Many kids with food allergies follow a similar path. As babies, their skin is red and inflamed from eczema. Then, as toddlers, they have their first reactions to foods such as peanut, milk or eggs.
The assumption is there must be a connection between the itchy skin condition and later food allergies, since the two so often go hand in hand. Up to 30 percent of children with moderate to severe eczema also develop one or more food allergies.
But the mystery is why. Studies have pinpointed few specific genes or molecular pathways that explain why children with one condition are prone to the other.
At present, “there is nothing that we can define that is causing this relationship,” says Dr. James Baker, director of the Mary H. Weiser Food Allergy Center at University of Michigan. “And to date, research has identified few ‘risk genes’ for food allergy.”
To get to the bottom of it, Baker and his University of Michigan colleagues have launched two large, multi-year studies.
The main one is the largest study ever on the genetics of food allergies and eczema. It involves analyzing the genome of tens of thousands of young adults with eczema alone, or with food allergies and eczema. Using large databases as well as patient samples, the researchers are searching for genetic variants that stand out in those who have both eczema and food allergies.
“We’re looking for the smoking gun,” Baker says.
Eczema-Food Allergy Link: What’s Unique?
Once the researchers identify the variants, they will then test the genomes of babies at high risk of developing food allergies. The babies are enrolled in a separate birth cohort study that’s following the infants and their families closely for three years. That study is looking at environmental, genetic, epigenetic and other factors associated with food allergy development.
The smoking gun isn’t likely to be one gene, but a combination of genes, perhaps all involved with the same immune or inflammatory pathways. The genetics likely combine with environmental factors to result in food allergies.
“We’re looking specifically to see if there are unique genes in the people that develop food allergy that aren’t present in the people who have eczema but don’t have food allergy,” Baker says.
“If you figure eczema is the predisposing condition – it’s the first thing that everyone has – yet only a minority develop food allergy, that should tell us there is something unique there,” he says.
Allergists call the progression of eczema to food allergy – as well as other allergic diseases such as asthma and allergic rhinitis – the “atopic march.”
“Eczema is the underpinning of the allergic march. It’s the first thing that happens,” notes Baker.
Quest for the Genetic Story
The U-M researchers conducting the whole genome study will analyze the genes of about 50,000 young adults with a history of eczema or eczema and food allergies. They’ll be compared against 500,000 healthy control subjects with neither condition.
The team expects to find a few dozen to potentially over 100 genetic variants that up the odds of food allergies, says Dr. Johann Gudjonsson, PhD. He’s one of the lead investigators on the study, a joint effort of the food allergy center and the university’s inflammatory skin disease research program.
“There are going to be multiple different genetic variants that are all contributing to it,” says the U-M professor of dermatology and skin molecular immunology. “Each one with a fairly small effect but, when combined, will be enough to get that person to full-blown food allergies.”
Conversely, there may be genetic variants that protect people with eczema against developing food allergies. The ambitious study on the eczema-food allergy link is funded with a grant from the National Institute of Health’s Consortium for Food Allergy Research (CoFAR).
The researchers are also sequencing single cells using skin, blood and mucosal samples to understand how the genes are expressed in and around cells that are involved in allergic reactions.
“It’s creating an atlas you can use to link the genetics with the biology of these diseases,” Gudjonsson says.
Leaky Skin or Something Else?
So what do scientists know so far about the eczema-food allergy link? One theory is that “people with eczema have leaky skin, that results in getting sensitized to food through the skin,” Baker says.
Studies estimate about 10 to 40 percent have a defect in the gene for filaggrin. That’s a structural protein important to building the skin’s barrier.
A study of nearly 900 children in Germany with food allergies and about same number of healthy controls found filaggrin mutations led to a higher risk of food allergies. Notably, it found kids with filaggrin defects more likely to have persistent egg and milk allergies.
But filaggrin gene mutations don’t explain all of the link. In the German study, while 83 percent of the food-allergic kids had eczema, only 24 percent had one of the four most common filaggrin mutations.
“The filaggrin genes are a genetic risk for development of food allergies,” says Gudjonsson. “There definitely is an element of something in the skin that contributes to food allergies, but it’s by no means the only thing. You need more.”
Eczema-Food Allergy Link: Treating the Skin
The skin barrier defect discoveries led to hopes that faithfully applying moisturizers could restore the barrier, preventing both eczema or even food allergy sensitization. But it hasn’t panned out in clinical studies.
The BEEP trial in the United Kingdom found that the daily use of over-the-counter emollients on newborns didn’t reduce eczema in high-risk kids.
A study by researchers in Norway divided 2,400 newborns into four groups. One group had emollients applied four times a week. A second group was introduced to eating peanut, milk, wheat and egg at three months old. A third group received both the skin moisturizers and the early food introduction. A control group received no interventions.
By age three, 44 kids developed a food allergy – 3 percent in the moisturizer group, 2.3 percent in the control group, 1.2 percent in the combined intervention group, and less than 1 percent (0.9 percent) in the food introduction group.
Gudjonsson and his team will look beyond leaky skin barrier to see: “are there more specific mechanisms and immune pathways involved?” He says the study “will help us map those pathways out.”
Tracking Babies with Allergies
Questions about why some kids have only eczema while others will also develop food allergies, even within the same family, intrigue Dr. Kelly O’Shea. She’s a clinical assistant professor at University of Michigan’s Food Allergy Center.
O’Shea is the lead investigator on a second big U-M study that aims to crack the code on the early life onset of food allergies. This study will track babies and their families, looking at everything from exposures to their microbiome and genetics.
Called the Michigan Sibling Immunity Birth Study (M-SIBS), the study aims to enroll 1,000 pregnant women and their infants. Candidates will be at higher risk of food allergies because of asthma or allergies in the family. The research team will collect blood, stool and vaginal samples, placenta and cord blood samples, and breast milk.
Babies will have allergy testing done at 5, 12, 24 and 36 months, and food allergies will be confirmed with food challenges. Researchers will collect home water and house dust samples. As well, they will take detailed information on diet, pets, skin routines and many factors that could potentially lead to allergy sensitization or protection.
In her family, O’Shea’s oldest daughter is allergic to egg, whereas her younger daughter never developed allergies. “I did everything by the book,” she says, including early introduction of foods such as egg. Regularly feeding infants foods such as egg and peanuts has been shown to cut down on allergy risk.
Understanding what’s driving the march from eczema to food allergies could lead to better treatments. It could also help physicians and parents know which children are most at risk. As well, a goal is to understand what’s modifiable in the environment to prevent them.
“It’s not all genetics. It’s not all environment…. There are layers,” O’Shea notes.
Related Reading:
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Dietitians’ Advice on How to Introduce Risky Solid Foods
