Improving male sperm function by identifying genetic variants in one-carbon nutrient pathways
Key Highlights
- Male fertility issues are estimated to account for up to 50% of infertility cases worldwide.
- Common misspellings in genes that influence sperm function can lead to impaired one-carbon nutrient metabolism, low sperm ATP concentrations, and decreased motility of sperm.
- Because the one-carbon nutrients methylfolate, choline, and betaine are closely linked to sperm cell function, individualized supplementation with these nutrients for patients who test positive for certain genetic variants can improve sperm ATP concentrations, which are important for normal motility and fertility.
- SNP Therapeutics has patented a genetic test, algorithm, and nutrition treatment approach for male factor low sperm ATP concentrations. By identifying and treating genetically induced metabolic blockages that interfere with sperm function, SNP Therapeutics’ program can improve patient outcomes and provide hope to couples facing infertility.
Introduction
Infertility is a prevalent concern worldwide, affecting an estimated 8-12% of couples. Of this number, approximately 50% of cases are due to male factor infertility. While fertility rates can be influenced by a number of factors, studies indicate that genetic aberrations such as chromosomal deletions, translocations, and single nucleotide polymorphisms (SNPs) are the underlying mechanism in up to 30% of infertility cases.
The one-carbon nutrients choline and betaine play critical roles in sperm motility as well as sperm cell mitochondrial structure and ATP concentrations. Metabolism of these nutrients can be affected by two common SNPs that result in altered levels of the above parameters. Choline and betaine can be obtained from the diet, but men who have one or both of the SNPs that affect choline and/or betaine metabolism may have higher dietary needs to support normal sperm function.
In response to a need for improved identification and treatment of individuals with genetic causes of infertility, SNP Therapeutics has developed a patented genetic test and targeted nutrition approach for male factor infertility. By determining each person’s genetic signature with an algorithmic system that examines hundreds of related SNPs, an individualized nutrition care plan can be implemented to treat male infertility and improve conception rates.
The Role of Genetic Variants in Sperm Function
nimal and human studies have established the role of genetics in male factor infertility, as reflected by the impact of the choline dehydrogenase (CHDH) gene on a number of parameters indicative of sperm function. CHDH is an enzyme that catalyzes the conversion of the one-carbon nutrient choline to betaine. Misspellings in one or both alleles of the CHDH gene will result in blockages in the choline-to-betaine pathway, causing a cascade of effects in the body, including effects on sperm function. In mice, deletion of the CHDH gene results in decreased ATP concentrations in sperm cells as well as impaired sperm motility, which is due to altered mitochondrial structure in these cells.
A common SNP (rs12676) has been found in the CHDH gene, with up to 40% of men and women identified as carriers of at least one altered allele in clinical studies.3,4 People with this SNP are more susceptible to organ dysfunction from dietary choline deficiency, and men with rs12676 also have higher rates of abnormal sperm mitochondrial structure, decreased sperm activity, and altered sperm motility. In addition, both sperm cells and hepatocytes from men who are homozygous for rs12676 have lower levels of CHDH protein. CHDH gene expression is also reduced in sperm cells of men homozygous for rs12676, indicating that this is a functional SNP.
While not in the CHDH gene itself, a SNP on the adjacent gene interleukin 17 beta receptor (IL17βR) has also been linked to male factor infertility. IL17βR can be affected by the variant rs1025689, which is specifically associated with higher rates of choline deficiency-induced symptoms in men and has been shown to cause altered sperm motility as well.6
In a 2012 study, researchers at UNC Chapel Hill found that men who were homozygous for rs1025689 had lower sperm counts compared to men who were heterozygous for this SNP. Sperm from men who were homozygous for the rs1025689 SNP also had lower levels of betaine and the cell membrane phospholipids glycerophosphocholine (GPCho) and phosphatidylcholine (PtdCho). All three of these compounds are metabolites of choline and would be expected to decrease with lower choline availability.
