Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Hur, Gyu Young; Broide, David H.

Among ADAM gene family members, ADAM33 was the first asthma-related gene identified by positional cloning using a genome-wide screening approach. 10 is associated with both asthma and airway hyperresponsiveness (AHR). 11 The finding that ADAM33 is expressed in lung structural cells, such as bronchial smooth muscle cells, suggest a potential mechanism for ADAM33 to contribute to airway remodeling. 11 Previous studies have investigated the contribution of single nucleotide polymorphisms (SNPs) in the ADAM33 gene to asthma outcomes including decline in lung function in asthma. In adult asthmatics, ADAM33 CC homozygotes of the rs528557 SNP had an excess annual decline in FEV1 compared to GG homozygotes. 12 In addition, in studies of the general population followed up for 25 years, ADAM33 genetic variants were reported to be associated with a rapid lung function decline. 13, 14 For example, subjects with ADAM33 homozygous minor alleles of either rs612709 or rs528557 had a significant decline in FEV1 of 9.6 mL/year (P = 0.021) or 4.9 mL/year (P = 0.033), respectively. 13 Another ADAM33 SNP rs3918395 AA allele was also associated with a rapid lung function decline (P = 4.34 × 10 −5 ). 14 Overall, these studies suggest that ADAM33 genetic variants are associated with a more rapid decline in lung function in adult asthmatics and in the normal general population. So far, no published studies have investigated whether ADAM33 genetic variants are associated with features of airway remodeling.