Asthma, Rhinitis, Other Respiratory Diseases
Association of a disintegrin and metalloprotease 33 (ADAM33) gene with asthma in ethnically diverse populations

https://doi.org/10.1016/S0091-6749(03)01939-0Get rights and content

Abstract

Background

Asthma is a complex genetic disease characterized by reversible intermittent airway obstruction and respiratory symptoms primarily caused by acute and chronic bronchial inflammation. Recently, a gene potentially involved in airway remodeling, a disintegrin and metalloprotease 33 (ADAM33), was implicated in asthma susceptibility.

Objective

We sought to determine whether polymorphisms in ADAM33 are associated with asthma or closely related phenotypes in 4 different asthma populations.

Methods

Eight single nucleotide polymorphisms (SNPs) were evaluated in the 3′ portion of ADAM33 in 4 unique asthma populations (African American, US white, US Hispanic, and Dutch white). These SNPs were previously reported to be associated with asthma in white populations from the United States and United Kingdom.

Results

Significant associations were observed with at least one SNP and asthma in each population (P = .0009–.04). Related phenotypes that included total serum IgE levels and skin test responsiveness were also associated (P = .003–.05). However, no single SNP was associated across all populations. Additionally, haplotype analysis revealed that no single haplotype accounted for asthma susceptibility risk, although potential risk haplotypes existed within some of the populations.

Conclusion

Replication of the original ADAM33 findings in these 4 additional asthma populations suggests that this gene (and perhaps others that interact with it) is important in the development and pathogenesis of asthma.

Section snippets

Methods

Asthma cases in the African American, US white, and US Hispanic populations were collected by using criteria established as part of the Collaborative Study on the Genetics of Asthma.7 Control subjects for this group had no history of asthma and no first-degree relatives with asthma. Dutch probands with clinical asthma were originally characterized between 1962 and 1975.8, 9 Between 1990 and 1998, 200 probands and their spouses, children, and available grandchildren were studied. The probands

Results

Some variability in allele frequency was observed among the 4 populations (Fig 1).2 For asthma susceptibility, significant associations were observed to at least one of the 8 SNPs within each population, but no single SNP was consistently associated with a specific asthma phenotype across all of the groups (Table I). The most significant associations were observed in the Dutch asthma population with SNPs ST+7 and V4 by using a codominant model (P = .0093 and P = .0009, respectively).

Discussion

The report of ADAM33 as a positionally cloned gene for asthma2 represents an important development in understanding susceptibility to asthma, allergy, and closely related phenotypes.12, 13 Thus, it is necessary to evaluate the importance of this observation by replicating it in different populations and further delineating the role of this gene in asthma. The purpose of this study was to evaluate variation in ADAM33 in 3 ethnic groups in the United States (African American, white, and

Acknowledgements

We thank all participants in the study and E. Gankema, H. Koops, M. Leever, D. Faber, Betsy Rechsteiner, Regina Smith, and Laurie Adams, who assisted in the clinical testing. We also thank C.I.M. Panhuysen, B. Meijer, G.G. Meijer, and Pamela Amelung for their work in patient recruitment.

Cited by (184)

  • Matrix metalloproteinase (MMP)-2 -1306 C > T gene polymorphism affects circulating levels of MMP-2 in Egyptian asthmatic patients

    2016, Gene Reports
    Citation Excerpt :

    Studies containing thousands of genetic variants have been used to establish associations among asthma and control cases (Ferreira et al., 2011). Thus, gene polymorphism may play a vital role in asthma pathogenesis and improve asthma management (Howard et al., 2003). Matrix metalloproteinases (MMPs) are a large group of calcium-dependent and zinc-containing endopeptidases that cleave proteins and proteoglycan constituents of the extracellular matrix (ECM), in addition to multiple non-matrix substrates including cytokines, chemokines, growth factors and growth factor receptors (Zitka et al., 2010).

  • Association of ADAM33 gene S1 and S2 transmembrane domain polymorphisms in COPD from South-Indian population

    2016, Egyptian Journal of Medical Human Genetics
    Citation Excerpt :

    It is suggested to play a role in the airway remodelling of the lungs [24]. Genetic linkage analysis and association studies of families with asthma across diverse ethnic back-grounds support a relationship between ADAM33 polymorphisms and asthma phenotypes expressed in AHR and other respiratory disorders [25–28]. The mouse orthologue of ADAM33 also lies in the region linked to AHR [14].

View all citing articles on Scopus

Supported by the Dutch Asthma Funds grant AF 95.09, and National Institutes of Health (NIH) grants R01HL/48341 and R01HL/66393.

View full text