Lactose, Gluten, Caffeine: The Genetics of Food Sensitivity

Reactions to lactose, gluten and caffeine are often grouped under the single term “food sensitivity”. Biologically, though, they have almost nothing in common. A reaction to lactose most often has to do with the activity of the enzyme lactase, a reaction to gluten with the particulars of the immune response, and a reaction to caffeine with the speed of its metabolism and the sensitivity of receptors.

It is precisely these differences that make genetic analysis useful. It helps to understand the biological mechanism by which the body’s reaction most likely forms, and what exactly can be assessed from DNA. In some cases a hereditary predisposition can be determined fairly precisely; in others, genetics only outlines a direction for further examination. In such situations, the genetic context is complemented by laboratory tests and clinical assessment.

For how food allergy and intolerance differ and what role genetics plays, see Food Allergy and Intolerance: How to Tell the Difference and What to Do”.

Three Mechanisms of Food Sensitivity

The word “sensitivity” conceals at least three different biological stories:

• lactose — the body lacks the enzyme lactase;

• gluten — the immune system is triggered;

• caffeine — it comes down to the speed at which the liver breaks the substance down and to the sensitivity of receptors in the brain.

This difference is not cosmetic. It affects how confidently a genetic test can say anything. Where everything depends on a single regulatory region, the answer is closer to “yes or no”. Where dozens of factors and external triggers are involved, genetics describes a probability, not a ready-made scenario. Each of these mechanisms has its own biology, and therefore different scope for genetic analysis.

Lactose: When the Body Lacks Lactase

Lactose is milk sugar. To absorb it, the small intestine produces the enzyme lactase, which breaks lactose down into glucose and galactose. Infants have plenty of lactase, but with age its production often declines. Undigested lactose then reaches the large intestine, where bacteria ferment it (Kharrat Helu et al., Nutrients, 2025).

A drop in lactase activity → undigested lactose enters the large intestine → bacterial fermentation → gas and bloating

The more dairy a person consumes at once, the more noticeable the reaction. This is why the body often handles a slice of hard cheese or half a cup of yoghurt calmly but reacts sharply to a glass of milk: lactose sensitivity is dose-dependent (Kharrat Helu et al., Nutrients, 2025).

The Genetic Basis

The amount of lactase in adulthood depends largely not on the lactase gene itself but on a regulatory region nearby. A variant in the MCM6 (minichromosome maintenance complex component 6) gene affects whether the LCT (lactase) gene will remain active after childhood. One well-studied variant, rs4988235, distinguishes two states: lactase persistence (the ability of an adult to digest milk and dairy products normally), when the enzyme stays active, and lactase non-persistence (a genetically determined fading of this ability with age), when activity falls (Kharrat Helu et al., Nutrients, 2025). This model has been confirmed primarily in European populations, and for Ukrainians, as members of an Eastern European population, it is applicable.

What a Genetic Test Can Show

The genotype in the MCM6/LCT region can show a predisposition to a decline in lactase in adulthood. But it does not measure your current enzyme level directly, and it does not account for the state of the gut after an infection or inflammation, when lactase can drop temporarily regardless of genetics. In other words, DNA speaks to a baseline predisposition, not to the current state of the mucosa.

Gluten: When the Immune System Reacts

With gluten the mechanism is entirely different. The problem is not a lack of enzyme but the reaction of the immune system. In people with coeliac disease, gluten triggers an immune response that damages the lining of the small intestine and impairs the absorption of nutrients. Coeliac disease is an autoimmune condition, not merely a food that is “hard to digest”. Separate from coeliac disease is gluten intolerance — a condition in which the body digests it poorly without an autoimmune reaction. The symptoms can be similar, but the mechanism is different, and no genetic markers for it have yet been identified (Sallese et al., Front. Nutr., 2020).

