Genome-wide association studies

What are we to make of genome-wide association studies (GWAS)? In an editorial highlighting 3 articles in this month’s issue (Wu et al.; Li et al.; and Mathias et al.), Donata Vercelli, MD, explores this question. Dr. Vercelli points out the advantage that GWAS offer over linkage and candidate gene studies; namely, that GWAS can look for susceptibility SNPs across a whole genome without a priori assumptions. That’s also the difficulty, because GWAS are now uncovering SNP associations from surprising gene families, and biological validation will be required for these results. Additionally, currently available GWAS technologies may contribute to variability of results because they do not account for rare SNPs and admixed populations. Finally, Dr. Vercelli talks about the bugbear of epigenetic influence, which is difficult to account for in GWAS.

As for the articles themselves:

Mathias et al. look at genome-wide associations in asthmatic and non-asthmatic African American and African Caribbean populations. They identify only 3 SNPs in 3 genes with significant association from combined analysis of the results of GWAS of each population. The role of the genes they single out–ADRA1B, PRNP, and DPP10–in asthma susceptibility is not yet understood. The authors also report that their results did not generalize to 2 white populations. They also stress the difficulties inherent to studying non-Caucasian populations by using genotyping platforms designed to assess variants common in Caucasians.

Li et al. investigate SNP associations in severe and difficult-to-treat, white, asthmatic populations using 14, highly replicated, candidate genes. Li and co-authors show that SNPs in two regions, RAD50-IL13 and HLA-DR/DQ, have consistent association with asthma, with SNPs in the RAD50 region having the strongest association. While the former regions have functional impact on Th2 cytokine expression and antigen-presentation respectively, RAD50 is involved in DNA repair and its effect on asthma susceptibility isn’t known. Li et al. propose that a RAD50 region characterized in mice as affecting Th cytokine expression may have a functional role in humans. The authors suggest that variants in the RAD50locus should be considered new asthma candidates.

Wu et al. report results of a GWA study that focused on previously published asthma candidate genes in the hope that this approach would improve signal detection. Out of 118 asthma candidate genes, 4 with multiple SNPs had significant associations in the pediatric asthma/Mexican population studied: TGFB1, IL1RL1, IL18R1, and DPP10.

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Omalizumab pre-treatment and immunotherapy

Following up on significant results from a study that demonstrated benefit of pre-treatment with omalizumab prior to initiation of specific allergen immunotherapy (SIT) in subjects with ragweed allergic rhinitis, Massanari et al. report their results from a similarly designed study in subjects with persistent allergic asthma undergoing SIT.

Study subjects with at least moderate persistent allergic asthma that was inadequately controlled by inhaled corticosteroid (ICS) therapy were enrolled to receive 13 weeks pre-treatment with omalizumab or placebo before initiation of 4 weeks cluster regimen SIT followed by 7 weeks of maintenance therapy.

Compared to placebo, the omalizumab group had fewer systemic allergic reactions (SARs) during SIT (placebo: 26.2%; omalizumab: 13.5%), improved asthma symptoms and rescue medication use during pre-treatment, and were more likely to achieve target maintenance dose. Discontinuations due to SARs, were higher in the placebo group (9.6%) than in the omalizumab group (5.0%)

Grade 3 respiratory SARs were most common. Among 30 documented SARs, 24 of the subjects were on placebo and 6 were on omalizumab. Additionally, 87% of the omalizumab group achieved targeted maintenance dose in contrast to 72% of the placebo group.

Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments.