Are seasonal allergy symptoms slowing your patients down? As healthcare practitioners, we know that Fall has truly arrived when we see an increase in patients with red, itchy eyes, congested sinuses and fits of sneezing. Far from being limited to respiratory symptoms, this allergenic patient picture can also include hives, rashes, shortness of breath, swelling and GI bloating.

Your patients likely know that they have seasonal allergies, and may be looking to you for symptomatic relief. But are you prepared to answer these patient questions? 

  • I tried antihistamines – why didn’t they work?
  • I’ve never had allergies before – why am I getting them now?
  • I got a cold months ago – why do I still have symptoms?

Patients may consider allergy symptoms annoying, but not serious. But you and I know that allergy symptoms are cries for help from a dysfunctional immune system. I’m sure you have many tools in your practitioner toolkit to support immune health. But have you considered where genetics fits in? Let’s take a closer look at which genetic factors influence the immune response, and how using integrated genetics can help you get to the root of your patients’ allergies this Fall. 

Allergy or Immune Hypersensitivity?


What your patients call an ‘allergy’, could in fact be a grouping of conditions caused by immune system hypersensitivity. In a healthy immune system, our defensive army only attacks foreign invaders like bacteria and viruses. But what happens when environmental and genetic factors combine to make the immune system too sensitive? It launches attacks against harmless substances.

To understand why this is problematic, let’s briefly review the underlying immune system mechanism: 

  • T-lymphocyte cells detect invaders and release inflammatory cytokines
  • Cytokines trigger B-cells to produce immunoglobulin-E antibodies
  • Antibodies bind to mast or basophil cell receptors
  • Mast cells or basophils release histamine and other inflammatory cytokines

Frequent triggering of this immune response when not needed can repeatedly flood our bodies with inflammatory cytokines. This further sensitizes the allergenic response, leading to more cytokine release. Before you know it, the body is caught in a vicious immune hypersensitivity-inflammation cycle.


The Dangers of Single Gene Analysis: Why DAO (the diamine oxidase gene) is Only Part of the Allergy Picture


We know that genetics plays a significant role in allergenic disease. Yet, identical twins are likely to have the same allergies only about 70% of the time, and non-identical twins about 40% of the time. What’s going on with the other 30% or 60%?


When faced with seasonal allergies, most clinicians look to traditional allergy genes such as DAO. This gene codes for diamine oxidase production – the enzyme responsible for inactivating or degrading histamine. Is looking at this gene extremely valuable? Absolutely. Patients with a genetic profile indicating low DAO production cannot effectively metabolize or excrete histamine, leading to histamine buildup. These patients may regularly experience allergies and, despite taking antihistamines, often remain quite symptomatic, especially if they lower the antihistamine dose or stop it entirely.


But does examining the DAO gene explain the twin statistics above? Or explain why antihistamines don’t resolve symptoms for all allergy sufferers? Unfortunately not.


There are a few important mechanisms that greatly augment the allergenic response by directly stimulating the mast cells. Thus, even in the absence of an actual allergen, the same allergy symptoms arise. Antihistamine treatment is only half (if not less) of the artillery needed to fight the battle raging within the immune system. Thankfully, genetic analysis can help us identify what other mechanisms are at play, and the strength of their impact.  


Beyond DAO: Genetic Factors That Stimulate the Allergy Response


For patients with DAO gene issues, the “fix” seems straightforward; lower histamine and avoid allergens. But even in these patients, you may need to look deeper. What happens if you don’t treat dysfunction in the stress pathway or sensitivity in the inflammation and immune system response?  The expression of genes affecting these factors will keep igniting the allergy reaction repeatedly such that the mast cells are never fully turned off. 


In my opinion, these other genes are almost more important than the classic “allergenic genes” such as DAO. Let’s take a closer look at how stress, inflammation and the immune response genes impact allergies, and which genes are key players.


Stress Genes


We know that stress significantly impacts all systems in the body. After 6 months of pandemic living and entering an uncertain fall, your patients’ stress levels may be at an all-time high.

Stress can stimulate and destabilize mast cells, forcing them to release histamine in the absence of an allergen. Stress also increases inflammatory cytokine production, especially IL6, and that further triggers the allergen response and worsens symptoms. Let’s examine 5 genes that you should consider when looking at the role of the stress response in allergies:


COMT and MAOA break down and clear out our stress hormones. Slow stress hormone breakdown, as seen with the variant coding of these genes, means they stick around in the body. The longer these hormones circulate, the more likely they are to have a profound negative impact. 


