Genetic pregnancy testing: Nutrigenomics for fertility

How nutrition and hormone balance are significant determinants of fertility and egg health, and how these require individualized approaches

About half of infertility cases are due to genetic causes [1]. Beyond the genes that directly cause infertility, there are nutrigenomic genes whose function you can influence with your diet and lifestyle. Modern technology has made genetic testing before pregnancy possible, and it is easy and inexpensive.

Often, understanding the genetic weaknesses correctly addressing them can help couples finally get pregnant after years of trying. 

Keep in mind, however, that since you have over 20,000 genes, trying to decipher your genetic information on your own can be overwhelming. In this article, we’ll cover different types of genetic testing before pregnancy, and how we use nutrigenomics to help our clients get pregnant despite low AMH and high FSH. 

How genetic testing helps with fertility for POF, DOR, and low AMH/high FSH

The two main categories of genetic testing before pregnancy include medical and nutrigenomics. Both can help you make appropriate management decisions [2].

In most cases, the genetic information is not diagnostic and needs to be interpreted as likelihood in context of your medical history, diet, and lifestyle. So, it’s important to work with a genetic counselor or nutrigenomic expert to prevent unnecessary overwhelm or using the wrong interventions. 

a)    Medical genetic testing for pregnancy for genes that cause infertility due to POF, DOR, or low AMH/high FSH.

Medical genetic carrier screening looks for genes that cause genetic diseases, including infertility. Preconception and prenatal genetic screening determine your risk of carrying a baby with a genetic abnormality [3]. 

Currently, some fertility doctors use screening tests for genetic testing before pregnancy to look for genes that may cause POF, DOR, and low AMH/high FSH.

These conditions are typically due to both genetics and the environment combined.

New technologies such as next-generation sequencing (NGS) have identified 75 genes linked to POI. These genes can contribute to premature ovarian insufficiency before the age of 40. 

Some of these genes relate to DNA repair and meiosis, the cell division process critical for egg production [4]. Others work in hormone production, hormone function, and follicle development [5]. 

Mutations that add DNA sequence to the FMR1 gene can cause fragile X syndrome, along with primary ovarian insufficiency with elevated FSH levels [6].

Commercial medical labs, such as Blueprint Genetics, test for some of these genes.

b)    Nutrigenomic testing 

Nutrigenomics studies how your genes influence your body’s response to food and health choices, especially when it comes to disease risks [7]. 

Your genes load the gun, while your environment pulls the trigger. These triggers can be nutrition, stress, lifestyle, inflammation, toxicity, and more.

While medical genetic testing before pregnancy typically finds genes that cause diseases, nutrigenomic tests typically find risk relationships [8]. These are milder genetic mutations that don’t overtly cause disease or infertility unless you pull the triggers with your environment. So, we often collaborate the genetic results with lab tests, such as blood and urine nutrient or hormone tests to determine if the genetic variant is at play.

Also, nutrigenomic research may tell you what you can do to avoid pulling the triggers and maximize your fertility despite your risk genes. 

Now, let’s look at a few categories of genes we test in our nutrigenomic panel and how we help our clients maximize their chance of pregnancy. 

Genetic testing for female fertility for POF, DOI, and low AMH/high FSH

A.  Vitamin conversion, delivery, and response genes

Folate

Folate (vitamin B9) is important for so many aspects of embryonic development. It forms a backbone for DNA, provides methyl groups, supports hormone balance, and reduces homocysteine [9,10].

If you have genes that affect your folate conversion, you may have suboptimal folate or methylation levels. So, you may need extra support to maximize your fertility. 

MTHFR is the best known one since it’s the bottleneck enzyme in folate activation [11]. However, other genes in this pathway and genes that produce folate transporters are also important. We also look at MTHFD1, the enzyme before MTHFR, and folate transporter genes such as FOLR1, FOLR2, and SLC19A1.

B12 (cobalamin)

A prolonged vitamin B12 deficiency can cause infertility by producing changes in the development of the egg or ovulation or changes resulting in defective implantation [12].

Vitamin B12 is also important for folate activation [13], so low B12 can increase homocysteine and thus blood clots. Elevated homocysteine is associated with unexplained infertility and miscarriage [14].

The most common form of B12 supplement is cyanocobalamin, which is often in fortified foods. However, there are other B12 that may be more effective, especially if you have certain genetic variants. These include methylcobalamin, hydroxocobalamin, and adenosylcobalamin.

Also, you need sufficient stomach acid and an intrinsic factor to absorb vitamin B12. If you have suboptimal digestion, which is common among our clients, you may need B12 through other routes, such as through the skin, under the tongue, or in your blood. Variants in TCN1 and TCN2, which absorb B12 in the stomach, influence this absorption [15].

