Allergies and genetics

ALSO KNOWN AS: Atopy; allergic rhinitis; hay fever; atopic dermatitis; anaphylaxis

DEFINITION Allergies are a disorder of the immune system. Allergic reactions occur when the immune system responds strongly to normally harmless substances, such as pet dander, pollen, or proteins in food, which are referred to as "allergens." Individuals can develop an allergy because of a genetic susceptibility inherited from their parents and subsequent exposure to that allergen; however, they also can develop allergies without any genetic risk factors.

Risk Factors

Individuals have a higher risk of developing allergies if they have family members with allergies or asthma. They also have a higher risk of developing an allergy if they have asthma or one or more allergies already, suggesting a shared genetic origin. Children are more likely to develop allergies than are adults, and allergies are more common in firstborn children and among children in smaller families. Those most at-risk in the United States are Puerto Ricans and African Americans, followed by Caucasians. Allergies are also more common in urban than in rural environments and more common in developed than in developing countries. Other environmental factors (such as exposure to cigarette smoke and pollution) as well as medical factors (such as infections, autoimmune disease, diet, and stress) can also affect allergy risk. Understanding the factors that contribute to allergy development is critical, as the number of people with allergies has been increasing worldwide.

Etiology and Genetics

Multiple factors modulate risk for allergic diseases, without a single causal agent; however, the most important component influencing whether a person will develop allergies is genetic predisposition. Atopy, characterized by high levels of immunoglobulin E (IgE), is the condition that underlies allergic diseases and is highly influenced by genetics. People who do not have a genetic predisposition toward developing allergic conditions have about a 15 percent risk of developing allergies, according to the American Academy of Allergy, Asthma, and Immunology. If one or more of a person’s parents or siblings have allergies, the risk for developing allergies is 30 to 60 percent or 25 to 35 percent, respectively. Monozygotic twins, who share 100 percent of their DNA, are more likely to have the same type of allergy than are twins, who share 50 percent of their DNA, suggesting that genetic factors are important in allergy risk. Even in twins, however, only about 50 to 60 percent of twins share the same allergic condition, demonstrating that nongenetic factors also influence allergies. As a result, allergy is considered a complex genetic disease because it does not follow the laws of Mendelian inheritance.

Because multiple allergic conditions exist and allergies are also influenced by exposure to allergens, determining specific genetic risk factors for allergies is challenging. Researchers have conducted large-scale genome-wide association studies in order to uncover mutations that might play a role in allergy development. A number of candidate susceptibility genes for allergic diseases have been identified: human leukocyte antigen DRB1 (HLA-DRB1), high-affinity IgE receptor (MS4A2), interleukins 4, 13, and 33 (IL4, IL13, and IL33), filaggrin FLG, DENND1B, and the alpha chain of the IL-4 receptor (IL4R), among others. DNA methylation—the epigenetic addition of methyl groups to DNA—may also affect gene expression and contribute to allergy development or its absence.

Several linkage studies suggest that the major histocompatibility complex class II region (MHC II) influences allergy. This genomic region contains human leukocyte antigen (HLA) genes, which encode antigen-presenting proteins on the cell surface. Genetic variation in genes determines the specificities of HLA proteins and whether the immune system will respond to a particular allergen. Several HLA haplotypes have been associated with specific allergies, such as the reported association between HLA-DRB1*15:01 allele and ragweed pollen allergies. Other HLA haplotypes are associated more generally with allergies, such as the association between particular HLADQB1*03 alleles and higher levels of IgE.

Other candidate genes for allergies include those related to immunoglobulins. Polymorphisms in the MS4A2 gene that encodes for the beta chain of the high-affinity receptor for IgE affect the extent to which the immune system responds against allergens and have been associated with allergy. Additionally, polymorphisms in genes encoding the IL13 and IL4 receptor alpha chain are associated with increased serum IgE levels as well as allergy risk. Another group of immunoglobulin-related genes, the T cell immunoglobulin and mucin domain (TIM) family genes, have been associated with protection from developing allergies. The PHF11 gene, which could be involved in immunoglobulin synthesis, is another immunoglobulin-related gene consistently linked to allergy risk.

