Aller genes
Five genome sites associated with food allergies have been identified
Alyona Sukhoputova, "Elements"
The main food allergens.
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The genetic mechanisms of allergy are still poorly known. Most of the problems are caused by food allergies, which have a delayed effect and a very wide range of possible symptoms. Often, it is simply not possible to reliably diagnose food allergies. In a recent study conducted in Germany, scientists were able to identify five independent regions of the human genome responsible for the presence of food allergies. All these areas were associated with the regulation of the immune response and the functioning of the so-called epithelial barrier on the mucous membranes of the digestive system. According to the authors, food allergy occurs largely due to the violation of this protective barrier, the ingress of an excessive amount of allergen beyond its limits and deviations in the work of leukocytes.
Recently, more and more children and adults suffer from allergies – hypersensitivity of the immune system to certain substances from the external environment (allergens). In response to the body's contact with such a substance (contact can occur in different ways: through the skin, mucous membranes of the respiratory tract, digestive system), inflammation begins, antibodies to this substance are produced. There are external signs of inflammation: redness, runny nose, sneezing, rash, swelling, etc.
According to how the allergen must enter the body in order to cause an appropriate reaction, different types of allergies are distinguished. Often the same substance can be harmless on the skin, and when it gets into the digestive system, it can cause a severe allergic reaction. Food allergies are particularly diverse in terms of symptoms and their severity and can pose a serious danger, as it is the main cause of anaphylactic shock.
Some people are more prone to allergic spectrum diseases, others – less. Such a tendency depends on the environment and the history of human contacts with certain possible allergens, as well as on heredity, that is, on genes. Scientists are actively engaged in research on how exactly this disease appears in people and why the number of patients has been growing in recent years, but much remains unknown.
In developed countries, 4-8% of residents suffer from at least one type of food allergy (S. H. Sicherer, H. A. Sampson, 2014. Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment). In general, it turns out that it is quite difficult to diagnose all food allergens for any large group of patients. Unlike skin allergies, where the methodology for assessing an allergic reaction is relatively well developed, the diagnosis of food allergies causes a number of difficulties. Previously, specialized questionnaires were mainly used, that is, patients themselves reported the presence or absence of allergy symptoms in themselves or their children. But it has been shown that about 80% of such reports are not confirmed experimentally. The reaction to food products may be delayed, the patient does not always take into account all the products consumed recently, and many apparent symptoms of food allergies may have a completely different cause, which is not so easy to track. And, of course, do not forget about the tendency of our brain to find relationships where there are none.
Testing in which patients are given suspected allergens under controlled conditions and then monitored for symptoms is much more accurate. However, their results may vary greatly depending on the specific methodology. So, by the type and taste of the product, the patient in most cases knows what he is being given, and the placebo effect works. From the certainty that a person is allergic to this product, he may even have an increased level of immunoglobulins, indicating inflammation. The symptoms of food allergies are so diverse that, to be sure, researchers simply record everything that happens to the patient's body during the test period. This again leads to overestimated estimates of the number of cases of food allergies.
In recent years, a more accurate method of assessing an allergic reaction has been used – Oral food challenge (OFC), which has already shown its effectiveness (H. A. Sampson et al., 2012. Standardization double-blind, placebo-controlled oral food challenges). Patients are given a small standardized portion of the allergen in such a form that they do not know what product they are receiving. Only those symptoms that occur consistently after the same time after receiving the product and do not repeat when receiving non-allergenic products are considered reliable.
Researchers from Germany conducted a genome-wide search for associations between genomic variants and phenotypic manifestations of food allergies. They analyzed the DNA sequences of 497 allergy sufferers and 2,387 people without allergic reactions. According to previous studies, in infancy, people most often suffer from intolerance to cow's milk and chicken eggs, older children have a very common allergy to peanuts (B. I. Nwaru et al., 2014. Prevalence of common food allergies in Europe: a systematic review and meta-analysis). These three types of food allergies were selected for further analysis. Allergy data was collected by the OFC method.
