How do our genes influence allergies?

By Kathryn McLaughlin

According to the American Academy of Allergy, Asthma and Immunology (AAAAI), allergies represent some of the most common chronic illnesses worldwide. Allergies are caused by the immune system mistaking a harmless substance for a dangerous intruder. This hypersensitivity causes the immune system to kick into action, overacting by producing antibodies (specifically Immunoglobulin E antibodies), triggering the release of inflammatory mediators such as histamine.

Allergies are complex and diverse in cause and symptoms. Common allergies include hay fever, allergic asthma, food allergies, and skin allergies. Symptoms can range from a slight skin rash, sneezing, and swelling, up to complete anaphylaxis. Recently in the UK and the USA, there have been high profile cases of the deaths of young people as a result of severe allergies.

Even if allergies are not life-threatening, allergies can cause sufferers to exhibit fear, anxiety, disordered eating (in the case of food allergies), and reduced quality of life.

Genetic link

The exact mechanism underlying why and how allergies develop is often unclear. However, it is known that allergies tend to run in families. In fact, a family history of allergic disease continues to be one of the most reliable measures for the prediction and diagnosis of an allergy. An individual with more than two first degree relatives with allergic disease is three times more likely to develop allergies than someone without affected relatives. Interestingly, the allergies they develop are not necessarily the same ones as their relatives have, indicating there might be a general mechanism for the development of the allergic response. This is supported by studies showing that genes involved in different allergic disease overlap to some degree.

Genetic links to complex disease have frequently been uncovered using genome wide association studies (GWAS). These studies look for genetic variants in a cohort with the disease or trait of interest that are more frequent than in a “normal” cohort or healthy controls. Generally, the idea is that lots of gene variants contribute a small effect size, that in combination lead to the disorder or trait. GWA studies have been successful in finding genetic links with complex diseases such as type II diabetes and schizophrenia, and allergies are no exception.

For allergic conditions, GWAS studies have often confirmed the involvement of previously suspected pathways, as well as identifying novel genes whose variation contributes to a predisposition for allergies. However, many of these findings require follow up studies to properly tease apart the mechanisms involved. Just because GWAS can identify potential genomic regions of interest does not mean that they can successfully point to the mechanism. This is particularly true given the heterogeneous nature of allergies and their symptoms. Why are variants in certain genes more common in people with allergies (or certain allergies)?

Genetic Mechanisms

For certain genes, the link is obvious. A study published in 2015 carried out a GWAS in US children, looking for genes that influence susceptibility to food allergies. They identified peanut allergy-specific gene variations, and also found that epigenetic patterns were altered at these genes. The peanut allergy susceptibility variants were found in the HLA-DR and-DQ regions, which are expressed in a range of immune cells, and were previously known to play a role in the regulation of the immune system, and specifically in the allergic response. The sequence that harbors this variation corresponds to the peptide-binding groove of the HLA molecule, which determines which antigen-derived peptides are bound and presented to T cells. This impacts the way the immune system responds to perceived threats, and therefore could account for allergen-specific sensitivities.

A more recent study confirmed these peanut allergy-specific findings, and found an additional genomic region more generally involved in food allergy: the SERPIN B gene cluster. This gene is found expressed in epithelial cells, including those of the upper gastrointestinal tract. This could contribute to hypersensitivity to certain foods and the development of a food allergy. In support of its link to immune-disorders, increased expression of this gene family have been previously linked to eczema.

Why have allergies increased over time?

One feature of allergies not readily explained by genetics is that allergy incidence has rapidly grown in recent years. In fact, food allergies in American adults have increased ten-fold in the last 35 years, amounting to almost 10% of the population. This does not appear to be explained purely by clinicians having better diagnostic tools and therefore picking allergies up more quickly. In fact, is seems that the prevalence is genuinely on the rise, especially in the Western world, and particularly in urban regions.

The true prevalence of allergies is difficult to determine, owing to their complex and diverse nature. Prevalence statistics can be biased by disparities in healthcare, socioeconomic status, awareness of food allergies, and diagnostic procedures. What we do know is that the prevalence is high; a recent meta-study found that around 10.8% of the American population are food allergic, with 19% believing they were food allergic. The authors highlight the need for more education of patients into the differences between allergies and intolerances, as well as encouragement to get a clinical evaluation and diagnosis if an allergy is expected.

The hygiene hypothesis

One of the leading theories for why allergies are on the rise is the hygiene hypothesis. This hypothesis essentially suggests that we are now too clean. We are less exposed to a variety of microbes, using more disinfectants, and we get less infections. All of this contributes to the immune system not being adequately “trained” to distinguish non-harmful invaders from the harmful pathogens.

There is also a hypothesis that since our lives are spent increasingly in doors and in front of computer screens, that reduced sun exposure and resulting deficiency in Vitamin D could contribute to an increase in allergies. Vitamin D is known to have a role in regulating immune response pathways.

Highlighting the importance of environmental factors is a review from 2015, which compiled evidence from multiple studies to examine the effects of the local environment on allergies and asthma by studying immigrant populations. Their results established that the overall prevalence allergic diseases in immigrants is lower than in the host country populations, and over time meets the level of the prevalence in the local population. This suggests a strong environmental influence on the development of allergies.

Of course, as with many complex genetic traits, genes are not the only driving factor of allergies. As well as genetics, the environment and lifestyle of the individual will also play an important role. The interplay of these factors will be deterministic in whether someone will develop allergies. The genetics of such complex traits determines an individual’s propensity to develop allergies, perhaps if the environment is also conducive to allergy development, a perfect storm will be created.

 

References

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