Allergy 2013 May (2)-3

CD53, a suppressor of inflammatory cytokine production, is associated with population asthma risk via the functional promoter polymorphism -1560 C>T.

Biochim Biophys Acta. 2013 Apr;1830(4):3011-8

Lee H, Bae S, Jang J, Choi BW, Park CS, Park JS, Lee SH, Yoon Y.

Department of Microbiology, Chung-Ang University College of Medicine, Seoul, Republic of Korea.


BACKGROUND: In this study, the association of asthma with CD53, a member of the tetraspanin family, was assessed for the first time in a mechanism-based study.

METHODS: Genetic polymorphisms of CD53 were analyzed in 591 subjects and confirmed in a replication study of 1001 subjects. CD53 mRNA and protein levels were measured in peripheral blood leukocytes, and the effects of the promoter polymorphisms on nuclear factor binding were examined by electrophoretic mobility shift assay. Cellular functional studies were conducted by siRNA transfections.

RESULTS: Among tagging SNPs of CD53, the -1560 C>T in the promoter region was significantly associated with asthma risk. Compared with the CC genotype, the CT and TT genotypes were associated with a higher asthma risk, with odd ratios of 1.74 (P=0.009) and 2.03 (P=0.004), respectively. These findings were confirmed in the replication study with odd ratios of 1.355 (P=0.047) and 1.495 (P=0.039), respectively. The -1560 C>T promoter SNP had functional effects on nuclear protein binding as well as mRNA and protein expression levels in peripheral blood leukocytes. When CD53 was knocked down by siRNA in THP-1 human monocytic cells stimulated with house dust mite, the production of inflammatory cytokines as well as NFκB activity was significantly over-activated, suggesting that CD53 suppresses over-activation of inflammatory responses.

CONCLUSIONS: The -1560 C>T SNP is a functional promoter polymorphism that is significantly associated with population asthma risk, and is thought to act by directly modulating nuclear protein binding, thereby altering the expression of CD53, a suppressor of inflammatory cytokine production. Copyright © 2012 Elsevier B.V.

PMID: 23313165


Comments :

Asthma is a common disease with significant genetic determinants, and twin studies have shown that the genetic component of asthma accounts for 36% to 79% of the disease. To date, many efforts have been made in identifying the genetic factors of asthma. Among them, however, only some were replicated. Lack of replication may be originated from non-functional SNPs which display positive association with disease phenotypes but do not have functional effects on gene expressions or protein activities. Non-functional SNP may represent a proxy marker for another yet-unidentified genetic variant. Among functional SNPs, promoter SNPs affect gene expression levels, while coding SNPs affect structures and activities of proteins. For my opinion, promoter SNPs with mild quantitative effects on gene expression levels may have more chance to affect the susceptibility of common disease compared with coding SNPs. Coding SNPs with drastic qualitative effects on the activity of protein may have more chance to be involved in more severe diseases such as tumor and genetic disorders. In the present study, we found a promoter SNP that directly affects nuclear protein binding and mRNA/protein expressions in peripheral leukocytes and also is associated with asthma susceptibility in Korean population. Disease association may differ in other ethnic groups owing to the differences in genomic LD pattern and environmental allergen exposure.

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