Thus, data from both animal and human studies points to the influence of rs12676 and rs1025689 SNPs on sperm function and one-carbon nutrient metabolism. The rs12676 SNP in particular appears to be linked to impaired CHDH activity, leading in turn to altered sperm function via the mechanisms described above. Both altered sperm motility and decreased ATP concentrations result in lower sperm activity and decreased fertility. Fortunately, betaine supplementation can correct fertility-related effects due to rs12676, returning both sperm motility and ATP levels to normal.
How Nutrition Affects Sperm Function
Not only are genetic factors linked to sperm health, but specific nutrients also impact male fertility. As outlined above, nutrition and genetics are intertwined such that genetic aberrations can cause missteps in a number of metabolic pathways, affecting an individual’s need for certain nutrients by changing the rate and efficiency with which their body metabolizes those nutrients.
Deficiencies of vitamins A, C, and E, as well as zinc and selenium, have been associated with male infertility in both human and animal studies. In addition, both the one-carbon nutrient choline and the CHDH enzyme are essential for normal male fertility.8 As mentioned previously, studies in mice have demonstrated that deletion of the CHDH gene results in markedly impaired sperm motility due to abnormal mitochondrial structure.
Another one-carbon nutrient, betaine, has been proposed as a necessary nutrient for normal sperm function as well. When the CHDH gene is deleted, mice sperm cells are characterized by low concentrations of ATP. If those animals are then supplemented with betaine (essentially bypassing the need for CHDH by supplying the end product of the reaction it catalyzes), ATP concentrations return to normal and progressive motility of sperm improves.
Betaine acts as an osmolyte, protecting sperm cells in osmotically stressful environments such as the epididymis. When betaine levels are low, which could be caused by either a missing CHDH gene or the rs12676 SNP on the CHDH gene, osmotic stress increases. This leads to activation of phospholipase A2, an enzyme that catalyzes a series of reactions resulting in the release of the fatty acids DHA and AA. Both of these fats inhibit sperm motility. In addition, mice without the CHDH gene have lower levels of PtdCho and GPCho, which normally help to protect sperm cells from osmotic stress. The 2012 study at UNC Chapel Hill also found that sperm cells from men with the rs1025689 SNP had lower concentrations of both of these phospholipids as well as betaine.
SNP Therapeutics Genetic Test and Nutrition Treatment for Poor Sperm Function
Research has demonstrated that men with one fertility-related SNP are highly likely to have the second SNP as well. In the 2012 study, for example, the presence of two minor rs12676 alleles carried a 100% chance of one minor allele for rs 1025689 and an 83% chance for both minor rs1025689 alleles, highlighting the interrelated nature of these genes.
By examining multiple genes that code for the one-carbon nutrient pathways related to sperm function, SNP Therapeutics has developed a powerful and effective tool for identifying and treating genetic conditions responsible for poor sperm function. SNP Therapeutics’ patented algorithm, developed from a clinical study of 246 men, uses a machine learning/AI model to determine the genetic signature of each individual.
Using each patient’s test results, a nutrition formulation is then created to address their requirements for the nutrients affected by their genetic signature. This method greatly increases the effectiveness of supplementation by tailoring nutrient types and levels to each individual rather than using population-wide nutrition guidelines, which do not take into account genetically-induced variations in nutrient metabolism.
Considerations for Practice
SNP Therapeutics patented test and nutrition treatment program provides genetic test results to healthcare practitioners and their patients, along with a comprehensive report that details each patient’s genetic signature and explains how the findings may impact their risk of poor sperm function. An individualized nutrition treatment plan developed from the test results is also provided in thorough, yet easily understandable language.
Partnering with SNP Therapeutics to provide a precise genetic test for couples at risk of or already experiencing idiopathic male factor infertility allows you to give individualized care that is truly cutting-edge. By addressing each patient’s nutritional needs based on their genetic test results, you can improve outcomes for your male patients with infertility issues, allowing couples to avoid the expense of assisted reproductive technologies such as in vitro-fertilization (IVF).
Gene-guided nutrition is the future of individualized healthcare. By tailoring nutrition treatment plans for each patient’s genetic signature, health outcomes could look very different for the next generation.