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.

Do you have any questions or comments about these studies? We want to hear from you. Please post your questions and comments below.

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.

Air cleaners and filters - A rostrum

We focus this week on a Rostrum contribution, "Air filters and air cleaners: Rostrum by the American Academy of Allergy, Asthma & Immunology Indoor Allergen Committee," by Sublett et al. (J Allergy Clin Immunol 2009;125:32-38). The authors tackle the topic of air cleaners and air filtration by providing technical information on efficiency testing, and specifications of available technology as well as summarizing a literature review on the effects of air cleaning on asthma and allergy. Two air cleaning modalities are covered: portable room air cleaners and whole-house systems installed in HVAC units. The published studies reviewed by the authors typically presented findings from a single method air cleaner across short durations up to 6 months. The authors note that most results demonstrated minimal or no benefit. Overall, HEPA-filtered, portable air cleaners, and HVAC filtration systems that used high-efficiency filters and frequent routine maintenance had limited benefits. Sublett and coauthors suggest that air cleaning should be viewed as mitigation of disease progression rather than treatment for asthma and allergies. The authors go on to conclude that short-duration, single-method studies are not enough to demonstrate mitigation and that long-duration studies involving multiple air-cleaning methods are needed.

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. All questions and comments will be forwarded to the authors for a response.

“Long-term clinical efficacy in grass pollen rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet”

The featured article for this first blog is “Long-term clinical efficacy in grass pollen rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet” (Durham et al. J Allergy Clin Immunol 2009;125:131-138.e7), from our January issue. The authors report, for the first time, long-term benefit associated with sublingual immunotherapy for timothy grass pollen studied in a multisite, randomized, placebo-controlled trial. They describe significant decreases in daily allergy symptoms as well as medication use both during the study and for 1 year after subjects’ participation ended. Durham and colleagues also report progressive changes in specific IgG4 and IgE-blocking factor in subjects receiving active treatment, demonstrating disease modification, which has been previously reported for subcutaneous administration. Because oral administration was associated with only mild, local adverse effects, such as oral pruritis, Durham et al. suggest that patient-administration with prescription is supported by the safety profile.

We asked lead author Stephen R. Durham, MD, to tell us a little more about this paper, and what follow-up studies are needed:

“The results of this multicentre trial confirm long-term efficacy of sublingual grass pollen allergen tablet immunotherapy and its disease modifying potential. It will be of great interest to see whether these long-term benefits are sustained for more than one year following discontinuation. Patients had confirmed IgE-mediated disease and a suboptimal response to usual pharmacotherapy. Although local side effects of itching/swelling in the mouth were common, in general they resolved within 1-2 weeks and were not bothersome and no serious side effects were observed. The data raise the question whether the treatment should be introduced earlier in the course of the disease and in a broader range of patients. As for the subcutaneous route, initial prescription of sublingual immunotherapy should be by a Specialist in Allergy, with observation of the first dose, whereas the treatment is thereafter suitable for home self-administration. Similar studies are required for other allergens and possible preventive effects should be explored in high risk children with sensitisation with/without associated early atopic disease.”

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. All questions and comments will be forwarded to the authors for a response.