Reply to Reijmerink et al

Abstract

We appreciate the comments from Reijmerink et al on our IL18R1 genetic association results published in the European Journal of Human Genetics.1 As we had pointed out in the paper, ours was a candidate gene study specifically exploring the hypothesis of genetic association between IL18R1 and asthma, as IL18R1 is a plausible candidate based on the available biological information. The observation that the SNPs in IL1RL1, IL18RAP and IL18R1 are associated with asthma in the Dutch asthma cohorts is interesting. We did not discuss the possibility of association with this gene cluster in our paper, as we were focused on IL18R1's association with asthma. A recent GWAS study to identify sequence variants affecting blood eosinophil counts reported significant association with the LD block containing IL1RL1, IL18R1, IL18RAP and SLC9A4, and this region is significantly associated with asthma (P=5.5 × 10−12) in a collection of 10 different populations.2 This study, along with the results pointed out by Reijmerink et al3 and our study,1 highlights the importance of this region in asthma-related phenotypes. As IL1RL1, IL18R1, IL18RAP and SLC9A4 are in tight linkage disequilibrium, we agree with Reijmerink et al's suggestion to take a closer look at this region in large asthma populations. Considering the LD pattern in this gene cluster, genotyping and analyzing additional SNPs may not resolve the questions raised here. We suggest deep sequencing of this region in a large population to identify functional variants and also suggest undertaking functional studies to pinpoint the biological association with the disease. We agree with the comments of Reijmerink et al on the significance of this region and highlight the importance of examining the flanking regions in all candidate gene studies. Recent efforts in setting up large databases for genetic association studies in asthma (GABRIEL consortium) and other diseases will be helpful to solve some of these questions.