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Methyl transferase hydrofolate reductase genetic variation and allergy


I have a 36-year-old female with history of asthma, allergic rhinitis, urticaria/angioedema and food allergy (peanut and some legumes) who wanted to inquire about her MTHFR gene mutation and its relation to her allergic conditions. She was found to be heterozygous for MTHFR C677T and A1298C mutation during a workup by her fertility doctor for her miscarriage. There is no history of cardiovascular disease, diabetes, or cancer. She was wondering if this gene is associated with her allergic conditions as her Google search has mentioned allergies, histamine intolerance etc. Are there any evidence base studies for any association?


The simple answer is no, there is no association with MTHFR and atopy, asthma, or mast cell activation syndrome. Methyl transferase is related to folate and dihydrofolate, particularly with formation of methionine from homocysteine and thymidine from uridine. Histamine N methyl transferase, not related to folate, is involved in histamine metabolism via methylation of histamine. The metabolism of histamine is via the methylation pathway or diamine oxidase. There are reports of multisystem complaints in subjects who suspect they have too much histamine, due to impaired metabolism or increased absorption from the diet or increased production or a combination. Some reports in lay literature conflate histamine intolerance and mast cell activation. I cannot find any compelling literature for this concept, but there are multiple descriptions of associations or perceived associations. MTHFR, involved in folate metabolism and methyl transferase, has been associated with the histamine reports and atopy partially based upon epidemiologic reports describing an association with atopy (1). However, there are more studies refuting the relationship of MTHFR and atopy or asthma (2,3,4).

In summary, there is no proven relationship between mutations in MTHFR and atopy or asthma. The existence of histamine intolerance and its potential relationship with methylation is undefined.

1. Husemoen, Lise Lotte N., et al. "The association between atopy and factors influencing folate metabolism: is low folate status causally related to the development of atopy?." International journal of epidemiology 35.4 (2006): 954-961.

2. McGowan, Emily C., et al. "Association between folate metabolites and the development of food allergy in children." The Journal of Allergy and Clinical Immunology: In Practice 8.1 (2020): 132-140.

3. Granell, R., et al. "The association between mother and child MTHFR C677T polymorphisms, dietary folate intake and childhood atopy in a populationā€based, longitudinal birth cohort." Clinical & Experimental Allergy 38.2 (2008): 320-328.

4. Thuesen, Betina Heinsbaek, et al. "Lack of association between the MTHFR (C677T) polymorphism and atopic disease." The clinical respiratory journal 3.2 (2009): 102-108.

I hope this information is of help to you and your practice.

All my best.
Dennis K. Ledford, MD, FAAAAI