The FOLR1 (folate receptor alpha) gene produces a folate receptor that is responsible for transporting folate and its derivatives into cells. Variations in this gene can affect the delivery of folate in the bloodstream to cells. A study found that individuals who were heterozygous for the polymorphism rs2071010 had elevated serum folate levels compared to those with the GG genotype, suggesting that the A allele may reduce FOLR1 function. Additionally, individuals with the AA genotype may be at increased risk for elevated homocysteine levels.

Folate Receptor 2 (FOLR2) is a member of the folate receptor (FOLR) family. Members of this gene family have a high affinity for folic acid. Polymorphisms in this gene allow for poor delivery of folic acid to the interior of cells. This can create a high plasma folic acid. This polymorphism does create a methylation deficiency. This polymorphism is associated with many disorders of pregnancy. This receptor is found in high quantities on the placenta, thymus and bone marrow. Can be affiliated with immune disorders.

Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid. This enzyme is the second enzyme in the folic acid conversion chain. Having a mutation in this enzyme can create a methylation deficiency with a MTHFR mutation.

AHCY helps breakdown S-adenosylhomocysteine (SAH), which is a strong inhibitor of methyltransferase activity.

Methylenetetrahydrofolate Dehydrogenase 1 enzyme handles 2 significant enzymes conversions in the production of L-MTHF. This common polymorphism causes a significant methylation deficiency due to the fact that it is utilized in two steps in methyl-folate production.

The MTHFR (methylenetetrahydrofolate reductase) gene encodes a metabolic enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (MTHF), the bioactive form of folate. Folate is a crucial mediator of one-carbon metabolism, which is necessary for a plethora of biochemical functions, such as nucleotide biosynthesis, amino acid metabolism, epigenetic maintenance, and oxidative defense. The polymorphism rs1801131, sometimes referred to as A1298C, results in an alanine substitution for a glutamate residue in the enzyme at position 429, which occurs near the binding site for an allosteric inhibitor, S-adenosyl-L-methionine (SAMe). Cell-based assays have shown that the enzyme produced by the G allele, which encodes an alanine residue, reduces MTHFR activity by about 30% compared to the enzyme produced by the T allele. Consistent with these findings, the GG genotype has been associated with increased risk for ischemic stroke and infertility due to decreased sperm production in men. Furthermore, individuals heterozygous for rs1801131 and rs1801133, another polymorphism in the MTHFR gene, have a more severe clinical phenotype that is similar to the AA genotype for rs1801133. Lastly, despite the prevalence of both minor alleles, the genotype combination rs1801131 GG and rs1801133 AA is nearly nonexistent in the population, suggesting it confers a significant genetic disadvantage.

The MTHFR (methylenetetrahydrofolate reductase) gene encodes a metabolic enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (MTHF), the bioactive form of folate. Folate is a crucial mediator of one-carbon metabolism, which is necessary for a plethora of biochemical functions, such as nucleotide biosynthesis, amino acid metabolism, epigenetic maintenance, and oxidative defense. The polymorphism rs1801133, sometimes referred to as C677T, results in a valine substitution for an alanine residue in the enzyme at position 222, which occurs near the binding site for a cofactor and the substrate, FAD and 5,10-methylenetetrahydrofolate respectively. Mechanistic studies have shown that the enzyme produced by the A allele, which encodes a valine residue, has reduced thermal stability and 55% reduced activity compared to the enzyme produced by the G allele. Consistent with these results, carriers of the A allele were found to have decreased levels of folate and increased levels of homocysteine. As a result, carriers of the A allele are at risk for neural tubes defects, vascular disease, stroke, migraine, depression, and infertility. Furthermore, individuals heterozygous for rs1801133 and rs1801131, another polymorphism in the MTHFR gene, have a more severe clinical phenotype that is similar to the AA genotype for rs1801133. Lastly, despite the prevalence of both minor alleles, the genotype combination rs1801131 GG and rs1801133 AA is nearly nonexistent in the population, suggesting it confers a significant genetic disadvantage.

MTHFS (methenyletetrahydrofolate synthase) is an enzyme that catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, a precursor of reduced folates. This polymorphism codes for a decreased function of the enzyme and results in poor utilization of Leucovorin (5-formyltetrahydrofolate).

