MTHFR and Vaccination: Much Ado About Nothing

Increasingly parents are coming to their children’s doctors with questions about MTHFR and vaccination. Can their child get a vaccination if the kid has tested positive for a genetic variation of MTHFR? Will their child be able to metabolize the vaccine ingredients? Whether on a blog, in a book, or from a friend, parents are finding statements that they should avoid vaccinations for any child with an “MTHFR mutation.” And they are (understandably) worried. But should they be?

What is MTHFR and why do we have it?

The object of all this fuss is an enzyme, methylenetetrahydrofolate reductase. (You can see why it’s abbreviated to MTHFR.) This enzyme has just one job: to help you convert one form of folate (5, 10-methylenetetrahydrofolate) to another form (5-methyltetrahydofolate, fondly known as 5-MTHF) [1]. In the process of doing so, homocysteine is converted to methionine [2]. The products of this interaction in turn are involved in many different processes in the body, ranging from regulation of genetic expression to the production of neurotransmitters.

MTHFR is a very old enzyme found in a variety of organisms. Like languages and barbecue recipes, it has developed a number of variations. The genetic variations that encode for these variations are called polymorphisms, and are found in up close to half of the US population. Two common polymorphisms are known as C677T and A1298C. The first variation, C677T, reduces enzyme function up to 40% in those who carry one copy of it (these are heterozygous carriers). C677T reduces MTHFR function by up to 70% in those who are homozygous or carry two copies of the SNP [3]. Up to 25% of Hispanics and 15% of non-Hispanic whites in the US are homozygous or have two copies of C677T, for instance. Considerably more individuals have at least one copy of C677T or A1298C [4]. These common genetic variations are what most people mean when they talk about “MTHFR.”

“Variation? I was told my child had a mutation!”

In order for a genetic variation to be a mutation, it needs to be rare — as in present in 1% or less of the population. Since the MTHFR variants mentioned above are considerably more common than that, it’s not a mutation. As well, we often think of a genetic variations as being the types of genetic mutations associated with congenital defects. However, as genetic testing has become more common and more genetic variations have been discovered, we have realized that variation is normal. Genetic variations bestow resilience and diversity.

Common genetic variations usually (though not always) are different than the type of mutations associated with congenital defects. Many common polymorphisms stick around for a reason: because they provide a benefit. And as it turns out, MTHFR variations such as C677T may provide a variety of benefits for those who have it, such as (in the case of C677T) reduced rates of colon cancer and some types of leukemias [5]. There may be other benefits. There’s a catch, though: C677T evolved in groups that had higher amounts of folates in their diets [6]. The benefits of C677T only show up if the person gets enough folate. Otherwise, for those who have two copies of the gene for C677T, some problems may develop: a risk of increased homocysteine or for having a child with a neural tube defect. (At one point it was thought it would raise the risk of having a blood clot [7], but more recent evidence has called that into question. [8]) But in general, even for someone with two copies of the C677T SNP, getting enough folate reduces or eliminates the risks associated with the variation. (The research on A1298C is conflicting regarding what risks, if any, are associated with it.)

One reason for the lack of harm may be because the body almost never has just one pathway for anything critical. For instance, MTHFR is not the only way for the body to convert homocysteine to methionine. As science has looked more closely at MTHFR polymorphisms, it’s become obvious that they are just normal variations, like eye color differences. They are not genetic anomalies that doom their bearers to sickness.

So what’s the problem with MTHFR and Vaccination?

Interestingly, even the writers of the blogs, the authors of the books, the recorders of the videos and podcasts don’t come right out and say what the problem is supposed to be with giving vaccines to those with MTHFR polymorphisms. However, many imply that it will lead to adverse events after vaccination (e.g. “vaccine injury”). They do not, however, substantiate this allegation. Many blogs I looked at just stated “don’t vaccinate” with no further rationale provided, let alone any references. A few provided a rationale (e.g. that it would supposedly impair the ability to “metabolize toxins”). Fewer still provided references — and those provided did not relate to the allegation. None addressed the question of “is there any proof that MTHFR causes vaccine injury?”

