Food allergy (FA), a condition caused by an immunoglobulin (Ig) E-mediated hypersensitivity reaction to food, is a growing clinical and public health problem in the U.S. and worldwide. FA affects approximately 5-8% children and 1-4% of adults. A positive family history is a well-recognized predictor of allergic diseases. Our preliminary data strongly suggest that genetic factors play an important role in FA. To date, few genetic studies of FA have been conducted. The central focus of this proposal is to conduct a genome-wide association (GWA) study to identify susceptibility genes for FA. We will utilize biological samples and epidemiological and clinical data from our ongoing multi-center FA study using a standard protocol. We propose a two-stage GWA study. Specifically, Aim1 (Stage 1 GWA study): We will genotype a total of 500 FA affected trios (mother, father, and FA affected child, a total of 1,500 subjects), using the Illumina Human1M-Duo Infinium HD BeadChip. We will test each SNP for association with FA using best available statistical methods. We will select SNPs reaching Stage 1 significance (p<10-4) to be further tested in Stage 2.
Aim2 (Stage 2 GWA study): We will genotype all the promising SNPs identified from Aim 1 in another 500 FA affected trios (mother, father, and FA affected child, a total of 1,500 subjects). We will perform joint analysis that will combine the 1,000 trios, a total of 3,000 subjects. We will use the genome-wide significance cutoff (p<10-7) in Stage 2. This study will be the first large-scale GWA study of FA in the U.S. Given our limited understanding of the etiology of FA and lack of highly favorable candidate genes of FA, a GWA study offers the best available approach to dissect genetic basis of FA. This study has the following strength: (1) a highly cost-efficient study by using existing study samples;(2) a large sample size that assures adequate statistical power for addressing the primary aims;(3) utilization of state-of-the-art, high-throughput genotyping technology and statistical methods;and (4) a highly interactive and experienced multidisciplinary research team. We anticipate that this study will lead to identification of novel genetic loci of FA, which will pave the road for the future investigation. Intensive follow-up work, including independent replications, fine mapping, sequencing, and functional studies, is required to further elucidate which specific variants are causal, what are the biological mechanisms, and how they interact with other genetic or environmental factors. A particular strength of this proposed study is that it offers a tremendous potential for future studies of FA, given the well-established infrastructure and resources. Collectively, this and future studies will help develop a promising paradigm for identifying individuals at high risk of FA, and developing effective strategies for prevention and treatment of FA.
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