While a number of familial aggregation and genetic studies of asthma and atopy have been reported previously, few studies have specifically examined genetic influence on food allergy and food-specific IgE. This study is one of the first to investigate familial aggregation of food allergy and the most common food-specific IgE levels in a large family-based studyin the U.S. The results demonstrated significant familial aggregation for food allergy and sensitization to food allergens. In addition, this study is the first to estimate heritability for the most common food-specific IgE levels in a large family-based study in the U.S. We observed the estimated heritability of food-specific IgE ranging from 0.15 to 0.35, and the estimated heritability of aeroallergen-specific IgE ranging from 0.24 to 0.38, which were statistically significant after adjusting for major covariates. These findings suggested that a substantial variation of total IgE, food-specific IgE and aeroallergen-specific IgE, respectively, can be explained by genetic components. Our findings of familial aggregation of atopic diseases (including eczema, seasonal allergy and asthma), and heritability estimate of total IgE (ĥ 2
=0.49) were comparable to previous studies. Previous studies documented familial aggregation and estimated heritability of total IgE between 0.45 and 0.80 [24
]. The consistency of our findings with previous studies lent support that our study findings were unlikely due to chance.
Of note, the heritability estimate for a complex trait indicates genetic contribution to the variance of a phenotype and it is strictly relative. Within a given population, the heritability estimate will change if there is a change in the distribution of a relevant environmental exposure. Heritability estimate may also be influenced by population characteristics. Recruited from the Chicago area, the study population consisted of predominantly Caucasians (~78%) and included subjects from a wide range of socio-economic strata, from lower middle to upper class. Based on expected outdoor environmental exposures and context of living, this study is directly generalizable to Chicago urban and suburban populations. However, this study sample is over-represented by families with food allergy as 83% of families reported at least one family member with an allergic response to food. To address this issue, we performed separate analyses on familial aggregation and heritability among families with at least one food allergic member and among those without a food allergic member. We performed these analyses to investigate whether a difference exists between these two types of families. Interestingly, similar patterns of familial aggregation between mother-offspring and index child-other siblings were observed in these two groups of families (Supplement ). Most familial aggregations between father-offspring were not significant among those without a food allergic member likely due to small sample size (N=99). Likewise, the estimated heritability of total and specific IgE in these two groups was comparable (Supplement ).
In addition to genetic contribution, shared environmental and lifestyle factors may also play a role in the observed familial aggregation of food allergy and food-sensitization. A number of longitudinal cohorts have observed an association between the development of atopy and epidemiologic factors which could be considered markers of less early life immune stimulation. These have included studies of: urban vs. rural lifestyle [28
], absence vs. presence of pets in the home [31
], birth order [34
], and day care exposure [36
]. Therefore, we applied a Mantel-Haenszel test statistics, which is also called Cochran’s Q, to examine the differences in inter-relationships among parents, index child and other siblings. The data revealed some differences between father- or mother-offspring and index-child other siblings on self-reported food allergy. However, the differences were not significant using the stringent definition of food allergy used in this study (results not shown). The results support the interplay of genetic and environmental factors on food allergy.
There are several strengths in the present study. First, our study has utilized a well characterized family cohort, and a stringent phenotypic definition of food allergy. Second, to our knowledge, our study is one of the largest family-based studies to investigate genetic contribution to food allergy. Third, our study is one of the first studies to examine a broad array of the most common food allergen- and aeroallergen-specific IgE levels in a single study. Our findings have important clinical and research implications for food allergy. To date, family history is a predominant predictor of allergic diseases. No specific genetic factors have been identified for food allergy. Our findings suggest that genetic susceptibility influences the development of food allergy, and genetic factors should be an important aspect to consider in future investigation on the etiology of food allergy.
Some limitations of our study should also be considered. First, one of the major challenges in conducting large-scale epidemiologic and genetic studies of FA is how to define FA in a large population. The double-blind, placebo-controlled food challenge has been promoted as the gold standard for establishing diagnosis[38
]. Such challenges are however, laborious, time-consuming and associated with risk of allergic reactions including anaphylaxis and are therefore not routinely performed in clinical practice or large research studies. Given the latter, we used a combination of timing, stringent clinical history, and established sIgE cutoffs to establish food allergy in this study. This approach has been suggested in previous reports when a double-blind placebo-controlled food challenge test is not available [15
]. Of note, our definition of food allergy is more stringent than most published large-scale epidemiological studies of food allergy [8
]. Importantly, our approach is similar to the ongoing National Institutes of Health (NIH) funded “Consortium of Food Allergy Research (CoFAR)”. Specifically, inclusion criteria provided at http://clinicaltrials.gov/ct2/show/NCT00356174
state that children with egg or milk allergy will be enrolled based upon “Clinical history of allergy to cow’s milk or egg and positive skin prick test (3 mm or larger) to cow’s milk or egg OR moderate to severe atopic dermatitis and a positive prick skin test to cow’s milk or egg OR positive oral food challenge (prior to study entry) to either cow’s milk or egg and a positive skin prick test to cow’s milk or egg” and during follow up study visits “Oral food challenges will occur at some visits, as clinically indicated.” We have recognized the possibility that our definition of food allergy may miss some individuals who have FA but do not meet all the above criteria, thus underestimating the incidence rate of FA in this study sample and moreover may decrease our statistical power to detect such association. Second, we only observed familial aggregation of food allergy and allergy to egg white between siblings due to the available sample size. Since enrollment continues, when the sample size becomes large enough we will investigate whether the familial aggregation will be observed for other specific types of food allergy. In addition, a portion of recruited families had no paternal data. Our results on “father-offspring” association need to be interpreted with caution and remain to be confirmed in future studies. Third, we did not include parental smoking as a covariate in the final analyses since parental smoking was not statistically significant in our preliminary analysis. Additionally, previous studies did not observe consistent patterns for the effect of parental smoking on allergic sensitization in children [46
The rapid advancements in human genetics have made it possible to conduct large-scale candidate gene studies and genome-wide scans in food allergy. We anticipate that we will enter an exciting era to better understand the genetics of food allergy. Major challenges in future genetic studies of food allergy will be to achieve a large enough study sample and to carefully phenotype study subjects with and without food allergy. At present, well-defined comprehensive phenotypic definitions are lacking in the literature and are necessary for conducting large-scale population or genetic studies. The phenotypic definition applied in this study can serve as a practical approach in a population setting.
In summary, this study documents strong evidence of familial aggregation of food allergy and sensitization to food allergens, as well as significant heritability of food-specific IgE. The findings indicate that genetic factors may play an important role in the pathogenesis of food allergy. Identification of susceptibility genes related to food-specific IgE and the development of clinical food allergy may facilitate better understanding of the causes and biological mechanisms of food allergy and ultimately lead to improved preventive and therapeutic strategies for food allergy.