Other genes associated with allergy in multiple studies include various components of immune response. CD14 encodes a cell-surface receptor intended to detect bacterial proteins, but variation in this gene is also associated with allergic responses to harmless allergens. Additionally, genes encoding transcription factors involved in the development of development T regulatory cells, such as GATA3, which regulates Th2 cytokine responses, and TBX21, which regulates Th2 cytokine responses, have also been associated with allergy.

Because both genes and environment factors in combination influence allergy risk, some researchers have investigated gene-gene and gene-environment interactions. For example, individuals who had certain polymorphisms in CD14 had high or low allergy risk depending on whether they had pets, whether they were exposed to tobacco smoke, or whether they lived on a farm in childhood. Additionally, interactions between polymorphisms in different genes, such as an interaction between GATA3 and IL13, can affect allergy risk. Moreover, ethnic background affects allergy susceptibility versus protection, as in the DENND1B variant associated with asthma development in European-descended children and protection in African Americans.

Symptoms

Allergy symptoms vary widely. Sneezing, runny nose, and sore throat are common with seasonal allergies, sometimes called "hay fever" or "allergic rhinitis." Allergic reactions can also affect the eyes, leading to redness, watery or itchy eyes, and swelling. Some allergies affect the skin, leading to rashes or hives. Others cause gastrointestinal symptoms such as vomiting or diarrhea. More severe allergic reactions can lead to anaphylaxis, which may include the symptoms listed above in addition to low blood pressure, difficulty breathing, or shock.

Screening and Diagnosis

A doctor may perform a skin test or blood test to test for allergies. In one type of skin test, a small drop of the possible allergen is either placed onto skin followed by scratching with a needle over the drop or injected into the skin. In another type of skin test, known as a "patch test," the potential allergen is placed in a small metal disk that is applied to the skin and kept there for a few days. With skin tests, if the individual is allergic to a substance, the test site will become red, swollen, and itchy. Another way to test for allergies involves taking a blood sample. The medical laboratory adds the allergen to the blood and then measures the immune response to the allergen. If the body produces many antibodies to attack the allergen, then the individual is allergic to the tested substance.

Treatment and Therapy

Several medications are available to relieve allergies. Oral and nasal antihistamines, such as diphenhydramine (Benadryl) and loratadine (Claritin), help with allergic rhinitis by blocking the action of histamine, a substance the body releases during an allergic reaction. Nasal sprays containing corticosteroids, such as mometasone (Nasonex) and fluticasone (Flonase), or nonsteroidal anti-inflammatory drugs (NSAIDs), such as cromolyn sodium (NasalCrom), are sprayed into the nose to reduce inflammation. Topical corticosteroids are also often used to treat skin allergies. Decongestants can also be used to alleviate allergy symptoms, sometimes in combination with antihistamines, as in fexofenadine (Allegra-D). Leukotriene receptor antagonists, such as Singulair, are another treatment that may be used to reduce inflammation-related allergy symptoms.

Immunotherapy, or allergy shots, is another treatment for allergies. People who receive immunotherapy have small amounts of allergens injected into their bodies. The doses of these allergens are increased over at least three to five years in order to develop the body’s immunity to them. When the patient experiences minimal symptoms for two seasons or more, the treatment is stopped.

Prevention and Outcomes

Some allergies, such as those to dairy and eggs, can be outgrown, while others, such as peanut allergies, tend to be lifelong. The simplest way to prevent allergic conditions or to reduce symptoms is to minimize exposure to the problematic allergen. For example, breastfeeding infants for four to six months, introducing low-risk solid foods, and then gradually exposing infants to highly allergenic foods such as cow’s milk and peanuts may help prevent allergy development; long delays have actually been found to increase that risk, however. Another promising prevention strategy may be to reduce early skin exposure to soaps and food residues. Eating a healthy diet and managing stress effectively can also help alleviate allergy symptoms.

