Risk factors which increase your risk of developing food allergy.
IgE mediated food allergy is increasingly becoming a public health concern with prevalence on the rise in the UK that it why it so important to understand what the risk factors contributing to it’s development. IgE-mediated food allergy is a complex disease meaning that both genetic and environmental risk factors affects its development. IgE-mediated food allergy is also a polygenic disease meaningit is influenced by more than one gene. Numerous risk factors have been proposed to contribute to food allergy or sensitization, in this podcast I will address a few of the most researched genetic and environmental risk factors that increase the risk of developing IgE-mediated food allergy.
Genetic risk factors
How do we know that genes play a role in the development of food allergy?
Well we need to observe if a trait is in inherited/ runs in families. Identical twin studies are valuable because identical twins share 100% of their genes whilst non-identical twins just like siblings on average share about 50% of their genes. If identical twins show more similarity on a given trait compared to non-identical twins, this provides evidence that genes significantly influence that trait.
Previous family and twin studies have shown that IgE-mediated food allergy is highly heritable (Liu et al 2009). Meaning that an individual can inherit a genetic marker that can predispose them to developing IgE-mediated food allergy. One study in the UK found that relatives have a significantly higher risk of developing peanut allergy than in the general populations. In a small twin study on peanut allergy, one study reported that the concordance rate of peanut allergy was 64.3% among identical twins and only 6.8% in non-identical twins (6.8%) This study also estimated heritability of peanut allergy at 81.6% (Sicherer et al 2000).
This demonstrates the influence genes have on IgE-mediated food allergy as those with more similar genetics backgrounds have a greater chance of developing IgE-mediated food allergy. Now we know that genes play role let’s dive a little deeper and investigate some of the most researched genes that have been found to influence food allergy development.
Now a gene is a small sequence of DNA on chromosomes, that codes for a particular sequence of amino acids, which make a specific protein. Within that sequence you can have variations. And these variations in genes are what we look for when investigating if a gene influences a trait. Genetic variation is very common in the general population and often contributes to the difference between population groups. These variations within genes can contribute in a small and additive manner to a complex disease such as food allergy and so incredibly useful to research (Visscher et al 2017).
In my master’s research project, I focused on looking at these variations which increase your risk of IgE- mediated food allergy. I performed a systematic literature review where I essentially reviewed all the primary literature out there that investigated a type of genetic variation called a SNP to see if certain SNP’s are associated to food allergy. I created a database of 251 candidate SNPs in 46 gene regions which were significantly associated with food allergy from 42 studies. I then used bioinformatic techniques to analysed these gene and SNP’s along with a further 19039 SNPs in a cohort of patients who were either food sensitised (egg, peanut or milk), inhalant sensitised (cat, dog, grass or dust mite) or atopic to both or either food or inhalant. I identified various variations in various gene regions associated to atopic sensitisation status.
HLA loci:
The most researched genetic region which has been shown to play a role in many atopic conditions such as asthma and food allergy is the HLA region. The HLA gene region codes for the Human Leukocyte Antigen complex. This is a group of proteins that are involved in the regulation of the immune system. (Tordesillas et al., 2017). These proteins are found on the surface of cells and are responsible for identifying foreign invaders in the body such as food proteins and binding to them (Tordesillas et al 2017). Genetic variations have been reported in the different parts of the HLA gene and this has been associated to food allergy. This is because these variations cause changes in the grooves of the HLA protein. Because this protein is involved in immune regulation, changes to its structure can affect the how it binds to allergens and this can trigger an immune response. Variations in the HLA regions can increase the risk of sensitization to a certain food allergens (Sturniolo et al 1999).
The dual allergy hypothesis
The next gene I am going to discuss is extremely important because of the dual allergen exposure hypothesis. The dual allergy hypothesis was revolutionary in many ways. Numerous studies have found research evidence to support this hypothesis and now genetic evidence backs this up. The dual allergen hypothesis states that exposure to food allergens through the skin can lead to allergy, while consumption of these foods at an early age may result in tolerance and reduce the infant’s chance of developing food allergy (Lack 2008). So, for example, if a baby has disrupted skin barrier by having eczema this could allow exposure to food proteins in the environment – such as peanut oil in creams or peanut residue on tables. Under the hypothesis, if these children avoid peanuts but are still exposed to them in the environment, through their skin they might be more likely to develop peanut allergy.
Genetic variations within the skin barrier genes can be responsible for defects in the skin barrier and provide a potential route for sensitization and potential risk of developing food allergy.
FLG:
The FLG gene has been investigated in many studies (Van Ginkel et al 2015; Marenholz et al 2017; Brough et al 2014; Asai et al 2013;). =The FLG gene codes for filaggrin, a structural protein involved in maintaining the skins structural integrity (McGrath et al 2008). Mutations in the FLG region comprise the skin’s permeability thus making someone more susceptible to developing IgE-mediated food allergy by enhancing allergen entry through the skin. One study showed a direct relationship between having eczema and FLG loss of function mutations (Venkataraman et al 2014).
There have been many genes studied which have roles in gene transcription, cell proliferation, cell migration, cell fate, cell adhesion, apoptosis and various epigenetic controls that have also been linked to food allergy however, I will not discuss this in this blog.
Environmental risk factors that increase your risk of developing food allergy.
Now let’s move on to some environmental risk factors that can increase the risk of a child developing food allergy, in this section I will discuss findings from studies which have investigated early introduction of food into the infant’s diet, moisturisation frequency and vitamin D status. Now I just want to clarify that I am only sharing study findings with you and I am not in any way offering advice on to how reduce the risk of developing food allergy in infants. It is really important that until the results are translated into Government guidance that parents continue to follow existing Government advice and discuss any questions or concerns they may have with their treating doctor, health visitor or allergy specialist.
