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April 4, 2012

Genetic link between cigarette smoking and COPD uncovered in study

Researchers at the RIKEN Advanced Science Institute have uncovered a genetic link between cigarette smoke and chronic obstructive pulmonary disease (COPD), the fourth leading cause of death worldwide. Their findings show that disruption of an enzyme, Alpha-(1,6)-Fucosyltransferase (Fut8), increases susceptibility to emphysema in mice exposed to cigarette smoke, providing much-needed insights in the development of clinical treatments for COPD.

A "core fucose" formed by the Fut8 enzyme.

Chronic obstructive pulmonary disease (COPD) is a disabling disease of the lungs in which the airways become constricted, limiting the flow of air to and from the lungs and making it hard to breathe. While smoking is by far the leading risk factor for COPD, only a minority of cigarette smokers actually develops the disease, and the genetic and environmental factors underlying COPD susceptibility remain largely unknown.

To shed light on these factors, the researchers focused on core fucosylation, a process whereby the Fut8 gene catalyzes the transfer of a fucose residue from a complex of fucose and guanosine diphosphate (GDP) to an oligosaccharide (Figure 1). A decrease in the quantity of "core fucose", the product of this reaction, was shown in the team's earlier research to contribute to COPD, but the connection with cigarette smoking was not clear.

In a paper published in the Journal of Biological Chemistry, the researchers explore this connection by examining the effects of cigarette smoke on mice with and without the Fut8 gene. In a striking demonstration of the strength of this connection, their results show that among mice exposed to cigarette smoke regularly, those without the Fut8 gene exhibit symptoms of emphysema after only 3 months, whereas those without the gene take twice as long to do so.

By revealing a key genetic factor underling smoking-induced susceptibility to COPD, the findings set the groundwork for developing new approaches to COPD prevention and early diagnosis, promising new therapeutic drugs for COPD sufferers around the world.

Reference

  • Congxiao Gao, Toshitaka Maeno, Fumi Ota, Manabu Ueno, Hiroaki Korekane, Shinji Takamatsu, Ken Shirato, Akio Matsumoto, Satoshi Kobayashi, Keiichi Yoshida, Shinobu Kitazume, Kazuaki Ohtsubo Tomoko Betsuyaku, Naoyuki Taniguchi. “Sensitivity of heterozygous α1, 6-fucosyltransferase knock out mice to cigarette smoke-induced emphysema: Implication of aberrant TGF-β signaling and MMP gene expression.” (2012) The Journal of Biological Chemistry. doi:10.1074/jbc.M111.315333

Contact

Naoyuki Taniguchi
Disease Glycomics Team
Chemical Biology Department
RIKEN Advanced Science Institute

Jens Wilkinson
RIKEN Global Relations and Research Coordination Office
Tel: +81-(0)48-462-1225 / Fax: +81-(0)48-463-3687
Email: pr@riken.jp

Figure 1: A "core fucose" formed by the fucosyltransferase (Fut8) enzyme.