FRAAs and Genetics – Finnell Study

For decades, doctors have recommended folic acid (FA) supplementation to prevent neural tube defects (NTDs) like spina bifida and anencephaly. Yet, despite widespread folate fortification programs, some women still experience NTD-affected pregnancies. Why?

New and ongoing research reveals a possible and surprising culprit: folate receptor autoantibodies (FR-autoantibodies). These immune generated autoantibodies can block folate uptake, depriving a developing fetus of this crucial nutrient. Even more intriguing, genetic variations in folate metabolism may increase a woman’s risk of producing these harmful antibodies.

This blog breaks down a groundbreaking study that explores how genetics, folate metabolism, and autoimmunity intersect to potentially influence pregnancy outcomes—and what it may mean for future prevention strategies.

Folate (vitamin B9) is essential for:
✔ DNA synthesis
✔ Cell division
✔ Neural tube formation in early embryos

Since the body can’t produce folate, we rely on:

• Dietary sources (leafy greens, legumes, fortified grains)
• Supplements (folic acid)

Folate is critical during pregnancy because of its involvement in all of the above. In fact, the United States’ food supply is fortified with folic acid (a synthetic form of folate) in an attempt to prevent neural tube defects. Unfortunately, this action has not yet eradicated neural tube defects. There must be other underlying causes.

Normally, the folate receptor-alpha (FR-α) helps transport folate into cells. This is one of the main transporters of folate, which has a very high affinity for folate. But some women produce autoantibodies against this folate receptor alpha that:

🚫 Bind to FR-α, blocking folate uptake (meaning folate cannot get into the cell)
🚫 Increase the risk of NTDs, cleft palate, autism, and infertility

This is a very important question, with limited research.  But researchers believe:

1. High homocysteine (Hcy) levels (due to low folate) cause homocysteinylation—a chemical modification of FR-α that makes it appear “foreign” to the immune system.
2. The body then attacks the modified FR-α, producing autoantibodies.
3. These antibodies cross-react with normal FR-α, further disrupting folate transport.

A team of researchers in China and at the Baylor College of Medicine in the US investigated whether genetic variations in folate metabolism genes influence FR-autoantibody levels in pregnant women. This was a very interesting study, published in 2018 in Birth Defects Research.

• 99 women with NTD-affected pregnancies
• 203 controls with healthy pregnancies

1. MTHFR rs1801133 (TT genotype)
   • 60% reduced enzyme activity, seemed to contribute to higher homocysteine
   • Strongly linked to elevated FR-autoantibodies (IgG & IgM)
2. DNMT3A rs7560488 (TT genotype)
   • First study linking this variant to higher FR-autoantibody IgG
   • Previously associated with myelomeningocele (severe spina bifida)
3. MTHFD2 rs828903 (GG genotype)
   • Increased FR-autoantibody IgM
   • May disrupt mitochondrial folate metabolism
4. No link with DHFR 19-bp deletion/insertion
   • This variant didn’t affect autoantibody levels

• Multiparous women had higher autoantibodies than first-time mothers.
• Age, BMI, and folate supplementation didn’t significantly affect antibody levels.

1. Not All Folate Supplements Work the Same
   • Women with MTHFR mutations may need methylfolate (5-MTHF) instead of folic acid. In general, it is estimated that up to 30% of people have trouble metabolizing synthetic folic acid due to genetic variations like MTHFR mutations. As a result, folic acid may not be able to be properly reduced and metabolized, thereby reducing its utility. Additionally, the presence of folate receptor autoantibodies will also impede proper folate transport and function.
   • High-dose folate might overcome antibody blockage.
2. Screening For FRAAs May Be Beneficial
   • Testing for FR-autoantibodies + genetic variants could identify high-risk women before pregnancy.
   • Immunomodulatory therapies (to reduce antibodies) may become an option. More research is required in this area.
3. More Research Is Needed
   • How exactly do these genes trigger autoantibodies? This is relatively unknown, therefore additional research is necessary. Trying to unlock the mechanism behind this would be paramount!
   • Will personalized folate regimens prevent NTDs in high-risk women? Personalized folate therapeutics may be developed if the science warrants such an endeavor!

This important study reveals a hidden connection between genetics, autoimmunity, and birth defects. While folic acid prevents many NTDs, some women remain at risk due to FR-autoantibodies driven by their DNA.

• Genetic testing (especially MTHFR) could help tailor pregnancy care.
• Future treatments may target autoantibodies, not just folate deficiency.
• If you’ve had an NTD pregnancy, ask your doctor about FR-autoantibody testing via the FRAT^® test.

By unraveling this complex interplay of genes, nutrition, and immunity, we may move closer to ending preventable birth defects—one discovery at a time.

• Should all women be screened for FR-autoantibodies with the FRAT^® test?
  • This may be a good “Best Practices” for physicians
• Could this explain other pregnancy complications?
  • It seems quite reasonable to investigate the presence of folate receptor autoantibodies in NTDs
• Will CRISPR or gene therapy one day fix these mutations
  • To be determined! Stay tuned as science uncovers more answers!

https://onlinelibrary.wiley.com/doi/10.1002/bdr2.1334

Disclaimer: This blog is for informational purposes only and not medical advice. Consult a healthcare provider for personalized recommendations. The FRAT^® test is a lab developed test performed in a CLIA certified lab. FRAT^® is NOT approved by the FDA and requires the authorization of a physician. Please consult your medical professional for more information.