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The mold genes: what you need to know

Article at a Glance
  • There are an estimated 111 fungal species with allergic properties.
  • Two outdoor airborne fungi have been associated with an increased risk of asthma development: Alternaria alternata and Cladosporium herbarum. 
  • Changes in the ITGB3 gene have been associated with an increased sensitivity to mold, especially in asthma sufferers. 
  • Certain XRCC4 and XRCC5 genotypes have been associated with a small increased risk of developing liver cancer in individuals with a high aflatoxin exposure.
  • There has been a lot of discussion, however, to date, the evidence of a link between HLA genotypes and increased susceptibility to mold toxins is limited at best.
Mold genes

The fuzzy weblike structures formed by molds are a common sight, which is not surprising given that the number of identified mold species number in the thousands, with likely millions more remaining undiscovered. Unlike plants, molds derive energy through the breakdown of organic matter, and especially like moist, warm conditions — which is why leaving your soft fruit out on the counter doesn’t end well.

While off putting mold (and other microbes) are vital to life, a fact which Louis Pasteur knew well:

Life would not long remain possible in the absence of microbes.

The vast majority of these molds live in harmony with us, rarely if ever causing disease, but that is not to say they are entirely harmless. Some species of mold can make people very ill. This is of particular interest to me at the moment as we are in the middle of renovating our house. Built in 1904 on damp fen land, and without modern materials, it’s fair to say there was always going to be an issue with damp and molds, which was then made worse through attempts to air-seal the house at some point in the 1970s/’80s. We’re now in the process of undoing that work and trying to work with the building, using eco-friendly, breathable materials to hopefully banish the damp and mold for good.

But when sensitive people are exposed, what health effects can molds have, and is there anything you can do to limit your risk?

Allergies and mold

The World Health Organization lists 111 fungal species as having allergic properties, with perhaps the most interesting being Penicillium, from which penicillin was first derived. The most common form of allergic hypersensitivity is caused by direct contact with mold or airborne mold spores, triggering the classic immune response leading to flushing, runny nose and weepy eyes in those with mild symptoms, or anaphylaxis in those with more severe forms. Indeed, allergy derived from a continuous exposure to high levels of mold/mold spores is associated with the development of several interestingly named disorders, such as Farmer’s lung or pigeon fancier’s lung.

Allergy testing

While not a perfect test, it is possible to test for hypersensitivity using an IgE test on a blood sample, or on the skin via a prick test. There have been a couple of studies looking at the prevalence of hypersensitivity to molds, with this German study reporting a rate of around 8% in children (R) with an increased incidence in individuals with underlying atopic conditions such as asthma. (R) The authors note that this is likely an underestimate due to the relatively small numbers of molds tested, but also note that relative to other allergens such as pollen, dust and animal fur, mold is the least potent. Having said that, based on my conversations with John and his experiences in Austin (where the mold count outdoors can often reach 20,000), it does seem people can develop health issues from exposure to mold in both buildings as well as in the air. There are even whole Facebook groups dedicated to practicing “mold avoidance,” which for these people means living in tents or RVs in the desert so as to avoid any contact with any mold at all.

Asthma

While those with asthma may be more susceptible to hypersensitization from indoor molds, there is no evidence that such molds can cause asthma. However, two outdoor airborne fungi have been associated with an increased risk of asthma development: Alternaria alternata and Cladosporium herbarum. (R) As these are both outdoor molds especially common to wooded areas, there is little that can be done to avoid them. One SNP of particular interest has been identified; rs2056131 in the ITGB3 gene, where the A allele is associated with an strong increased risk of mold sensitization in asthma sufferers. (RITGB3 encodes for an integrin subunit; these molecules are typically expressed onto the surface of the cell and act to bind other cells or particles. So it is possible to see a mechanistic link whereby changes in ITGB3 promote adherence of mold or mold spores leading to hypersensitization.

What is interesting is that this is a relatively common SNP (37% of the global population are carriers), so the fact that mold-related symptoms only appear in an asthma sub-group shows that if the SNP is associated with increased mold/mold-spore binding, what little effect it has in the healthy general population.

Mycotoxins and toxicity

Certain fungi produce toxins known as mycotoxins as a defense mechanism. At an individual level, we’re protected against this as we have an inbuilt aversion to eating moldy foods. But food can become contaminated with molds in the food chain, leading to the buildup of harmful mycotoxins. For example, many grains contain mycotoxin because they grow moldy through the long process of harvest to storage. Aflatoxin is perhaps the most well known of the mycotoxins, which can commonly be found in corn, peanuts and other tree nut-based products. However, levels are tightly regulated, so health issues only arise when these food controls are flouted, or in individuals with existing hypersensitivities.

