The candidate gene approach in asthma: what happens with the neighbours?

In the last few decades, multiple genes important in asthma and atopy development have been identified. A successful approach has been to investigate candidate genes, that is, genes with a

biologically plausible function.1 This approach has also been applied by Zhu _et al_2 in a previous issue of this journal. They analysed _IL18R1_, an interesting candidate gene for asthma

and atopy, and provided replicated evidence in three European populations that SNPs located in _IL18R1_ were associated with asthma.2 Specifically, SNP rs1420099, rs1362348, and rs1974657

were associated with asthma in these three populations. IL-18 receptor is a key immunoregulator; the gene product of _IL18R1_ forms the alpha chain of the IL-18 receptor.3 Binding of IL-18

to the IL-18 receptor can stimulate Th1 as well as Th2 cytokine release.4 These findings may indeed point towards a role of IL18R1 in the pathophysiology of asthma.2 _IL18R1_ is localized in

the IL1 receptor cluster on chromosome 2q12. In its close vicinity reside _IL1R2_, _IL1RL_, _IL1RL2_, _IL1RL1_, and _IL18RAP_. We have recently undertaken a candidate gene approach

analysing genes located in a region of strong linkage disequilibrium (LD) in this gene cluster, that is, _IL18R1_, as well as _IL1RL1_ and _IL18RAP_, in two Dutch asthma and one Dutch

rhinitis cohort.5 We reported replicated evidence for association of SNPs in this gene cluster with asthma phenotypes in our two Dutch asthma populations. For _IL18R1_, four SNPs were

associated with asthma and bronchial hyperresponsiveness in a combined analysis of the two asthma cohorts (_P_<0.05); these SNPs, that is, rs12999364, rs1558627, rs2270297, and rs1035130,

were not genotyped by Zhu _et al._ Furthermore, we found significant associations with SNPs in _IL1RL1_ and _IL18RAP._ A haplotype from SNPs in _IL1RL1_ and _IL18R1_ was significantly

associated with bronchial hyperresponsiveness. Strong LD was detected between SNPs in the three genes in this region. _IL1RL1_ encodes the receptor for IL-33, which is located on mast cells,

Th2 cells, regulatory T cells, and macrophages, and is also present in serum in a soluble form.6, 7, 8 IL1RL1 is a member of the Toll-like receptor superfamily and can either stimulate or

inhibit Th2 responses by influencing TLR pathway signalling.9, 10, 11, 12 There is increasing evidence that this gene is important in atopic diseases such as eczema and asthma;

interestingly, a recent large genome-wide association study also indicated _IL1RL1_ to be important in asthma, and thus _IL1RL1_ is also a plausible candidate gene for asthma.5, 13, 14 In

their paper, Zhu _et al_ mentioned the limitation of not analysing SNPs located in _IL18R2_ (also known as _IL18RAP_). SNPs in _IL1RL1_ and _IL18RAP_, next to _IL18R1_, may also contribute

to the genetic association signal on chromosome 2q12. We suggest that genetic association studies in regions with strong LD may not be conclusive as to which gene or genes are causal in

disease development. It would therefore be of interest to investigate also _IL1RL1_ and _IL18RAP_ in the populations described by Zhu _et al._ Moreover, we suggest the investigation of this

region in populations with different LD characteristics and to perform functional studies. Our observations imply that, once positive genetic associations are identified, it is worthwhile to

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dermatitis. _Hum Mol Genet_ 2005; 14: 2919–2927. Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pulmonology, University Medical

Center Groningen, University of Groningen, Groningen, The Netherlands Naomi E Reijmerink & Dirkje S Postma * Department of Pediatrics, Beatrix Children's Hospital, University

Medical Center Groningen, University of Groningen, Groningen, The Netherlands Naomi E Reijmerink * Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's

Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Gerard H Koppelman Authors * Naomi E Reijmerink View author publications You can also

search for this author inPubMed Google Scholar * Dirkje S Postma View author publications You can also search for this author inPubMed Google Scholar * Gerard H Koppelman View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Gerard H Koppelman. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS

ARTICLE CITE THIS ARTICLE Reijmerink, N., Postma, D. & Koppelman, G. The candidate gene approach in asthma: what happens with the neighbours?. _Eur J Hum Genet_ 18, 17 (2010).

https://doi.org/10.1038/ejhg.2009.128 Download citation * Published: 05 August 2009 * Issue Date: January 2010 * DOI: https://doi.org/10.1038/ejhg.2009.128 SHARE THIS ARTICLE Anyone you

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