Gluten enters the gut → in people with a genetic predisposition to coeliac disease the immune system recognises its fragments as a threat → inflammation is triggered → the villi of the small intestine are damaged

The Genetic Basis

The key role is played not by individual “disease genes” but by variants in the HLA region — the HLA-DQA1 (major histocompatibility complex, class II, DQ alpha 1) and HLA-DQB1 (major histocompatibility complex, class II, DQ beta 1) genes. Certain combinations of them form the DQ2 and DQ8 haplotypes associated with coeliac disease. A meta-analysis of data from adults with coeliac disease showed that almost all of them carry DQ2 or DQ8 (Aboulaghras et al., Int. J. Mol. Sci., 2023). But there is a crucial detail here: these haplotypes are a necessary but not a sufficient condition — carrying them is far more widespread in the population than coeliac disease itself (Sallese et al., Front. Nutr., 2020).

What a Genetic Test Can Show

The genetics of gluten works, as it were, the other way round compared with lactose. If the HLA DQ2 and DQ8 polymorphisms are absent, coeliac disease can be ruled out with near certainty. If they are present, this means only a predisposition, not a diagnosis, and does not guarantee that the condition will ever develop. So the presence of a haplotype does not replace a gastroenterological examination, while its absence rather removes one of the suspicions. It is also worth remembering that discomfort from wheat and wheat products occurs even without coeliac disease — this is non-coeliac sensitivity, a condition with no autoimmune mechanism and none of the characteristic markers of coeliac disease. The role of innate immunity, FODMAPs (fructans) and other components of wheat is under active discussion, but there is no clear understanding of the mechanism yet.

Caffeine: When It Comes Down to Speed

Caffeine blocks the adenosine receptors in the brain — the very ones that signal tiredness. As long as caffeine occupies a receptor, the sense of tiredness is pushed back. It is then broken down by liver enzymes. How quickly this happens and how strongly you feel the effect of caffeine depend on two different things.

Caffeine blocks the adenosine receptors → the sense of tiredness is delayed → the liver gradually breaks caffeine down → in “slow” metabolisers it acts longer and feels stronger

The Genetic Basis

The speed of breakdown is governed mainly by an enzyme encoded by the CYP1A2 (cytochrome P450 family 1 subfamily A member 2) gene. The rs762551 variant loosely divides people into “fast” and “slow” metabolisers (Popa et al., Nutrients, 2025). How strongly the brain responds to caffeine is governed by a different link — the ADORA2A (adenosine A2A receptor) gene. Its rs5751876 variant is linked to a higher sensitivity to caffeine (Grgic et al., Nutrients, 2020).

What a Genetic Test Can Show

Genetics describes a probability and a direction, not an exact dose. It can suggest why a late coffee keeps you from sleeping, or why your heart races and you get a tremor from a single cup. But the actual reaction also depends on other habits, smoking, pregnancy, medications and the amount of caffeinated drinks consumed.

The Scope and Limits of a Genetic Test

In each of these cases, genetic analysis provides a different amount of information:

• lactose — the predisposition reads almost as a “yes or no”;

• gluten — genetics rules coeliac disease out rather than confirming it;

• caffeine — genetics gives a probabilistic adjustment, not an exact dose.

Food sensitivity, then, spans different biological mechanisms, and so the scope of genetic analysis differs too. Its results do not replace laboratory tests or clinical assessment but complement them, helping you understand the body’s hereditary features and interpret them in the context of symptoms and examination findings.

This approach underlies the “Allergies, intolerances and tastes” DNA test, which analyses the genetic features linked to the body’s reaction to lactose, gluten, caffeine and other indicators.

One Reaction to Food — Different Biological Causes

Milk, bread and coffee are often seen as foods that may harm health and “do not suit everyone”. Yet the causes of such an individual response can be entirely different, and so the scope of genetic analysis differs as well. In some cases it makes it possible to assess a hereditary predisposition fairly precisely; in others, it only complements the clinical picture. This is why the results of a DNA test should be interpreted with the biological mechanism in question in mind. It helps you understand your own features better and choose the next steps of examination together with your doctor.

What Else Is Worth Knowing

Why does milk cause bloating only in some people?