When making a claim that something beneficial causes harm, it’s important to show evidence that it actually causes harm. Given how common the C677T and A1298C polymorphisms are, if they did cause problems with vaccination, we would see a much higher rate of significant adverse events [9]. However, the rate of serious adverse events is much, much, much lower — by many orders of magnitude — than the occurrence of C677T and A1298C in the population. Fewer than one in a million children have a serious reaction to a vaccination [10]. Twenty-five percent of Hispanics (1 in 4) and 15% of non-Hispanic whites (roughly 1 in 6) are homozygous for C677T, but only 1 in 14,000-16,000 people receiving DTaP have a moderate or severe reaction, like high fevers over 105F, or seizures. Since 40% of the US population has one copy of the C677T or A1298C polymorphisms, but far, far fewer have even a moderate reaction to vaccinations, it’s obvious that these MTHFR variants aren’t linked to vaccination reactions.

The one study referenced by some sites making this claim is a 2008 study that looked at the rate of adverse events after smallpox vaccination in adults with MTHFR polymorphisms compared to controls [11]. The problems with using this to support a recommendation against vaccination in MTHFR are:

• The “adverse events” consisted of mildly higher fevers, swollen lymph glands, and some skin rashes in a few individuals.
• Smallpox vaccine was notorious for causing adverse events. If the worst “vaccine injury” it caused in those with MTHFR variations were the mild effects listed above, it’s highly unlikely that MTHFR would cause any noticeable problems with the vaccines on the childhood vaccine schedule, which are tame in comparison.
• Finally, smallpox vaccine is no longer given today. If ever there is a reason to give it again (e.g. biological warfare), parents would gladly trade the “adverse effects” shown above for the real-life devastation caused by smallpox.

Extensive searches of PubMed turned up no other studies linking MTHFR to adverse effects of vaccination. Additional searches through the internet, including discussion forums and freely—available lecture materials and books from speakers on the topic showed no evidence presented for the claim.

Update, 05-29-2019:

In a May 2019 article in The Atlantic, “Why Anti-vax Doctors Are Ordering 23andMe tests”,  Sarah Zhang talked with the authors of this 2008 paper on smallpox vaccine and MTHFr,  David Reif and James Crowe. James Crowe notes that:  ‘“It’s just not even a valid study by today’s methodology.” To use it for granting vaccine exemptions now, he says, is “illogical and inappropriate.”’ The Atlantic article goes on to discuss that the original studies suggesting that MTHFr had adverse effects were not borne out by later studies. [12]

No evidence of harm

Claims of harm need to be backed up with proof. This is especially true when asking people to avoid doing something that is beneficial, such as getting vaccines. Yet the numerous materials checked for this article failed to support their claims.

Some sites that claim MTHFR reduces the ability of the liver to “metabolize toxins” alluded to the theoretical concern that MTHFR polymorphisms might reduce the amounts of glutathione produced by the liver through the transsulfuration pathway. Setting aside the allegation that the minute amounts of excipients in vaccines are toxic (a claim that has been refuted repeatedly by studies showing that vaccines are safe [13]), the claim that MTHFR affects liver detoxification pathways has not been proven. It’s not that liver detoxification hasn’t been studied. And glutathione is being studied intensely at this time. But the pathways that MTHFR affects are not involved in liver detoxification. Glutathione production, for instance, is regulated most heavily by glutathione synthetase and the availability of cysteine. And glutathione, too, is produced by numerous different pathways [14].

An extensive search of the literature did turn up one (recent) study looking at the effect of MTHFR polymorphisms on glutathione production. It found that retinas from mice with MTHFR polymorphisms had as much glutathione as did retinas from mice without the MTHFR variations [15].

