ADAM33 polymorphism: association with bronchial hyper-responsiveness in Korean asthmatics J. H. Lee* 1 , H.-S. Parkw 1 , S. W. Park*, A. S. Jang*, S. T. Uh*, T. Rhim*, C.-S. Park*, S.-J. Hongz, S. T. Holgate§, J. W. Holloway§ and H. D. Shinz *Asthma Genome Research Center, Soonchunhyang University Hospital, Bucheon, Korea, wDepartment of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea, zDepartment of Pediatrics, Ulsan University Hospital, Seoul, Korea, §Infection, Inflammation and Repair Division, School of Medicine, University of Southampton, MP810, Southampton General Hospital, Southampton SO16 6YD, UK and zDepartment of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Korea Summary Background A disintegrin and metalloprotease 33 (ADAM33) is expressed in the lung by fibroblasts and bronchial smooth muscle cells. Given its structure and cellular provenance, ADAM33 may be associated with airway remodelling and bronchial hyper-responsiveness. Single nucleotide polymorphisms (SNPs) and haplotypes of the ADAM33 gene have previously been associated with asthma susceptibility in the Caucasian population. Objective and Methods To assess whether genetic variants of ADAM33 are related to asthma in a Korean population, we conducted an association study of the ADAM33 gene with asthma susceptibility, bronchial hyper-reactivity and serum IgE in Korean asthmatics (n 5 326) and normal controls (n 5 151). Five of the 14 polymorphisms originally reported to be associated with asthma development (S1 G4A, T1 T4C, V-1 C4A, V1 T4A, V4 C4G) were genotyped using single base extension and electrophoresis. Haplotypes and their frequencies were inferred using the algorithm implemented by the software Arlequin. Allele frequencies of each SNP and haplotypes were compared between the patients and the normal controls using logistic regression analysis. Results There was no significant difference in the distribution of SNPs and the six haplotypes between asthmatics and normal controls. All single SNPs and six haplotypes in ADAM33 were also analysed for the association with level of PC 20 using general linear models. The distribution of the T1 T4C SNP and one haplotype (ht4: GCGG) showed significant association with log-transformed PC 20 methacholine level in the asthma patients (P 5 0.03 and 0.0007, respectively, using a co- dominant model). Conclusion Polymorphism of ADAM33 may contribute to development of BHR in asthma. Keywords ADAM33 gene, asthma, bronchial hyper-reactivity, Korean population Submitted 19 September 2003; revised 4 February 2004; accepted 24 March 2004 Introduction Asthma is a common and heterogeneous respiratory disease characterized by intermittent airways obstruction and re- spiratory symptoms that are caused by chronic airway inflammation and remodelling [1]. This airway inflammation and remodelling is one of the main causes of bronchial hyper- responsiveness (BHR), which characterizes the pathophysiol- ogy of asthma. The remodelling process has been linked to aberrant epithelial–mesenchymal signalling and proliferation of biosynthetically active myofibroblasts that represent precursors of smooth muscle [2]. The ADAM (a disintegrin and metalloproteinase) gene family, of which currently there are 34 members, is a sub- group of the zinc-dependent metalloproteinase superfamily [3, 4]. While biologic roles have been elucidated in some family members including roles in sperm–egg fusion, myo- genesis and growth factor shedding, others are yet to have their function elucidated. A number of ADAM proteins have been shown to be expressed on the cell surface and to have protease activity [5–8]. Other functions of ADAM proteins include mediating cell–cell interaction through the disintegrin domain and mediating cell–cell fusion events [9, 10]. The gene encoding a disintegrin and metalloprotease 33 (ADAM33) has recently been identified as a susceptibility gene for asthma using a positional cloning strategy [11]. In a genomewide scan of 460 Caucasian families enriched for doctor-diagnosed asthma, evidence for linkage was found on 20p13 with a maximum logarithm of odds (LOD) of 2.94 at the marker D20S482 (12.1 cM) which further increased to 3.93 when BHR was included in the definition of asthma. Physical mapping and direct cDNA selection identified 40 genes in the 1 Equally contributed as first authors. Correspondence: Prof. Choon-Sik Park, Division of Allergy and Respira- tory Medicine, Department of Internal Medicine Soonchunhyang Uni- versity Bucheon Hospital, 1174, Jung Dong, Wonmi Ku, Bucheon, Gyeonggi Do, 420-021, Korea. E-mail: mdcspark@unitel.co.kr Clin Exp Allergy 2004; 34:860–865 doi:10.1111/j.1365-2222.2004.01977.x r 2004 Blackwell Publishing Ltd 860