MTR (Methionine Synthase) codes for the enzyme that catalyzes the final step in methionine biosynthesis. Polymorphisms in this gene lead to poor recycling of methionine from homocysteine. This enzyme work in coordination with MTRR and requires both MTHF and B12 for proper functioning. Deficiencies in Methionine leads to poor methylation that is associated with numerous neurological, cardiovascular and immunological disease states, as well as, infertility and birth defects.

Methionine Synthase Reductase is an enzyme responsible for the production of methionine, a very important amino acid. Polymorphisms in this enzyme require an increased amount of Methyl B12 to help this reaction

The MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase) gene encodes an enzyme that regenerates methionine synthase, an enzyme encoded by the MTR gene, to a functional state. As a results, MTRR is also known as methionine synthase reductase, and it has a key role maintaining folate-methionine homeostasis. The polymorphism rs1801394 results in a methionine substitution for an isoleucine residue in the enzyme at position 22, and biochemical studies have found that the enzyme encoded by the G allele has a lower affinity for its target, methionine synthase, than the enzyme encoded by the A allele. These results suggest that carriers of the G allele, which produces a protein containing a methionine residue, may have reduced regeneration of methionine synthase and reduced conversion of homocysteine to methionine. Congruently, numerous studies have shown that G allele carriers have elevated homocysteine levels, which can be mediated by supplementation with folate. The G allele was also found to be a risk factor for neural tube defects and Down syndrome. Lastly, risk of neural tube defects was increased in G allele carriers who were also deficient in vitamin B12

The SLC19A1 gene encodes the reduced folate carrier (RFC) protein. Mutations in the RFC are associated with reduced plasma folate.

The protein product of the transcobalamin 1 (TCN1) gene binds Vitamin B12 and protects it from the low pH environment of the human stomach. Individuals homozygous for the G allele of the TCN1 SNP, rs526934, are predicted to have lower serum B12.

The protein product of the Transcobalamin 2 gene, TCN2, binds the active form of vitamin B-12. Individuals with the G/G phenotype at rs1801198 have decreased serum B-12 and increased homocysteine when compared to individuals with the C/C phenotype.

The CUBN (cubilin) gene encodes a receptor for intrinsic factor-cobalamin (Cbl-IF) complexes, and it is essential for intestinal absorption of vitamin B12. The polymorphism rs1801222 results in a phenylalanine substitution for a cysteine residue at position 253 in the protein. The A allele, which encodes a phenylalanine residue, is associated with reduced plasma levels of vitamin B12 and increased levels of homocysteine. Additionally, the A allele has been associated with risk for neural tube defects.

The MAT1A (methionine adenosyltransferase 1A) gene encodes an enzyme that transfers the adenosyl moiety of ATP to methionine to form S-adenosylmethionine (SAMe), the universal methyl donor. SAMe is essential to hundreds of biological reactions for modifying biomolecules, such as lipids, proteins, and nucleic acids. Additionally, SAMe is needed for epigenetic regulation, hormone and neurotransmitter synthesis, and detoxification. When SAMe donates a methyl group, S-adenosyl homocysteine is produced, and homocysteine needs to be processed through the methionine cycle or the transsulfuration pathway to prevent excess oxidative stress. The polymorphism rs7087728 occurs in the 3' untranslated region of MAT1A; therefore, the variation may alter mRNA stability. Individuals with the GG genotype had increased levels of urinary 8-OHdG, a marker of oxidative DNA damage. Unlike the response in A allele carriers, vitamin B6, which can support homocysteine clearance, was not effective at reducing levels of oxidative DNA damage in individuals with the GG genotype. This suggests that the DNA damage observed in individuals with the GG genotype may be due to decreased methylation due to reduced SAMe production. In summary, individuals with the GG genotype may be at increased risk for reduced MAT1A activity, SAMe production, and methylation capacity.