Very high doses of aflatoxin have been associated with an increased cancer risk; two possible SNPs have been identified in the DNA repair genes XRCC4 and XRCC5. The A allele of both rs3734091 and rs28383151 was associated with a small increased risk of developing liver cancer in individuals with a high aflatoxin exposure. (R) While the importance of DNA repair in cancer is well understood, the role aflatoxin plays in this remains unknown.

Infectivity and mold

Infection represents the third mechanism by which molds can impact human health. While fungal/mold infections are serious in immunocompromised individuals, such infections in healthy immunocompetent individuals are typically superficial — think thrush (Candida) or athlete’s foot (Trichophyton) — however, these fungi can sometimes cause more severe health issues.

Candida is typically thought of as commensal, in that it exists in our gut happily and normally does us no harm; however, dysregulation of the gut environment can flip Candida into pathogenic action. John has done a couple of great posts on the matter and I have another one coming soon, which cover this in more detail.

Any other mold genes? What about HLA?

When you start talking about allergy and autoimmune disorders a major region to focus on is the human leukocyte antigen (HLA) complex, a series of genes which encode for something known as the major histocompatibility complex. These cell surface proteins are key in regulating how our immune system responds to foreign pathogens, such as molds, and are also an area of tremendous variation.

Now if you google HLA and Mold you get a lot of hits, sounds promising… but when you begin to dig a little deeper you run into dead ends. There is lots of talk about particular HLA types associating with susceptibility to molds, and you will most likely come across a table like this which lists HLA types and susceptibility risks:

RiskDRDQPopulation Frequency (%)Total (%)
Multiple Risks4316.928.6
11/1239.7
1452
Susceptible72/314.824.5
1369.7
172-
184-
No recognized risk83, 4, 62.32.3
Low-risk793.75.6
1271.1
990.8

The most important thing to state is that I wasn’t able to find published research explaining these groupings or presenting any evidence of a link between HLA types and susceptibility to mold. Digging deeper, look at the two rightmost columns. Here, I’ve added in the frequency these HLA types appear in the Caucasian population (R).

Straight away you can see that apparently 28.6% of Caucasians are at a high risk of mold issues, with a further 24.5% susceptible. The table also lists risk factors for other conditions which I’ve omitted, but the only HLA types listed without issue account for 7.9% of the population.

With numbers like those, it suggests rather that we’re all susceptible to mold, with only a lucky few resistant. But once again, there is no data to describe why these groupings are used. In this case, I think HLA typing for mold might be interesting, but is currently a big waste of time.

This position seems to be backed up by clinicians like Dr. Neil Nathan, a mold specialist in California, who has written in his book Mold and Mycotoxins that he observes little to no difference in treating patients with HLA SNPs as opposed to those who do not carry the polymorphisms. To quote Dr. Nathan:

My personal experience, having evaluated hundreds of patients with this test, is that I have not noted much correlation between clinical improvement and this test. This means that those with the so called “dreaded” genes have often done as well, or better, than those without those genes. Accordingly, I have not found this test to be useful in determining who will respond to treatment from those who won’t.

Summing up

The purpose of this post was to act as an intro to a series of posts we’re going to do about molds, with a focus on available tests and genetic risks. Currently there are a couple of SNPs which may be of interest to those with existing allergies. However, the widely sold HLA test doesn’t seem to have any basis in (published) science and so it’s unclear what it can tell people.

Regardless, long-term, high exposures to molds can undoubtedly have chronic health impacts and so finding ways to reduce or eliminate long term exposures are desirable.

Moving on we’ve got upcoming posts about how molds present in the diet may be related to health issues, and how these can link in with genetic variants in the ITGB3, XRCC4 and XRCC5 genes.

Aaron Gardner

Dr Aaron Gardner is a life-scientist with a strong background in genetics and medical research, and a particular interest in the developing fields of personalised medicine and nutrition.

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2 Comments

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  1. Betty Lacy says:

    Hi Aaron, I’m doing some deep diving into my Promethease report to see if I have a mold-susceptible gene. I understand this will not make a difference in treatment since so many of us humans are mold-sensitive and treatment is the same. Still, I am interested in whether I have the gene since exposure since I have been plagued with a number of sinus infections at least 1-2/ year for 10 years or so. I’m looking for some solutions. Question is how you go about testing for exposure? ARE you using ERMI? My research has led me to Chromosome 6 where the HLA genes exist. Now i need to know the specific genes and coding for the gene; ie rs-_________? Thank you for your site I found it very helpful.

    • Hi Betty,

      Sorry for the slow reply I didn’t see the notification that you’d posted. Unfortunately, assuming you have a 23andme or similar report it’s not possible to classify your HLA subtype. This comes from a more specific test, which I wouldn’t necessarily recommend.

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