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Role of ADAM33 in the development and progression of asthma
The gene encoding ADisintegrin And Metalloprotease (ADAM) 33 was the first asthma susceptibility gene to be discovered by positional cloning.1 In 460 families enriched with asthma, linkage analysis using microsatellite markers spaced ∼9 cM apart revealed a region on chromosome 20p13 that carried one or more asthma genes, achieving a Maximum Lod Score (MLS) of 2.24 at 9.99 cM. The addition of further markers at 1.2 cM increased the MLS to 2.94 at 12.1 cM which further rose to 3.93 when bronchial hyperresponsiveness was included in the definition of asthma despite halving the sample size, thereby exceeding the threshold for genome wide significance. Physical mapping, direct cDNA selection, and sequencing of DNA cloned into bacterial artificial chromosomes (BACs) identified 25 candidate genes. Linkage disequilibrium mapping of single nucleotide polymorphisms (SNPs) on 23 genes spanning the peak of linkage together with case-control and family based association analyses revealed that ADAM33 accounted for the linkage signal.
Several features of this initial report raised questions regarding the generalisability of the results.2 Firstly, although significant evidence for linkage was observed, this region on chromosome 20p had not been identified in previous genome wide screens in asthma. Secondly, the initial publication did not have a truly independent replication sample. Thirdly, no single SNP demonstrated significant association in both the UK and US populations that made up the total sample when these were analysed separately. Finally, no functional data regarding the role of associated SNPs in alteration of gene expression and/or function and in the development of asthma phenotypes were presented.
Since 2002 there have been a …
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