Scientists found out on which parts of the chromosomes of allergic people compared with healthy people increased variability due to single nucleotide substitutions (SNP): the complete DNA sequences of all study participants were compared between "healthy" and "sick". Each person has their own special sequence of nucleic acids, but if you divide the genome into separate genes, then each gene will have several variants in which this gene can exist. That's the number of such options that scientists were interested in: if sick people had significantly more such options than healthy people, then this site was assumed to have a connection with the allergy disease. There are always more wrong ways to "assemble" something than the right ones, so the increased diversity in some part of the chromosome suggests that something is broken in this particular part of patients. At this stage, it does not matter exactly how it is broken – it may even be different for everyone - it is important which genes work incorrectly in patients. In this way, it is possible to determine which genes should work normally so that there is no allergy.
Variability in different parts of chromosomes in people with allergies: a – any type of food allergy (497 cases vs. 2387 – control); b – peanut allergy (220 cases); c – allergy to chicken eggs (288 cases); d – allergy to cow's milk (169 cases). The horizontal axis indicates the number of the chromosome under study, the vertical axis indicates the significance of variability in this area. The pink line shows the level of significance after which differences in variability from healthy people were considered reliable. Graphs from the discussed article in Nature Communications
As a result, the researchers found five DNA sites where disorders are most common in people with allergies to peanuts, eggs and cow's milk. The first site lies on the first chromosome and belongs to the complex responsible for the normal development of the epidermis. It is directly adjacent to the Filaggrin gene (Filaggrin, filament aggregating protein), a structural protein involved in the formation of a protective epithelial barrier. Mutations in this gene are closely related to eczema, an inflammatory skin disease of a complex nature, in the occurrence of which a large role is assigned to immune disorders. For reasons of occurrence and manifestations, it is close to diseases of the allergic spectrum and often occurs in allergy sufferers. The researchers additionally checked the correlation between the found SNP and the allergy disease by excluding eczema patients from the sample. The mutation turned out to be associated with food allergies of all three types, regardless of the presence or absence of eczema in the carrier. The filaggrin gene works mainly on the mucous membranes of the oral cavity and esophagus, when its operation is disrupted, it is in these areas that a defective skin barrier is formed, allowing an excessive amount of allergen into the body.
Another site was found between the interleukin 4, interleukin 13 genes and one of the cytokine genes on the fifth chromosome. Violations at this site are also often associated with eczema, however, even here a correlation with allergies was found both in the group of subjects with eczema and in the group without it. Both of these interleukins are involved in the inflammatory reaction during allergies, are associated with the work of blood lymphocytes and regulatory T-cells of mucous surfaces.
The third site is located on the eleventh chromosome. One single nucleotide substitution was found in it, which is simultaneously associated with both eczema and food allergies to peanuts, eggs and cow's milk. In the group without eczema, the association of this mutation with allergy could not be shown. According to previous work, it is known that violations in this area are also associated with other types of allergies, including food and skin. It turns out that violations in this area simultaneously lead to a number of allergic diseases, and not only to food allergies.
Increased variability associated with food allergies was found in a section of genes encoding serpine proteins on the eighteenth chromosome. The two most frequent SNPs at this site both turned out to be in the regulatory parts of the genes. One is located at the site that regulates the work of immune and inflammatory response genes, including T cells of the second type (Type 2 helper T cells; see subtypes of T helper cells), the other is involved in the tissue-specific expression of serpin B10 in the blood. Unfortunately, the functions of the serpin B10 protein have not yet been studied, but it is known that it is also expressed in the skin and mucous membranes.
Finally, scientists have confirmed the connection of violations on the site of human leukocyte antigens of the sixth chromosome with food allergy to peanuts; other food allergies were not associated with this site.
All identified areas together determine approximately 10.2% probability of having food allergies of the three types studied. The rest of the variability is explained by other, not yet identified, genes and, of course, external conditions.
During the development of inflammation in the framework of asthma or eczema, an increase in the activity of serpins and interleukins 4 and 13, activated with the participation of T cells of the second type, is observed. A study of food allergies to peanuts, chicken eggs and cow's milk has shown that the disorders associated with the disease are in the regulatory regions of genes encoding the same links. In addition, both eczema and food allergies are closely associated with disruption of the epithelial barrier. For food allergies, the most important defect of the protective barrier of the mucous membranes of the upper part of the digestive system.
Previously, researchers were limited only to food allergies to peanuts and largely relied on less reliable methods of diagnosis. In this work, a large sample, more accurate methods for detecting allergies and a study of three types of allergies simultaneously allowed us to detect five sections of chromosomes at once, violations in which are associated with food allergies and other allergic diseases.
A source: Ingo Marenholz et al., Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy // Nature Communications. 2017.
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