The genetics of asthma: ADAM33 as an example of a susceptibility gene.
The ability to identify novel disease genes by positional cloning led to the identification of a disintegrin and metalloprotease (ADAM)33 gene on chromosome 20p13 as a susceptibility gene for asthma. Case-control and family-based association studies have mostly confirmed a link between ADAM33 and asthma. Its restricted expression to mesenchymal cells as well as its association with bronchial hyperresponsiveness and accelerated decline in lung function over time point strongly to its involvement in the structural airway components of asthma, such as remodeling. Extensive alternative splicing, expression during branching morphogensis in the developing fetus, impaired lung function in childhood, the production of a soluble form linked to chronic asthma, and tight epigenetic regulation indicate a level of complexity in the way ADAM33 influences disease phenotype. Its recent association with chronic obstructive pulmonary disease as well as with asthma and lung development points to functions relating to airway wall modeling and remodeling as a general morphogenetic repair gene rather than being restricted to asthma.
Holgate
Stephen T
ST
Infection, Inflammation, and Repair Division, MP810, F Level, South Block, Southampton General Hospital, Southampton SO16 6YD, UK. sth@soton.ac.uk
Yang
Youwen
Y
Haitchi
Hans-Michael
HM
Powell
Rob M
RM
Holloway
John W
JW
Yoshisue
Hajime
H
Pang
Yun Yun
YY
Cakebread
Julie
J
Davies
Donna E
DE
D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D001249:Asthma / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans
D004247:DNA; D051722:ADAM Proteins; C450441:ADAM33 protein, human