Korean J Intern Med.  2016 Mar;31(2):375-385. 10.3904/kjim.2014.390.

Association of autophagy related gene polymorphisms with neutrophilic airway inflammation in adult asthma

• Pham DL
• Kim SH
• Losol P
• Yang EM
• Shin YS
• Ye YM
• Park HS

• KMID: 2373813
• DOI: http://doi.org/10.3904/kjim.2014.390

Abstract

BACKGROUND/AIMS
Role of autophagy in neutrophil function and the association of autophagy and autophagy related (ATG) gene polymorphisms with asthma susceptibility were suggested. In this study, we investigated the genetic association of ATG5 and ATG7 polymorphisms with asthma risk, severity and neutrophilic airway inflammation.
METHODS
We recruited 408 asthma patients and 201 healthy controls. Sputum neutrophil counts were determined by H&E staining. Serum interleukin 8 (IL-8) levels were measured by enzyme-linked immunosorbent assay (ELISA). Genetic polymorphisms of ATG5 (-769T>C, -335G>A, and 8830C>T) and ATG7 (-100A>G and 25108G>C) were genotyped. The functional activities of ATG5 -769T>C and -335G>A variants were investigated by luciferase reporter assays.
RESULTS
No associations of ATG5 and ATG7 polymorphisms with asthma susceptibility and severity were found. ATG5 -769T>C and -335G>A were in complete linkage disequilibrium. In the asthma group, GA/AA genotypes at ATG5 -335G>A were associated with higher neutrophil counts in sputum (p < 0.05); CC/TT genotype at ATG5 8830C>T associated with lower FEV1% predicted value (p < 0.05). DNA fragments containing ATG5 -769T and -335G alleles had higher promoter activities compared to those with -769C and -335A in both human airway epithelial cells (A549, p < 0.01) and human mast cell (HMC-1, p < 0.001). GG and CC genotype at ATG7 -100A>G and 25108G>C were significantly associated with high serum levels of IL-8 (p < 0.05 for both variants).
CONCLUSIONS
Genetic polymorphisms of ATG5 and ATG7 could contribute to neutrophilic airway inflammation in the pathogenesis of adult asthma.

Keyword

Asthma; Autophagy; Polymorphism, genetic; Neutrophils

MeSH Terms

Adolescent
Adult
Asthma/blood/*genetics/immunology/pathology
Autophagy/*genetics
Autophagy-Related Protein 5/*genetics
Autophagy-Related Protein 7/*genetics
Case-Control Studies
Cell Line
Female
Gene Frequency
Genes, Reporter
Genetic Predisposition to Disease
Haplotypes
Heterozygote
Homozygote
Humans
Interleukin-8/blood
Male
Middle Aged
Neutrophil Infiltration/*genetics
Neutrophils/immunology/metabolism/*pathology
Phenotype
*Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Risk Factors
Severity of Illness Index
Transfection
Young Adult
Autophagy-Related Protein 5
Autophagy-Related Protein 7
Interleukin-8