FOXD1 variants and recurrent miscarriage

Researchers found that women with variations in their FOXD1 gene are TEN times more likely to have recurrent miscarriage compared to women without these variants. This is a more potent cause for miscarriage than any previously studied factor. In fact, FOXD1 variants were found ONLY in women with recurrent miscarriage. They were not found in women without recurrent miscarriage.

Recurrent miscarriage background

Recurrent miscarriage (RSA) is clinically defined by at least three pregnancy losses prior to the 20th week of pregnancy. Approximately 1% of couples attempting pregnancy will suffer from RSA. Evaluation of the causes of RSA is extensive and includes evaluating a woman for problems with her uterus, immune system, hormones, blood clotting system, and testing for possible systemic diseases such as infections, diabetes and Celiac disease. Both the woman and her partner also have a chromosome analysis.

However, roughly 50% of the time, the causes(s) of RSA are not found. Numerous attempts have been made to look for specific gene mutations that may cause RSA. Several candidate genes (e.g. AMN, TM, EPCR, VEGF, p53, eNOS, JAK2, MTHFR, WNT6) have been studied but definitive evidence that they cause RSA was lacking.

One theory to explain the lack of ability to find a candidate gene is that reproduction is such a complex process that RSA might be caused by the accumulated effects of hundreds of genes and their interactions with the environment. This is known as a quantitative trait. Another example of a quantitative trait is height. There isn’t one gene that determines whether someone will be taller or shorter. There are hundreds of genes which, by themselves, only have a tiny impact on height but together can add up to a big difference.

Using this theory of miscarriage as a quantitative trait, researchers, using a mouse experimental model, identified a possible gene that is important in human reproduction. This gene is known as the FOXD1 gene. This gene is located on the long arm of chromosome 5. FOXD1 seems to control two crucial genes implicated in pregnancy maintenance.

PGF (Placental Growth Factor) gene

The PGF gene is very active in placental cells (which come from the fetus) and the uterine lining (which comes from the mother). The PGF protein helps promote new blood vessel formation. For a successful pregnancy, new blood vessels must be formed in the uterus to bring the needed nutrients and oxygen to the placenta. Uterine NK cells are a type of white blood cells that are found in the uterine lining and are thought to be essential for helping the immune system communicate with the cells of the placenta. It has also been shown that uterine NK cells play an important role in the formation of new blood vessels in the uterine lining. NK cells also have very active PGF genes.

C3 (Complement 3) gene

In order to understand the importance of the C3 gene, it is first important to understand the complement system. The complement system is a series of proteins that are part of the immune system that enhances (complements) the ability of antibodies and immune cells to fight off infections from bacteria and viruses and remove damaged cells from an organism.

During a normal pregnancy, the mother’s immune system attacks the “foreign” cells of the placenta using the complement system. In order for a pregnancy to survive, the mother’s complement system must be regulated just the right amount. Either too much or too little regulation of the complement system will result in loss of the pregnancy.

One of the proteins in the complement system is called C3 (it is produced by the C3 gene). If the C3 gene is over active or under active, it can overwhelm the delicate balance and allow the mother’s complement system to destroy the placenta and cause a miscarriage.

Where does the FOXD1 gene come in?

The FOXD1 gene acts as sort of a master controller of other genes. Scientists have identified different variants in this gene. These variants have different effects on the Pgf and C3 gene activity.

 FOXD1-Ala356Gly  Decreased PGF Reduced blood vessel formation
  Decreased C3 Complement destroys placenta
 FOXD1-429AlaAla  Decreased PGF Reduced blood vessel formation
  Increased C3 Complement destroys placenta
 FOXD1-Ile364Met No effect on PGF None
  Increased C3 Complement destroys placenta

Is there a treatment?

There are no studies that have looked at the treatment of FOXD1 variants for improving the chance for live birth in patients with RSA. However, use of heparin may be of benefit for those women whose FOXD1 mutations increase C3 levels and / or lower PGF levels.

Another cause for RSA are high levels of antiphospholipid antibodies (APA). These antibodies also cause miscarriage by activating the complement system. Heparin, which is normally used as a treatment for blood clotting, can block the activation of complement. Heparin has been used safely as a treatment for APA induced miscarriage for many years.

In order to work, PGF must first attach to a receptor. Heparin has also been shown to help the PGF protein to bind to its receptor and so it increases PGF activity. It is possible that even if PGF levels near the placenta are low that heparin might be able to help compensate.

Aldosterone increases PGF. Especially under low glucose conditions. Changes to your diet can increase aldosterone levels. Cutting sodium intake will increase aldosterone and high levels of potassium will also.

Platelet rich plasma or PRP contains high concentrations of platelets. Platelets contain a number of growth factors including PGF, platelet-derived angiogenesis factor (PDAF) and vascular endothelial growth factor (VEGF). Infusion of PRP into the uterine cavity could result in increased blood vessel formation despite a PGF deficiency.

However, heparin would not be advised for those variants that already have reduced C3 levels. It is also possible that heparin might block the complement too much and also result in miscarriage.