Vitamin D

Decades of clinical studies have confirmed the role of vitamin D with regard to genetic testing for female fertility. Compared to women with low vitamin D, women who have sufficient vitamin D levels have more live births, a greater number of positive pregnancy tests, and more pregnancies [16].

Variants in vitamin D receptor (VDR) and vitamin D-binding protein (GC) may lower your response to vitamin D supplementation [17]. So, we recommend that clients with these variants routinely test for blood vitamin D levels, and supplement with vitamin D3 and K2 accordingly.

Iodine and selenium

Iodine and selenium are important for thyroid function and pregnancy. 

FOXE1 variants increase the risk of hypothyroidism and other thyroid conditions [18], so you may need to ensure that you have enough iodine and routinely check your thyroid labs.            

DIO2 converts thyroid hormones using selenium as a cofactor. Some variants in this gene correlate with low thyroid levels and insulin resistance [19].               

B. Blood clot genes

Abnormal blood clots can lead to recurrent miscarriage [20]. If you have these genes, your doctor may prescribe blood thinners during pregnancy. In our genetic panel, we test for variants inside factor V and factor X. 

C. Estrogen metabolism / estrogen dominance risk

Estrogen dominance is when you have excessive estrogen function relative to progesterone in your body. It can happen due to [21]:

• Age, as progesterone declines faster than estrogen as you age
• Inability to detox used estrogen and substances that act like estrogens (xenoestrogens), such as parabens, phthalates, and bisphenol-A
• Increased conversion of estrogen into more toxic and inflammatory forms

Estrogen dominance can contribute to polycystic ovarian syndrome (PCOS), endometriosis, fibroids, premenstrual syndrome, and infertility.

We generally recommend that all TTC couples reduce their hormone disruptor exposures as much as possible. These include switching to nontoxic skincare, cosmetics, and homecare products, and eating organic foods. This will reduce their exposure to xenoestrogens, which can contribute to infertility.

In addition, we coordinate the nutrigenomics of estrogen metabolism with the precision urine hormone test (DUTCH) so we can pinpoint how to correct your estrogen dominance. For example, both COMT and glutathione pathway genes help detox estrogen in different ways, but they need different support if you have weak versions of these genes [22,23]. 

D. Follicular sensitivity

Your ovarian reserve depends on your follicle’s sensitivity to FSH (follicle-stimulating hormone).  The sensitive follicle will get selected for maturation and ovulation. If your follicles are insensitive, you may struggle with ovulation, egg quality, and fertility.

Variants inside FSH receptors can make the follicles less sensitive to FSH [24]. These can increase the risk of PCOS [25]. Women with this variant may need to be meticulous and careful about their blood sugar and may need progesterone support during pregnancy. 

E. Metabolic risk factor

Making a baby demands a lot of your metabolism, so many women with blood sugar issues or obesity struggle with fertility. Also, they’re at a higher risk of complications once they get pregnant. In some cases, they’re not aware of their blood sugar or metabolic problems until they’re TTC or pregnant. 

Fortunately, you can address most of these metabolic problems naturally – with the right diet, exercise, and supplemental support. Knowing your genetic tendencies for these problems can help you become proactive about them. For example, some genetic variants may make saturated fats extra bad for your metabolic risk, or you may need more magnesium to prevent hypertension. 

To get your genes tested and interpreted by our holistic fertility coach, book a consultation here.