The EAT study and LEAP study – early introduction of food into the infant’s diet.
There’s a misunderstanding that by completely avoiding and not introducing an infant/child to the item, they won’t develop an allergy. However, we’ve seen in various studies that this proves the opposite. The Learning Early about Peanut Allergy (LEAP) study was a ground breaking study which investigated whether early introduction of peanut’s into a child diet reduce the risk of food allergy development. This study identified 640 infants between the ages of 4-11 months with either severe eczema, egg allergy or both. These infants were considered high-risk for peanut allergy and were randomly assigned to two groups. One group consumed peanuts and one group that avoided consumption. Infants assigned to the group which consumed peanuts were given at least 1 ¼ teaspoon of either smooth peanut butter or Bamba, a peanut-containing snack consumed regularly by children in Israel. The study showed that early consumption benefited both groups in reducing the prevalence of peanut allergy and this supports the dual allergy hypothesis (Feeney et al 2016). Another study was the Enquiring About Tolerance study (EAT) study for short. The EAT study tested the hypothesis that the early introduction of certain allergenic foods into infants’ diets may stop them developing allergy to those foods. EAT followed the same basic hypothesis as that followed by LEAP but whereas LEAP focused on peanut allergy in high-risk children (i.e. those who already have egg allergy and/or eczema), EAT looked at the introduction of a wider range of foods in the general population. The EAT study recruited 1,303 mothers and their infants onto the study. All mothers on the study were to breastfeed exclusively until their infants were three months of age at which point they were randomly split randomly into two groups. One group followed standard UK government advice and were asked to exclusively breastfeed for around six months, after which introduction of allergenic foods was a matter of parental choice. The second group was asked to introduce six allergenic foods from the age of three months alongside continued breastfeeding with the help of a dietician and support from the study When all of the participants originally recruited to the study (including those who did not adhere strictly to the study protocol) were included, the results were not significant. However, introducing allergenic foods into the infant diet from three months may be effective in food allergy prevention when sufficient amounts of allergenic foods are consumed. There was a nonsignificant 20% lower relative risk of food allergy in the early-introduction group than in the standard-introduction group. The early introduction of allergenic foods was found to be safe, with no cases of anaphylaxis during the initial introduction of the foods and no adverse effects on breast-feeding or growth (Perkin et al 2016a and 2016b).
Moisturization
It is has been demonstrated by multiple studies that a disrupted and inflamed skin barrier is the root cause for the development of sensitisation and food allergy. Could it be that if we prevent damage to the skin barrier that food allergy will reduce. How do we prevent damage to the skin barrier? Well The Barrier Enhancement for Eczema Prevention (BEEP) study investigated the hypothesis that intensive moisturization from birth would prevent the development of eczema by enhancing the skin barrier. However, found that moisturization intervention did not prevent eczema and there was a nonsignificant increase in food sensitization and food allergy at 2 years of age in some infants who were moisturizing more (Chalmers et al 2017). Now remember the EAT study I talked about earlier well families involved in the EAT study completed questionnaire that included questions about frequency and type of moisturizer applied, use of corticosteroid creams, and parental report of dry skin or eczema. Infants were also examined for visible eczema at enrolment visit. A relationship was observed between parent-reported moisturization frequency at 3 months of age and the subsequent development of food allergy. This relationship was present both in infants with and without eczema. This finding supports the notion that regular application of moisturizers to the skin of young infants may promote the development of food allergy. Now there are 2 possible explanations for these findings: firstly, the moisturizers might be facilitating the passage of food allergens across the skin barrier, or that moisturizers might be damaging the skin barrier and allowing the passage of the food allergen aeroallergens. These findings are potentially of great significance and further research is required to understand the mechanism of action and to really understand whether moisturizers facilitate food and aeroallergen uptake and if moisturizers can become contaminated by these allergens from the hands or the environment. it is also important to also understand whether the effects are limited to certain types of moisturizer or to specific susceptible individuals (Perkin et al 2021).
Vitamin D
In the past decade there has been a rise in the number of studies investigating the role of vitamin D in the prevention IgE-mediated food allergy, however this remains controversial (Matsui et al 2019). Many cells of the adaptive immune system express the vitamin D receptor, making them capable of being vitamin responsive therefore it is plausible that vitamin D might be required for regulatory immunologic mechanisms that are important in preventing IgE-mediated food allergyffa and establishing oral tolerance. Many studies report an association between sunlight, the season of birth and latitude as risk factors for IgE-mediated food allergy. The Australian HealthNuts study shows that children born in summer have a 55% lower chance of developing IgE-mediated food allergy when compared to children born in other seasons (Martin et al 2011). In one study vitamin D insufficiency in infants was related to a 11-fold higher risk of developing peanut allergy and a 10-fold higher risk of developing multiple food allergies (Allen et al 2013). Still, this finding is only valid for children with parents born in Australia rather than those who had parents who migrated to Australia. Studies show an association with prolonged low vitamin D levels and IgE-mediated food allergy but not with low vitamin D and IgE mediated food allergy when analysed at a single point in time. Consequently, suggesting that many vitamin D status are needed in early in life to impact immunity long term.
Other known predictors of food allergy include parental atopy so if the parents having atopic conditions such as asthma, atopic eczema or food allergy and child atopy, increasing gestational age pet ownership, antibiotic use and gut health and microbiome. If you would like me to discuss these in other risk factors then please to do leave a review or contact on my various social media platforms to let me know all will be provided in the show notes.
References:
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https://www.food.gov.uk/research/food-allergy-and-intolerance-research/eat-study-early-introduction-of-allergenic-foods-to-induce-tolerance