Angela Knapp: Applying Genetic Polymorphisms to Fertility

Angela Knapp, Executive Director of Martha’s Vineyard Youth Task Force, shared a post on LinkedIn:

“Applying Genetic Polymorphisms to Fertility – part I

The clinical utility of the Defy Your DNA program does not end with the report. The multiple SNPs tested on the DYD offer further information related to myriad health concerns. For example, genetic polymorphisms covered in the DYD panel can be applied to infertility.

Nearly 50% of couples under the age of 30 years old are unable to conceive within their first 3 months of trying and 12-15% of couples are unable to conceive within the first year. One third of infertility issues are due to the male, one third are due to the female and one third have an unidentified cause within the conventional medical model.

Some of the most well studied SNP’s related to infertility involve MTRR, MTR and MTHFR.  Some of the less well researched, but remarkable SNPs related to fertility and recurring spontaneous abortion include CYP 1A1, NOS3, the vitamin D receptor genes and APOE.

Also available from Kashi Health are the Factor II and V polymorphisms that play a role in fetal loss. And it very well may be a combination of these SNPs with multiple factors that lead to infertility.

Nevertheless, investigation into the presence of relevant single nucleotide polymorphisms and the resulting ability to bypass biochemical obstructions may support increased ability to conceive and maintain pregnancy.

Homocysteine is a well-known cardiovascular risk factor, but did you know homocysteine levels play a role in determining pregnancy outcomes?

Homocysteine conversion into methionine is reliant on MTHFR, MTR and MTRR enzymes. While MTHFR (methylenetetrahydrofolate reductase) is an enzyme that converts folate into its active form allowing it to enter the methionine cycle, MTR (methionine synthase) and MTRR (methionine synthase reductase) both relate to cobalamin’s role in the methionine cycle.

MTR is responsible for introducing 5-MTHF into the methionine cycle while MTRR is responsible for the recycling of B12 into the active form, methylcobalamin, before it can be used to convert homocysteine into methionine.

The root word in these products is meth- implying the transfer of a methyl group or one-carbon group which is integral to biochemical pathways throughout our physiology.

A recent 2016 study of 51 women with preeclampsia found elevated levels of plasma homocysteine coupled with low serum folate and B12.

Because elevated levels of homocysteine may correlate with reduced transulfuration, a 2016 study from Reproductive Biomedicine Online postulates that reduces transulfuration causes oxidative stress by preventing sufficient production of the body’s master intracellular antioxidant, glutathione.

A smaller study showed that the rate of MTHFR C677T and elevated homocysteine was significantly higher in unexplained female sterility and recurrent pregnancy loss as compared to the control group.Additionally, low follicular fluid homocysteine level is associate with a better chance of clinical pregnancy in assisted reproduction.

In 2014, an article titled Folate Metabolism and Human Reproduction showed improved anti-mullerian hormone levels and increased egg retrieval in IVF patients with MTFHR C677T after supplemented with 0.8 mg of folate.

A 2015 Chinese meta-analysis confirmed that MTRR 66A>G and MTR 2756 A>G were significantly associated with increased neural tube defects.

Previously, a 2013 meta-analysis found MTRR A66G was associated with neural tube defects but MTR 2756 did not have a significant correlation.

Environmental Epigenetics published a fascinating mouse study in 2017 expressing the role of MTRR mutations in growth defects and congenital malformations. The exceptional outcome of this study touted the generational adaptation of female mice with the polymorphism became more sensitive to folate rich environments.

As we know, humans do not evolve quite as quickly as the mouse model which suggest increased folate and cobalamin supplementation may be beneficial.

Our ability to metabolize nutrients plays an vital role in our health, including the ability to conceive and maintain pregnancy. There are multiple SNPs that may be interfering with our ability to conceive.

Single nucleotide polymorphism testing offers clues into the infertility puzzle. Identifying key SNPs allows direct supplementation and the potential to improve fertility outcomes.

1. Chandra, A., Copen, C.E., and Stephen, E.H. (2013). Infertility and Impaired Fecundity in the United States, 1982-2010: Data From the National Survey of Family Growth. National Health Statistics Reports, 67, 1-19. Retrieved February 7, 2018, from (PDF – 328 KB)
2. Shahbazian, N., Jafari, R. M., and Haghnia, S. (2016). The evaluation of serum homocysteine, folic acid, and vitamin B12 in patients complicated with preeclampsia. Electronic Physician, 8(10), 3057–3061.
3. Menezo YJ, Silvestris E, Dale B, Elder K. (2016) Oxidative stress and alterations in DNA methylation: two sides of the same coin in reproduction. Reproductive Biomedicine Online, 33(6):668-683.
4. D’Uva, M., Di Micco, P., Strina, I., Alviggi, C., Iannuzzo, M., Ranieri, A., … De Placido, G. (2007). Hyperhomocysteinemia in women with unexplained sterility or recurrent early pregnancy loss from Southern Italy: a preliminary report. Thrombosis Journal, 5, 10.
5. Ocal, P., Ersoylu, B., Cepni, I., Guralp, O., Atakul, N., Irez, T., & Idil, M. (2012). The association between homocysteine in the follicular fluid with embryo quality and pregnancy rate in assisted reproductive techniques. Journal of Assisted Reproduction and Genetics, 29(4), 299–304.
6. Thaler, C. J. (2014). Folate Metabolism and Human Reproduction. Geburtshilfe Und Frauenheilkunde, 74(9), 845–851.
7. Wang, Y., Liu, Y., Ji, W., Qin, H., Wu, H., Xu, D., … Wang, Z. (2015). Analysis of MTR and MTRR Polymorphisms for Neural Tube Defects Risk Association. Medicine, 94(35), e1367.
8. Padmanabhan, N., Rakoczy, J., Kondratowicz, M., Menelaou, K., Blake, G. E. T., & Watson, E. D. (2017). Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolism. Environmental Epigenetics, 3(4), dvx014.”

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