The BHMT (betaine-homocysteine S-methyltransferase) gene encodes an essential enzyme that consume betaine, or trimethylglycine, to convert homocysteine to dimethylglycine and methionine. Therefore, BHMT both detoxifies homocysteine and generates methionine needed to maintain methylation capacity. It is primarily expressed in the liver and kidneys. The polymorphism rs3733890 results in a glutamine substitution for an arginine residue at position 239. The A allele, which encodes a glutamine residue, results in more partitioning of choline, a precursor of betaine, for phosphatidylcholine synthesis via the cytidine diphosphate (CDP)-choline pathway, suggesting that less betaine is available for detoxification of homocysteine and regeneration of methionine. Likewise, carriers of the A allele have been shown to have reduced levels of betaine and dimethylglycine. Furthermore, folate was shown to be a less effective treatment to lower homocysteine levels in carrier of the A allele with hyperhomocysteinemia. Nevertheless, increased intake of choline in A allele carriers can increase flux to betaine synthesis to support BHMT activity. In summary, A allele carriers may benefit from increased choline or betaine intake, especially when managing high levels of homocysteine.

CBS (cystathionine beta-synthase) gene encodes an enzyme that catalyzes the first step in the transsulfuration pathway. More specifically, CBS, a pyridoxal 5'-phosphatedependent enzyme, consumes serine to convert homocysteine to cystathionine, which is further catabolized to generate substrate for glutathione synthesis. Therefore, homocysteine clearance and glutathione synthesis converge on the function of CBS. The polymorphism rs234706 results in a nucleotide substitution in exon 8. Carriers of the G allele have been found to have higher levels of homocysteine and lower levels of cystathionine and betaine, consistent with reduced CBS activity. Furthermore, individuals with the GG genotype had higher plasma homocysteine following the ingestion of a methionine load, and individuals with the GG genotype were less responsive to folate supplementation to lower homocysteine levels. Lastly, the GG genotype is associated with increased risk for coronary artery disease.

The Vitamin D (calcitriol) Receptor is a member of the nuclear receptor family. Upon activation by vitamin D ( a secosteroid), the VDR causes the activation or deactivation of protein production by the cell. Impaired vitamin D function can result in significant immune weakness and increased cancer risk, as well as, early bone loss, an increased risk of cognitive decline and mood disorders.

GC aka DBP (Vit. D Binding Protein) gene codes for Vit. D binding protein. This protein belongs to the albumin family and is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types. It is manufactured in the hepatic parenchymal cells. DBP is capable of binding to all forms of Vit D including ergocalciferol (vitamin D2) and cholecaldiferol (vitamin D3), the 25-hydroxylated forms (calcifediol) and the active hormonal product, 1,25-dihydroxyvitamin D (calcitriol). The major proportion of vitamin D in blood is bound to this protein. It transports vitamin D metabolites between skin, liver and kidney, and then on to the various target tissues. It binds to vitamin D and its plasma metabolites and transports them to target tissues. Polymorphisms in this gene decrease the affinity of the protein to Vit. D which reduces the response rate to Vit. D therapy. Patients with these polymorphisms require high doses of Vit D supplementation.

The SIRT1 (sirtuin 1) gene encodes a nicotinamide adenine dinucleotide (NAD+) and zinc-dependent histone deacetylase. SIRT1 is an important epigenetic regulator that responds to metabolic and oxidative stress to activate genes related to mitochondrial biogenesis and ATP production. SIRT1 activates PGC-1? through the SIRT1/PGC-1? axis, which responds to the cytosolic ratio of NAD+ to NADH. The polymorphism rs1467568 occurs in the eighth intron, and studies have found that G allele carriers may be at risk for increased BMI and obesity. Studies have also shown that SIRT1 expression was lower in overweight or obese individuals than it was in lean individuals. Together, these results suggest that G allele carriers may have reduced SIRT1 expression, restricting the SIRT1/PGC-1? axis and mitochondrial biogenesis. Furthermore, studies have found that physical activity and calorie restriction, known activators of SIRT1, can effectively address excess weight in G allele carriers. Lastly, BMI was noticeably higher in G allele carriers with low vitamin E, indicating that antioxidants may support SIRT1 and mitochondrial activity in G allele carriers as well.

