EDITORIAL 263 ADAM33 and asthma statistical association is not revealed in ....................................................................................... a particular population irrespective of Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from size does not necessarily mean that the gene in question is not contributing to Is big beautiful? The continuing story of the phenotype, but the mode of its influence may be complex involving ADAM33 and asthma gene-gene or gene-environmental inter- actions.14 However, as the number of S T Holgate, J W Holloway independent studies increases, it would be valuable to accrue the evidence ................................................................................... systematically as was reported for link- age analysis for asthma on chromosome Role of ADAM33 in the development and progression of asthma 5 (the Consortium on Asthma Genetics).15 With the recent establish- ment of the Network of Excellence for he gene encoding A Disintegrin And asthma in four unique asthma popula- Asthma and Allergy (GA2LEN), there is Metalloprotease (ADAM) 33 was tions comprising African American, US a unique opportunity to further develop the first asthma susceptibility gene white, US Hispanic, and Dutch white T 1 meta-analyses for candidates such as to be discovered by positional cloning. populations. Significant associations ADAM33. The study by Blakey et al is an In 460 families enriched with asthma, with at least one SNP and asthma were excellent example of the power of this linkage analysis using microsatellite found in each of the populations approach. markers spaced ,9 cM apart revealed (p = 0.0009–0.04) with multiple SNPs At present the SNPs that cause the a region on chromosome 20p13 that associating with asthma or its partial dysfunction in ADAM33 predisposing to carried one or more asthma genes, phenotypes in some of the populations. asthma are not yet clear, although achieving a Maximum Lod Score Further replication has been reported in several SNPs (T1, F+1 and ST+7) are (MLS) of 2.24 at 9.99 cM. The addition separate case-control and family based coming through in a number of differ- of further markers at 1.2 cM increased association studies in Germany,4 Korea,5 6 ent studies as being associated with the MLS to 2.94 at 12.1 cM which and Japan. However, there are two asthma. However, because of the very further rose to 3.93 when bronchial published studies showing no evidence 7 8 large degree of linkage disequilibrium hyperresponsiveness was included in of association or weak association. between many SNPs in ADAM33 so far the definition of asthma despite halving It is therefore timely that, in this issue identified (possibly in excess of 100), the sample size, thereby exceeding the of Thorax, Blakey and colleagues report genetics alone is unlikely to cast much threshold for genome wide significance. the result of a meta-analysis involving further light on the disease related Physical mapping, direct cDNA selec- eight separate populations totalling variants although new analytical meth- tion, and sequencing of DNA cloned into 1299 cases and 1665 controls used in odologies are being developed.16 Some bacterial artificial chromosomes (BACs) case-control association analysis and clues about how ADAM33 may influ- identified 25 candidate genes. Linkage 4561 families used in transmission ence the asthma phenotype are emer- 9 http://thorax.bmj.com/ disequilibrium mapping of single disequilibrium tests (TDTs). In both ging. In 200 Dutch patients with asthma nucleotide polymorphisms (SNPs) on types of analysis several SNPs were who had regular lung function measure- 23 genes spanning the peak of linkage significantly associated with asthma. ments made over 20 years, the rare together with case-control and family The important point the authors made alleles of the SNPs S-2, T-1 and T-2 of based association analyses revealed that is that, based on allele frequencies for the ADAM33 gene were associated with a ADAM33 accounted for the linkage the ST+7 G allele of 84.9% in the significant excess decline in baseline signal. asthmatic population and 79.1% in the forced expiratory volume in 1 second Several features of this initial report controls and an asthma prevalence of 17 (FEV1) of 23.7–30 ml/year. These data raised questions regarding the generali- 8%, this SNP would potentially contri- imply a role for ADAM33 in airway wall on September 26, 2021 by guest. Protected copyright. sability of the results.2 Firstly, although bute to ,50 000 excess asthma cases in remodelling which is known to contri- significant evidence for linkage was the UK population. bute to chronic airflow obstruction in observed, this region on chromosome What is important to point out is that moderate to severe asthma.18 A second 20p had not been identified in previous most case-control and family based study conducted in infants born of genome wide screens in asthma. association studies looking for disease