Contribution of ADAM33 polymorphisms to the population risk of asthma

Background: ADAM 33 is the first gene identified as a candidate for asthma by positional cloning techniques, with association studies reaching impressive statistical significance. It has a postulated role in myogenesis, airway modelling, and signalling via protein shedding. Concerns over the methodology of the initial study have led to several attempts at replication, with inconsistent results. Method: To clarify the role of ADAM33 in determining the risk of asthma in the general population, new transmission disequilibrium and case- control studies were undertaken followed by a meta- analysis of all existing data. Results: Studies in Icelandic and UK populations revealed no association when taken in isolation. The meta- analysis, however, showed that the F+ 1 and ST+ 7 variants were significantly associated with asthma in both types of study. Conclusions: The additional risk imparted by this variation would account for 50 000 excess asthma cases in the UK alone. This study also demonstrates the size of study required to investigate such hypotheses adequately.