The PPARGC1A (PPARG coactivator 1 alpha) gene encodes a transcriptional coactivator, termed PGC-1?, that enhances mitochondrial biogenesis and function. PGC-1? activity leads to the transcription of TFAM, which translocates to the mitochondrial matrix where it stimulates mitochondrial DNA replication and expression of other mitochondrial gene needed for replication. The polymorphism rs8192678 results in a serine substitution for a glycine at position 487, and the T allele encodes a serine residue. Individuals with the TT genotype were found to have reduced mitochondrial DNA copy number, less endurance exercise capacity, and increased risk of metabolic dysfunction, suggesting that mitochondrial content is decreased. Additionally, carriers of the T allele may have increased risk of polycystic ovary syndrome (PCOS), which often coincides with metabolic dysfunction.

The TFAM (transcription factor A, mitochondrial) gene codes a transcription factor that promotes the expression of genes essential for mitochondrial DNA replication and repair. The polymorphism rs1937 results in a threonine substitution for a serine residue at position 12, which occurs in the mitochondrial signaling sequence. Individuals with the GG genotype were found to have reduced endurance exercise capacity and decreased longevity, suggesting that ability of the mitochondria to produce sufficient energy may be decreased. Furthermore, the GG genotype was associated with increased risk for Alzheimer disease.

The NQO1 (NAD(P)H quinone dehydrogenase 1) gene encodes a riboflavin-dependent enzyme that protects against oxidative stress. Moreover, it regenerates the antioxidant capacity of CoQ10 by reducing it. The polymorphism rs1800566 results in a serine substitution for a proline residue at position 187, which occurs in the FAD-binding site. The A allele, which encodes a serine residue, produces a variant with reduced stability due to reduced ability to bind FAD, a necessary co-factor. Because CoQ10 is sensitive to oxidative stress, molecular studies suggest that NOQ1 has a role in maintaining CoQ10 status, and a clinical study found an association with NOQ1 and CoQ10 status and response to supplementation. Lastly, molecular studies have found that NOQ1 function is also dependent on adequate levels of riboflavin.

The NPC1L1 (NPC1 like intracellular cholesterol transporter 1) gene encodes a transmembrane protein that has a crucial role in the intestinal absorption of cholesterol, vitamin E, and CoQ10. The polymorphism rs2072183 results in a nucleotide substitution in exon 2. Carriers of the minor, C allele were shown to be less responsive to CoQ10 supplementation, suggesting that intestinal absorption may be reduced.

The NFE2L2 (NFE2 like bZIP transcription factor 2) gene encodes a transcription factor, known as NRF2, that has a crucial role in the regulation of a network of antioxidant genes. NRF2 activates expression of genes with a conserved promoter sequence called the antioxidant response elements (ARE). Genes with an ARE include superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), etc. Therefore, NRF2 is a master regulator of oxidant and antioxidant balance. The polymorphism rs6721961 occurs in the promoter region of NFE2L2, and mechanistic studies have found that the variant encoded by the T allele has reduced promoter activity and mRNA levels. Consistent with these findings, carriers of the T allele have been shown to have lower total antioxidant capacity. T allele carriers had less SOD, CAT, GPX, and glutathione activity. Furthermore, T allele carriers are at increased risk for insulin resistance and vascular stiffness.

The SOD2 (superoxide dismutase 2) gene encodes a mitochondrial enzyme that uses iron and manganese to covert superoxide, a byproduct of the mitochondrial electron transport chain, to hydrogen peroxide and oxygen. As a results, SOD2 clears mitochondrial reactive oxygen species (ROS), conferring protection against mitochondrial damage and cell death. The polymorphism rs4880 results in a valine substitution for an alanine residue in the enzyme at position 16. Mechanistic studies have shown that the G allele, which encodes a valine residue, has decreased basal activity of SOD2. Furthermore, SOD2 can be upregulated by inflammatory signals in cells carrying the G allele, but prolonged cellular stress resulted in an accumulation of toxic metabolic by-products, suggesting that the efficiency of cellular detoxification pathways was reduced with the G allele. Clinical studies have also found that the GG genotype is associated with increased risk for kidney dysfunction and hepatotoxicity in response to various pharmacological treatments.

COMT is an important enzyme involved in the metabolism of multiple important endogenous molecules, including the neurotransmitter dopamine and the hormone estrogen. It is implicated in a variety of disorders like OCD, anxiety, breast cancer, and so on.

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