How integrated genetics can help your allergy patients
By Dr. Penny Kendall-Reed, NDFeatures
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?
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.
DAO (diamine oxidase gene) 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.
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 the following genes impact allergies, and which are key players.
Stress Genes: 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 TNF-α. IL6 is known increase mast cell numbers, TNF-α is 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-αare intimately related and each influences the production and effect of the other. That is why it is so important to look at bothgenes 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.
DR. PENNY KENDALL-REED, N.D., is a naturopathic doctor in Toronto. After graduating from McGill University in Neurobiology, she earned a degree in Naturopathic Medicine from the Canadian College of Naturopathic Medicine, where she received the Dr. Allen Tyler Award for Most Outstanding Clinician. Dr. Kendall-Reed is the author of five national bestselling books, and recently released her latest, “Fix Your Genes to Fit Your Jeans,” which she co-authored with her husband, Dr. Stephen Reed. In 2013 she was voted Naturopath of the Year and in 2018 was the recipient of the top Naturopathic Doctor.
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