In early 2024, researchers working at National Jewish Health announced the results of research to predict the likelihood that an individual would develop allergies. They applied a special gentle tape to the forearms of infants younger than two months to gather skin samples that were tested for the presence of abnormal lipids and proteins. The children were then followed to see if they developed allergies. The study was the first step in identifying conditions that could lead to the development of allergies; scientists hoped this could lead to treatments to prevent or minimize the risk of developing allergies.

Bibliography

American Academy of Allergy, Asthma & Immunology. "Allergic Reactions: Tips to Remember." AAAAI.org. American Academy of Allergy, Asthma & Immunology, 2013. Web. 28 July 2014.

American Academy of Allergy, Asthma & Immunology. "Who Gets Allergies?." WebMD. WebMD.com, 18 May 2014.

Berdyshev, Evgeny et al. "Skin biomarkers predict the development of food allergy in early life." Journal of Allergy and Clinical Immunology, vol. 153, May 2024, pp. 1456-1463, DOI: 10.1016/j.jaci.2024.02.014. Accessed 4 Sept. 2024.

Contie, Vicki, Lesley Earl, Belle Waring, and Harrison Wein. "Red, Itchy Skin? Get the Skinny on Dermatitis." NIH News in Health. NIH Office of Communications and Public Liaison, Apr. 2012. Web. 18 July 2014.

Contopoulos-Ioannidis, D. G., I. N. Kouri, and J. P. Ioannidis. “Genetic Predisposition to Asthma and Atopy.” Respiration 74.1 (2007): 8–12. Print.

Demirdag, Yesim and Sami Bahna. "The Role of Genetics in Food Allergy." Expert Review of Clinical Immunology, vol. 18, pp. 401-11, 22 Mar. 2022, www.tandfonline.com/doi/full/10.1080/1744666X.2022.2054414. Accessed 4 Sept. 2024.

Grammatikos, A. P. “The Genetic and Environmental Basis of Atopic Diseases.”Annals of Medicine 40.7 (2008): 482–95. Print.

Ober, Carole, and Tsung-Chieh Yao. "The Genetics of Asthma and Allergic Disease: A 21st Century Perspective." Allergic Responses. Spec. issue ofImmunological Review 242.1 (2011): 10–30. PDF file.

Paul, Marla. "Food Allergy Is Linked to Skin Exposure and Genetics." Northwestern Now, 6 Apr. 2018, news.northwestern.edu/stories/2018/april/food-allergy-is-linked-to-skin-exposure-and-genetics. Accessed 4 Sept. 2024.

"Prevention of Allergies and Asthma in Children." Review by Thanai Pongdee. The American Academy Of Allergy, Asthma & Immunology, www.aaaai.org/conditions-and-treatments/library/allergy-library/prevention-of-allergies-and-asthma-in-children. Accessed 4 Sept. 2024.

Thomsen, S. F., K. O. Kyvik, and V. Backer. “Etiological Relationships in Atopy: A Review of Twin Studies.” Twin Research and Human Genetics 11.2 (2008): 112–20. Print.

Torres-Borrego, J., A. B. Molina-Terán, and C. Montes-Mendoza. “Prevalence and Associated Factors of Allergic Rhinitis and Atopic Dermatitis in Children.” Allergologia et Immunopathologia 36.2 (2008): 90–100. Print.

Westly, Erica. "Seeking a Gene Genie." Nature 479.7374 (2011): S10–S11. PDF file.

Xiumei Hong, et al. "Genome-Wide Association Study Identifies Peanut Allergy-Specific Loci and Evidence of Epigenetic Mediation in US Children." Nature Communications, vol 6, no. 1, 2015, doi: 10.1038/ncomms7304. Accessed 4 Sept. 2024.