References

1. Zorrilla M, Yatsenko AN. The Genetics of Infertility: Current Status of the Field. Curr Genet Med Rep. 2013;1. doi:10.1007/s40142-013-0027-1
2. Foresta C, Ferlin A, Gianaroli L, Dallapiccola B. Guidelines for the appropriate use of genetic tests in infertile couples. Eur J Hum Genet. 2002;10: 303–312. doi:10.1038/sj.ejhg.5200805
3. Carrier Screening. [cited 23 Dec 2021]. Available: https://www.acog.org/womens-health/faqs/carrier-screening
4. França MM, Mendonca BB. Genetics of Primary Ovarian Insufficiency in the Next-Generation Sequencing Era. J Endocr Soc. 2020;4: bvz037. doi:10.1210/jendso/bvz037
5. Chapman C, Cree L, Shelling AN. The genetics of premature ovarian failure: current perspectives. Int J Womens Health. 2015;7: 799–810. doi:10.2147/IJWH.S64024
6. Hunter JE, Berry-Kravis E, Hipp H, Todd PK. FMR1 Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1998. Available: https://www.ncbi.nlm.nih.gov/pubmed/20301558
7. NCI dictionary of Cancer Terms. In: National Cancer Institute [Internet]. 2 Feb 2011 [cited 23 Dec 2021]. Available: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/nutrigenomics
8. Neeha VS, Kinth P. Nutrigenomics research: a review. J Food Sci Technol. 2013;50: 415–428. doi:10.1007/s13197-012-0775-z
9. Forges T, Monnier-Barbarino P, Alberto JM, Guéant-Rodriguez RM, Daval JL, Guéant JL. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007;13: 225–238. doi:10.1093/humupd/dml063
10. Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nat Rev Genet. 2001;2: 21–32. doi:10.1038/35047554
11. CDC. MTHFR gene, folic acid, and preventing neural tube defects. In: Centers for Disease Control and Prevention [Internet]. 7 Jul 2020 [cited 23 Dec 2021]. Available: https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.html
12. Bennett M. Vitamin B12 deficiency, infertility and recurrent fetal loss. J Reprod Med. 2001;46: 209–212. Available: https://www.ncbi.nlm.nih.gov/pubmed/11304860
13. Surendran S, Adaikalakoteswari A, Saravanan P, Shatwaan IA, Lovegrove JA, Vimaleswaran KS. An update on vitamin B12-related gene polymorphisms and B12 status. Genes Nutr. 2018;13: 2. doi:10.1186/s12263-018-0591-9
14. Dubey P, Gupta N, Dwivedi S, Swaroop N, Lal P, Thawani V. Hyperhomocysteinemia: a risk factor in unexplained infertility. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2016;2: 165–171. Available: https://www.ijrcog.org/index.php/ijrcog/article/view/203
15. Hu Y, Raffield LM, Polfus LM, Moscati A, Nadkarni G, Preuss MH, et al. A common TCN1 loss-of-function variant is associated with lower vitamin B12 concentration in African Americans. Blood. 2018;131: 2859–2863. doi:10.1182/blood-2018-03-841023
16. Pilz S, Zittermann A, Obeid R, Hahn A, Pludowski P, Trummer C, et al. The Role of Vitamin D in Fertility and during Pregnancy and Lactation: A Review of Clinical Data. Int J Environ Res Public Health. 2018;15. doi:10.3390/ijerph15102241
17. Laing B, Ferguson LR. Genetic variations in Vitamin D metabolism genes and the microbiome, in the presence of adverse environmental changes, increase immune dysregulation. Austin J Nutr Metab. 2015. Available: https://www.researchgate.net/profile/Bobbi-Laing-campbell/publication/282981065_Austin_Journal_of_Nutrition_Metabolism_The_Vitamin_D_Receptor_Gene_VDR/links/56257e2808aeedae57daeb65/Austin-Journal-of-Nutrition-Metabolism-The-Vitamin-D-Receptor-Gene-VDR.pdf
18. Denny JC, Crawford DC, Ritchie MD, Bielinski SJ, Basford MA, Bradford Y, et al. Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies. Am J Hum Genet. 2011;89: 529–542. doi:10.1016/j.ajhg.2011.09.008
19. Verloop H, Dekkers OM, Peeters RP, Schoones JW, Smit JWA. Genetics in endocrinology: genetic variation in deiodinases: a systematic review of potential clinical effects in humans. Eur J Endocrinol. 2014;171: R123–35. doi:10.1530/EJE-14-0302
20. Bick RL, Hoppensteadt D. Recurrent miscarriage syndrome and infertility due to blood coagulation protein/platelet defects: a review and update. Clin Appl Thromb Hemost. 2005;11: 1–13. doi:10.1177/107602960501100101
21. Whole health library. [cited 23 Dec 2021]. Available: https://www.va.gov/WHOLEHEALTHLIBRARY/tools/estrogen-dominance.asp
22. Schendzielorz N, Rysa A, Reenila I, Raasmaja A, Mannisto PT. Complex estrogenic regulation of catechol-O-methyltransferase (COMT) in rats. J Physiol Pharmacol. 2011;62: 483–490. Available: https://www.ncbi.nlm.nih.gov/pubmed/22100850
23. Saxena A, Dhillon VS, Shahid M, Khalil HS, Rani M, Prasad DAS T, et al. GSTP1 methylation and polymorphism increase the risk of breast cancer and the effects of diet and lifestyle in breast cancer patients. Exp Ther Med. 2012;4: 1097–1103. doi:10.3892/etm.2012.710
24. Renzi A, Petersen CG, Vagnini LD, Oliveira-Pelegrin GR, Mauri AL, Massaro FC, et al. The fshr gene polymorphism (rs 6165 – ala/ala genotype) is associated with the use of higher doses of recombinant FSH during IVF/ICSI treatment. Fertil Steril. 2014;102: e120–e121. doi:10.1016/j.fertnstert.2014.07.412
25. Laven JSE. Follicle Stimulating Hormone Receptor (FSHR) Polymorphisms and Polycystic Ovary Syndrome (PCOS). Front Endocrinol . 2019;10: 23. doi:10.3389/fendo.2019.00023