This happens because of the varying activity of the enzyme lactase, which depends on genetics. With age, lactase production often declines, and undigested lactose ferments in the large intestine, causing bloating. How early and how strongly this happens depends largely on a variant in the MCM6/LCT regulatory region. It is also important to remember that the reaction to lactose is dose-dependent (Kharrat Helu et al., Nutrients, 2025).

Can lactose intolerance be determined from DNA?

DNA shows a predisposition to a decline in lactase, but not the current state of the gut. The genotype in the MCM6 region affects lactase non-persistence in adulthood (Kharrat Helu et al., Nutrients, 2025). However, enzyme activity can drop temporarily after infections or inflammation, so when symptoms appear, both self-observation and a doctor’s consultation matter.

Does having the HLA-DQ2 variants mean I have coeliac disease?

No, it is a predisposition, not a diagnosis. The DQ2 and DQ8 haplotypes are present in almost everyone with coeliac disease, but carrying them is far more widespread than the disease itself (Aboulaghras et al., Int. J. Mol. Sci., 2023). The presence of a haplotype means only a possibility, not a guarantee that the condition will develop.

Why do I get the shakes after coffee?

Because of the varying speed at which caffeine is broken down and the sensitivity of receptors. A variant of the CYP1A2 gene affects how quickly the liver breaks caffeine down (Popa et al., Nutrients, 2025), while an ADORA2A variant affects the brain’s sensitivity to it (Grgic et al., Nutrients, 2020). In “slow” metabolisers with a sensitive receptor, even a single cup of coffee can provoke a racing heartbeat.

Is it worth cutting out gluten without tests?

If you remove gluten before diagnosis, tests for coeliac disease can become falsely negative, because the immune response fades without the trigger. A decision about a gluten-free diet is better made together with a doctor, drawing on both the genetic context and laboratory tests.

Can a genetic test be used to tailor my diet?

Genetics suggests what you are predisposed to — a decline in lactase, coeliac disease or a marked reaction to caffeine — but the choice and/or adjustment of a diet also depends on your current lifestyle, the state of your digestive tract and any accompanying conditions. So the results are better used as a starting point for decisions made together with a specialist.

For which hereditary features the test analyses in this area and how they are interpreted in the report, see “Allergies and intolerances and DNA: what a genetic test says about your body’s reactions” (№57).

The results of a genetic test are not a diagnosis and do not replace a doctor’s consultation. An Apixmed Prism report provides genetic context that complements the findings of examinations and helps you make decisions together with your doctor.

Sources

1. Kharrat Helu, N., Al Ashkar, H., Kovacs, N. et al. (2025). Lactase Persistence-Associated rs4988235 Polymorphism: A Novel Genetic Link to Cardiovascular Risk via Modulation of ApoB100 and ApoAI. Nutrients, 17(17), 2741. https://doi.org/10.3390/nu17172741
2. Aboulaghras, S., Piancatelli, D., Taghzouti, K. et al. (2023). Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease. International Journal of Molecular Sciences, 24(2), 1188. https://doi.org/10.3390/ijms24021188
3. Sallese, M., Lopetuso, L. R., Efthymakis, K., & Neri, M. (2020). Beyond the HLA Genes in Gluten-Related Disorders. Frontiers in Nutrition, 7, 575844. https://doi.org/10.3389/fnut.2020.575844
4. Popa, L. C., Abu-Awwad, A., Farcas, S. S. et al. (2025). Genotype–Drug–Diet Interactions in Metabolic Regulation: CYP1A2 rs762551 Modulates the Effect of Caffeine on Lipid and Glucose Profiles in the Context of Pharmacotherapy. Nutrients, 17(14), 2288. https://doi.org/10.3390/nu17142288
5. Grgic, J., Pickering, C., Bishop, D. J. et al. (2020). ADORA2A C Allele Carriers Exhibit Ergogenic Responses to Caffeine Supplementation. Nutrients, 12(3), 741. https://doi.org/10.3390/nu12030741