Are food allergies and intolerances genetic?

Food allergies and intolerances are on the rise,¹ or at least, the diagnosis and awareness of them is. This has been blamed on environmental factors, the so-called hygiene hypothesis suggests that increased cleanliness and therefore reduced exposure of babies to germs leaves their immune systems essentially twiddling their thumbs, looking for something to do, and thus they get all excited and go nuts when they see something harmless like a peanut or dairy protein. But do genetics play a role? Both of my daughters had food allergies/intolerances as bubs, reacting to dairy, soy, egg and coconut through my breastmilk and forcing me to subsist on a diet of air and cardboard. My husband and I both suffer hayfever and cat allergies, while my MIL is allergic to shellfish, my SIL is allergic to peanuts and was to eggs as a child, and her son is allergic to sesame. So, I have no doubt that food allergies and intolerances are at least partially genetic. But what does the science say?

We’ll start with the most famous and well-understood genetic food intolerance; lactose intolerance. Lactose is digested by the enzyme lactase, whose gene is designated LCT. In most mammals, lactase is produced mainly by babies in order to digest breastmilk, and levels then decline substantially. Its thought that certain proteins act as ‘transcriptional repressors’ to stop the lactase gene from being produced.²  This still happens in a large proportion of the world’s population. Then, somewhere in Europe about 4000-5000 years ago, a mutation occurred, not in the lactase gene itself, but about 14000 DNA bases upstream of LCT, that is, before it on the same chromosome.³ This section of DNA is a regulatory region, and it is thought that this mutation creates a site for other proteins to bind, specifically proteins that act as transcriptional enhancers and thus encourage continued lactase production. In communities with livestock, this mutation gave a survival advantage as it gave people an extra source of calories and nutrients. As a result, it spread and is now the most common variant in people of certain European descent,³ a great example of evolution in action. Other variants of the same regulatory region that also cause continued lactase are found in some Middle Eastern and African populations. Anguita-Ruiz, et al. ² developed an interactive map where you can see how common variants that allow continued lactase production are across the world. You can find it here https://coblabugr.shinyapps.io/lactasepersistence/, and see that in Australia, about 50% of people are genetically lactose tolerant. Of course, that figure would be higher in Australians of European descent and lower in other populations.  It should come as no surprise that Indigenous Australians are mostly lactose intolerant,⁴ as they did not exactly have a lot of options for milk production- can you imagine trying to milk a kangaroo?

Things are less clear for other food allergies and intolerances. Twin and family studies have shown that there is a genetic influence, but how strong it is varies significantly from study to study, with the heritability ranging from 15%-82% and the risk to siblings ranging from 1.3-12 times the risk of the rest of the population.⁵ This may be because of different allergies studied, some just looked at peanuts and some looked at a range of foods, as well as how allergies were defined, some relied on skin prick and others on oral challenge, which is important as some kids will have a positive skin prick but can eat the food with no sign of an allergic reaction.

As for the specific genes, its unsurprising that most genes found in studies are involved in the immune system. This includes multiple interleukins, which are secreted by white blood cells and act as messengers to other immune cells to either activate or suppress an immune reaction, and genes of the Major Histocompatibility Complex (MHC).⁵ The MHC is full of immune system genes, including human leukocyte antigen (HLA) genes. HLA genes are highly variable, with over 38000 variants currently recognised (https://www.ebi.ac.uk/ipd/imgt/hla/about/statistics/). The proteins encoded by these genes are expressed on cell surfaces and essentially tell immune cells that this is your own cell, so please leave it alone.⁶ These are the genes that are looked at when trying to find a organ donor match; if a transplanted organ has HLA different to that of the recipient, the immune system will not recognise it and attack it, causing organ rejection. HLA genes have also been implicated in a number of auto-immune diseases, which makes sense as auto-immune diseases occur when a bodies immune system misfires and attacks its own cells. For allergies, HLA genes are implicated in not only food allergies, but also asthma and hayfever.⁵ In addition to signalling self, HLA also present proteins from pathogens, e.g. viruses or bacteria, to immune cells to tell them there is an infection that needs fighting. But different HLA variants have different ‘preferences’ and strengths for different proteins. This is important from an evolutionary standpoint, diversity in these genes gives a population some protection against a wide range of germs. But it does mean that some people have HLA variants with liking for otherwise harmless food proteins and present them for an immune response, i.e. an allergic reaction.

In addition to genetics, it’s been discovered that how and when bubs are exposed to allergens affects their chances of developing a food allergy. In particular, it seems that early introduction of allergens orally (from 4 months) reduces the chance of allergy, while introduction through the skin, in dust or skin products, increases it.¹ So if you have a baby, please check all your moisturisers, soaps etc and avoid them if they contain any food products! Interestingly, it seems genetics may influence how skin exposure increases allergy risk. One of the top genes associated with food allergies is called filaggrin (FLG).⁵ Filaggrin binds to keratin in the skin and helps maintain the skin barrier, it helps keep stuff from outside the body, outside the body. Mutations in the filaggrin gene can stop the barrier being as effective and mean allergens on the skin can travel inside the body and be shown to the immune system.⁷ This is a good example of gene-environment interaction, showing how genetics can make you susceptible to an environmental trigger.

So are food allergies and intolerances genetic? For lactose intolerance it’s an easy yes. For others, like most things I’ve looked at here, it seems to be a mix of genetics and environment, probably with a decent amount of luck thrown in.

References

1. Benedé S, Blázquez AB, Chiang D, et al. The rise of food allergy: Environmental factors and emerging treatments. EBioMedicine 2016;7:27-34. doi: 10.1016/j.ebiom.2016.04.012 [published Online First: 2016/06/21]

2. Anguita-Ruiz A, Aguilera CM, Gil Á. Genetics of Lactose Intolerance: An Updated Review and Online Interactive World Maps of Phenotype and Genotype Frequencies. Nutrients 2020;12(9) doi: 10.3390/nu12092689 [published Online First: 2020/09/10]

3. Liebert A, López S, Jones BL, et al. World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection. Hum Genet 2017;136(11-12):1445-53. doi: 10.1007/s00439-017-1847-y [published Online First: 2017/10/25]

4. Brand JC, Gracey MS, Spargo RM, et al. Lactose malabsorption in Australian Aborigines. The American Journal of Clinical Nutrition 1983;37(3):449-52. doi: https://doi.org/10.1093/ajcn/37.3.449

5. Kanchan K, Clay S, Irizar H, et al. Current insights into the genetics of food allergy. J Allergy Clin Immunol 2021;147(1):15-28. doi: 10.1016/j.jaci.2020.10.039 [published Online First: 2021/01/14]

6. Choo SY. The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei Med J 2007;48(1):11-23. doi: 10.3349/ymj.2007.48.1.11 [published Online First: 2007/02/28]

7. Sandilands A, Sutherland C, Irvine AD, et al. Filaggrin in the frontline: role in skin barrier function and disease. J Cell Sci 2009;122(Pt 9):1285-94. doi: 10.1242/jcs.033969 [published Online First: 2009/04/24]