NR3C2 and FKBP5 variant alleles alter the normal feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis. NR3C2 codes for the mineralocorticoid receptor. Those with the variant allele have reduced expression and activation of the receptor, which leads to a decreased feedback response to cortisol. FKBP5 produces a protein that blocks cortisol from binding to the glucocorticoid receptor. Patients carrying the variant allele produce more of this protein leading to impaired negative feedback.  The result? Patients carrying the variant alleles of these genes get trapped in the sympathetic side of the nervous system, chronically producing more stress hormones (even in the absence of stress), destabilizing their mast cells. 


CRHR1 produces receptors for Corticotropin Releasing Hormone (CRH). When stimulated they activate the HPA-axis stress response, which again increases the allergenic response. Those with the variant coding for this gene produce more receptors leading to a more vigorous and long-lasting stress response with subsequent for mast cell stimulation. These patients may experience strong and long-lasting allergenic symptoms. 


Inflammation Genes


Inflammatory cytokines are produced during infections, trauma, allergies, fevers and stress. Regardless of why these cytokines are being produced, they have the potential to induce and prolong the allergic reaction. Patients that produce an overabundance of inflammatory cytokines, particularly IL6 (Interleukin-6) and TNF-α (Tumour Necrosis Factor alpha), may continue to experience symptoms such as sinus congestion, dry cough and breathing difficulties for months on end even though the original stimulus is long gone.

Let’s examine the two genes that produce the pro-inflammatory cytokines IL6 and TNFα.


IL6 is known increase mast cell numbers


TNF-α crucial for mast cell development. 


Patients that produce more of these cytokines have a heightened inflammatory load and a more reactive immune system with larger numbers of overly sensitive mast cells. Anything that triggers their immune system, whether a true allergy or colds and flu, injury or environmental stress, can result in severe allergic-type symptoms. Knowing how much IL6 or TNF-α your patients produce in response to immune stimulation is invaluable information as a clinician. It can help identify which patients need more cytokine reduction (versus histamine reduction) support during allergy season.  IL6 and TNF-α are intimately related and each influences the production and effect of the other. That is why it is so important to look at both genes when assessing your patient.  Individuals variant for one or both genes should have therapy directed at controlling the excess cytokine load in addition to promoting mast cell stability. 


Genes Affecting The Immune Response to Viruses and Bacteria and Environmental Pollutants

Viruses and bacteria are invaders our immune system is supposed to protect us from. But in a hypersensitive system, that reaction can be far too strong resulting in excess inflammation, allergic reactivity and autoimmunity. 

IRF5 and HLADQB1 are two important genes that influence our reaction to viruses, bacteria, and pollutants. 

 IRF5 is a member of the interferon regulatory family and plays a role in virus-mediated activation, cellular growth and differentiation and immune system activity. Patients with genetic variants produce more interferon, which stimulates higher levels of interleukin production, increased allergy and inflammation and greater risk of autoimmune disease.  

HLADQB1 is one of the major histocompatibility complex genes. The human leukocyte antigen (HLA) system genes are responsible for making the cell-surface proteins that regulate the immune response.  Individuals with variant coding have an amplified allergic and asthmatic response. These patients need higher doses of mast cell stabilization to calm and shut off symptoms. 


Get to Allergenic Root Cause with GeneRx


Now that you understand the importance of looking outside DAO to include genes that impact stress, inflammation and the immune response, the real question is: how do you integrate interpretation of all these genes together?


There are many genetic reports on the market that provide basic genetic analysis. The problem? Most reports only analyze one gene at a time. Imagine if you looked at each of these 10 genes in isolation. How accurate would such an analysis be? And would it give you the information you need to banish your patients’ allergies for good?


My GeneRx report provides meaningful information on each of these genes that you can easily use in clinical practice. Most importantly, the report will show you how to integrate interpretation of these genes. Including detailed protocols with diet, lifestyle and supplement recommendations, GeneRx can be a vital part of your practice. Simply upload your patients’ raw 23andMe data and get ready to start improving patient outcomes.


Are you ready to use personal genetic testing to get to the root of your patients’ allergies and offer truly individualized treatment recommendations? Download a sample GeneRx report to see how it compares with your current genetic report, or learn more about how GeneRx differs from other reports.