Food allergy (FA), a hypersensitivity reaction to food, is a growing clinical and public health problem in the U.S. and worldwide. FA is a complex trait, as a result of multiple genetic and environmental factors and their interactions. However, specific genetic markers that can modulate individual susceptibility to FA remain to be determined. Our ongoing genome-wide association study (GWAS) of FA in the Chicago Cohort is the first study to comprehensively identify susceptibility variants for FA. Similar to other GWAS, it treats the genetic effects from the paternally- and maternally-transmitted allele on FA equally, such that FA-associated imprinted genes could not be identified. Moreover, no study has examined maternally-mediated genetic effects on FA. As an early childhood onset disease, maternal genotypes may play crucial roles in the development of FA, possibly through their influence on the intrauterine environment. <p/>To complement our GWAS of FA and search for the missing heritability, the central focus of this study is to examine maternal and imprinting effectson FA, two types of parent-of-origin effects (POE), by leveraging the existing GWAS data generated in 851 FA families from the Chicago Cohort. Specifically, we propose to accomplish two primary aims. Aim1: we will test maternally-mediated genetic effects on FA in 631 Caucasian families (~80% of the samples from the GWAS of FA) using log-linear likelihood ratio tests (LL-LRT), which are able to examine genetic effects through the offspring, mother, and both. We also will conduct pathway analysis of maternal genetic effects on FA. Aim2: We will test for imprinting effects, which represent the relative risk of FA cases inheriting a maternally-transmitted allele vs. the risk of FA cases inheriting a paternally-transmitted allele, in 631 Caucasian FA families using LL-LRT after the adjustment of confounding effects from maternal genotypes. This study will be the first large-scale genome-wide study of POE on FA. This represents a significant step forward in complementing our understanding of the genetic basis of FA. <p/>The findings could partially explain the missing heritability of the genome regarding the genetic susceptibility of FA. We anticipate that this study may transform our understanding of FA and lead to the identification of novel genetic mechanisms of FA, which will help us to develop a promising paradigm for identifying individuals at high risk for FA, and ultimately design effective strategies for the prevention and treatment of FA.
PUBLIC HEALTH RELEVANCE: Food allergy (FA) is a major clinical and public health problem in the U.S. and worldwide; and is also the most common cause of emergency room visits for anaphylaxis. The main focus of this proposal is to help us understand if maternal genetic variants are associated with FA, and if the inherited allele of offspring influences the risk of FA depending on his/her parents' gender (i.e., imprinting effect), which has never been investigated before.