The articles don’t present any other evidence or rationale for their claims that MTHFR might impede liver detoxification functions. There are some vague references to a few small-sample studies looking at levels of glutathione in children with autism, and some others looking at the incidence of MTHFR polymorphisms in children with autism. Some of these appear to be in the same study, and the matter is not yet settled. However, this does not prove any link between MTHFR and glutathione (or autism), as the studies did not establish that link.

So claims are made, but no evidence of harm is provided, and there is no evidence that the MTHFR variations have the effect they are claimed to have.

Conclusion

In “Much Ado About Nothing”, Shakespeare has his characters come together — and draw apart — based upon nothing but ill-founded rumors. Similarly, the claim that those with MTHFR should not be vaccinated appears to be founded upon rumors and hearsay — nothing more.

As a parent, I understand very well the desire to protect children from risks. In deciding what risks are worth taking action on, we weigh out known benefits against what we know of the risks. It’s understandable and prudent to investigate even rumored risks. But if the claims of risk are unfounded, unsubstantiated, or simply a rumor, we don’t let it outweigh the known benefits.

Over and over again, studies show that vaccinations are safe and provide well-known, well-studied benefits for children (and adults). The claims of MTHFR variations being a problem in vaccination, on the other hand, are rumors. Don’t let rumors about MTHFR put your child at risk of disease.

Got MTHFR? It’s okay. No need to fear vaccines. You can vaccinate!

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[1] http://omim.org/entry/607093

[2] Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. Journal of Inherited Metabolic Disease. 2011;34(1):75–81. doi:10.1007/s10545–010–9177–4.

[3] Kim Robien, Cornelia M. Ulrich; 5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Leukemia Risk: A HuGE Minireview, American Journal of Epidemiology, Volume 157, Issue 7, 1 April 2003, Pages 571–582, https://doi.org/10.1093/aje/kwg024

[4] Dean L.. Methylenetetrahydrofolate Reductase Deficiency. Medical Genetics Summaries. NCBI; Last updated October 27, 2016; https://www.ncbi.nlm.nih.gov/books/NBK66131/. Accessed November 15, 2017.

[5] Rosenberg N, Murata M, Ikeda Y, et al. The Frequent 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphism Is Associated with a Common Haplotype in Whites, Japanese, and Africans. American Journal of Human Genetics. 2002;70(3):758-762.

[6] I am using folates to refer to all sources of folate, including folic acid. To date folic acid has not been found to cause harm, in the general population, when taken as advised by a licensed medical provider. However, please do not take supplements without talking to your healthcare provider first; they can interact with medications and conditions. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257747/.

[7] https://rarediseases.info.nih.gov/diseases/10953/mthfr—gene—variant

[8] Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6. doi: 10.1038/gim.2012.165. Epub 2013 Jan 3. Retrieved 11/27/2017

[9] Significant adverse events include convulsions and anaphylaxis.

[10] http://www.vaccines.com/vaccine—side—effects.cfm

[11] Reif DM, McKinney BA, Motsinger AA, et al. Genetic Basis for Adverse Events Following Smallpox Vaccination. The Journal of infectious diseases. 2008;198(1):16–22. doi:10.1086/588670.

[12] Zhang S. Why Anti-vax Doctors Are Ordering 23andMe Tests. The Atlantic. May 2019. https://www.theatlantic.com/science/archive/2019/05/vaccines-dna-23andme/589915/. Accessed May 29, 2019.

[13] http://www.vaccines.com/vaccine—side—effects.cfm

[14] Lu SC. REGULATION OF GLUTATHIONE SYNTHESIS. Molecular aspects of medicine. 2009;30(1–2):42–59. doi:10.1016/j.mam.2008.05.005

[15] Analysis of MTHFR, CBS, glutathione, taurine, and hydrogen sulfide levels in retinas of hyperhomocysteinemic mice. / Cui, Xuezhi; Navneet, Soumya; Wang, Jing; Roon, Penny; Chen, Wei; Xian, Ming; Smith, Sylvia B. In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 4, 01.04.2017, p. 1954–1963