 1. The frequency of haplotype CAC (constructed by the ancestral allele C of rs738992, ancestral allele A of rs130287, and derived allele C of rs130293) was significantly lower in HAPE-s (0.056) than HAPE-r (0.208, P = 0.0008) subjects with an OR of 0.23 and 95% CI from 0.09 to 0.57, indicating an association of this haplotype with resistance to HAPE (Table 4). There were no significant associations of other haplotypes in block 1 with HAPE-s (Table 4). There were no significant differences in frequencies of the observed haplotypes in the block 2 between the HAPE-s and HAPE-r groups (data not shown).


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.

Kobayashi N, Hanaoka M, Droma Y, Ito M, Katsuyama Y, Kubo K, Ota M - PLoS ONE (2013)

Linkage disequilibrium (LD) plot of six SNPs of the TIMP3 gene.LD plots were prepared from both subject groups; D’ values that correspond to SNP pairs are expressed as percentages and are shown within the respective squares. Higher D’ values are indicated with a brighter red color. These six SNPs constitute two haplotype blocks that span 11 kb and 7 kb of the TIMP3 gene.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3750038&req=5

pone-0071993-g001: Linkage disequilibrium (LD) plot of six SNPs of the TIMP3 gene.LD plots were prepared from both subject groups; D’ values that correspond to SNP pairs are expressed as percentages and are shown within the respective squares. Higher D’ values are indicated with a brighter red color. These six SNPs constitute two haplotype blocks that span 11 kb and 7 kb of the TIMP3 gene.
Mentions: These six SNPs in TIMP3 constructed two haplotype blocks in Japanese HAPE-s and HAPE-r subjects according to the D’ values of pair-wise LD (Figure 1). Block 1 was composed of three SNPs (rs738992, rs130287, and rs130293) within a span of 11 kb and block 2 was composed of two SNPs (rs2071947 and rs9862) within a span of 7 kb of the TIMP3 gene (Figure 1). We identified four common haplotypes with a frequency of more than 0.05 in block 1. The frequency of haplotype CAC (constructed by the ancestral allele C of rs738992, ancestral allele A of rs130287, and derived allele C of rs130293) was significantly lower in HAPE-s (0.056) than HAPE-r (0.208, P = 0.0008) subjects with an OR of 0.23 and 95% CI from 0.09 to 0.57, indicating an association of this haplotype with resistance to HAPE (Table 4). There were no significant associations of other haplotypes in block 1 with HAPE-s (Table 4). There were no significant differences in frequencies of the observed haplotypes in the block 2 between the HAPE-s and HAPE-r groups (data not shown).

Bottom Line: A haplotype CAC carrying allele C of rs130293 was associated with resistance to HAPE.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus