ADAM33 haplotypes are associated with asthma in a large Australian population

The ADAM33 gene has recently been identified as being a potentially important asthma candidate gene, and polymorphisms in this gene have been shown to be associated with asthma and bronchial hyperresponsiveness in Caucasian individuals from several populations. We performed chip-based matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry using the MassARRAY system and multiplexed genotyping assays to investigate the association between 10 single nucleotide polymorphisms (SNPs) in the ADAM33 gene (F_+1, Q_- 1, S_1, ST_+4, ST_+7, V_-2, V_-1, V_2, V_4, V_5) and asthma and asthma severity in a large Australian Caucasian population of nonasthmatic controls (n = 473), and patients with mild (n = 292), moderate (n = 238) and severe (n = 82) asthma. No significant association was found between any one of the 10 SNPs and asthma or asthma severity, however, there was a significant global haplotypic association with asthma (P = 0.0002) and disease severity (P = 0.0001), driven by the combination of two key SNPs, V_-1 and ST_+7. A meta-analysis of all the genetic studies conducted to date found significant between-study heterogeneity, likely to reflect population stratification. Our analysis of ADAM33 haplotypes further suggests a likely role for ADAM33 in the asthma phenotype, although it does not exclude an association with another locus in linkage disequilibrium with ADAM33.