allergic/asthmatic parents in Northern Secondly, the initial publication did related genes in complex disorders are England (NACMAAS) has revealed posi- not have a truly independent replication statistically underpowered and that far tive associations between SNPs of sample. Thirdly, no single SNP demon- larger sample sizes are needed. Part of ADAM33 and increased airway resis- strated significant association in both the reason for this is the existence of tance measured by plethysmography at the UK and US populations that made genetic heterogeneity with any one gene age 3 and again at age 5 years, with the up the total sample when these were varying in its influence over a disease strongest effect seen in the homo- analysed separately. Finally, no func- phenotype between populations with zygotes.19 20 These data support the idea tional data regarding the role of asso- differing genetic backgrounds and dif- that alterations in the expression or ciated SNPs in alteration of gene fering environmental exposures.10 11 For function of ADAM33 is in some way expression and/or function and in the example, natural selection may have involved in impairing lung function in development of asthma phenotypes acted on a disease gene haplotype early life and, as a consequence, increas- were presented. differentially in different populations ing the risk of asthma developing. Since 2002 there have been a number as recently described for the IL-4 locus The initial study1 as well as others35 of separate replication studies in diverse on chromosome 5q31–34.12 Another have revealed some of the strongest ethnic populations. The first by Howard example is the NOD2/CARD 15 gene associations when bronchial hyperre- et al3 examined eight SNPs in the 39 on chromosome 16 which has been sponsiveness (BHR) is incorporated into portion of ADAM33 reported in the associated with Crohn’s disease in some the asthma phenotype. The cellular original study to be associated with but not all populations.13 Because a provenance of ADAM33 mRNA and www.thoraxjnl.com 264 EDITORIAL protein in being restricted to mesen- future challenge. We are now entering 11 Ioannidis JP, Ntzani EE, Trikalinos TA, et al. Replication validity of genetic association studies. Thorax: first published as 10.1136/thx.2004.038471 on 24 March 2005. Downloaded from chymal cell types (fibroblasts, myofibro- the new research era of translational Nat Genet 2001;29:306–9. blasts and smooth muscle) reinforces science and the rebirth of experimental 12 Sakagami T, Witherspoon DJ, Nakajima T, et al. the view that this molecule is involved medicine as a research focus.29 Local adaptation and population differentiation at the interleukin 13 and interleukin 4 loci. Genes in the pathophysiology of BHR and Thorax 2005;60:263–264. Immun 2004;5:389–97. airway remodelling rather than the doi: 10.1136/thx.2004.031385 13 Arnott ID, Nimmo ER, Drummond HE, et al. immunological or inflammatory compo- NOD2/CARD15, TLR4 and CD14 mutations in 121 Scottish and Irish Crohn’s disease patients: nents of asthma. Expression of full ...................... evidence for genetic heterogeneity within Europe? length ADAM33 in mammalian cell Authors’ affiliations Genes Immun 2004;5:417–25. lines has shown that the metallopro- S T Holgate, J W Holloway, Allergy and 14 Vercelli D. Genetics, epigenetics, and the environment: switching, buffering, releasing. tease domain of ADAM33 is func- Inflammation Research, Division of Infection, J Allergy Clin Immunol 2004;113:381–6. 22 23 tional but the biological targets of Inflammation and Repair, School of Medicine, 15 Lonjou C, Barnes K, Chen H, et al. A first trial of the metalloprotease activity are as yet Southampton General Hospital, Southampton retrospective collaboration for positional cloning unknown. In cell based sheddase assays SO16 6YD, UK in complex inheritance: assay of the cytokine J W Holloway, Division of Human Genetics, region on chromosome 5 by the Consortium on ADAM33 functioned as a negative reg- Asthma Genetics (COAG). Proc Natl Acad Sci ulator of b-amyloid precursor peptide School of Medicine, Southampton General USA 2000;97:10942–7. (APP) cleavage and mediated some Hospital, Southampton SO16 6YD, UK 16 Bureau A, Dupuis J, Falls K, et al. Identifying SNPs predictive of phenotype using random constitutive shedding of stem cell factor forests. Genet Epidemiol 2005;28:171–82. (SCF, ckit ligand); however, the kinetics Correspondence to: Professor S T Holgate, 17 Jongepier H, Boezen HM, Dijkstra A, et al. Allergy and Inflammation Research, MP810, of these cleavage reactions would indi- Polymorphisms of the ADAM33 gene are Level D, Centre Block, Southampton General associated with accelerated lung function decline cate that these two proteins are not the Hospital, Southampton SO16 6YD, UK; sth@ in asthma. Clin Exp Allergy 2004;34:757–60. natural substrates.23 soton.ac.uk 18 Bel EH. Clinical phenotypes of asthma. Curr Opin Six alternatively spliced variants of Pulm Med 2004;10:44–50.