METHYLATION PANEL

DNA methylation constitutes an important component of the epigenetic network. DNA methylation plays an important role in various cellular processes such as regulation of gene expression, X chromosome inactivation, and genomic imprinting. DNA methylation can lead to changes in gene expression due to nutritional and environmental influences, resulting in a variety of phenotypes with the potential for reduced growth and health (Yıldırım, Z., & Küçükkendirci, H. 2023). Hence, genes encoding enzymes involved in methylation and polymorphisms in these genes cause the methylation cycle to malfunction. Since vitamins and minerals, which act as coenzymes that affect the activities of those enzymes as well as enzymes, are important components of the methylation cycle, their deficiency or excess contributes to the disruption of the balance.

 

Cystathionine β-Synthase Gene (CBS)

Cystathionine β-synthase gene (CBS) is the gene that encodes the vitamin B6-dependent cystathionine β-synthase (CBS) enzyme, which converts homocysteine into cystathionine with serine, one of the main pathways of homocysteine metabolism (Tilley, M. M. et al., 2011). Cystathionine β-synthase catalyses the first step of transsulfuration. This enzyme has tetramer structure and three additional ligands as: pyridoxal 5-phosphate (active form of vit B6), S-adenosylmethionine (SAM) and heme protein, which they function as cofactors (Zuhra et al., 2020). The heme cofactor in its structure acts as a redox sensor and uses SAM as an activator. (Kraus et al.1998; Renga B., 2011). CBS enzyme deficiency causes homocystinuria, an inherited autosomal recessive metabolic disorder that leads to elevated homocysteine plasma concentrations (Shi H. et al.,2015). Hyperhomocysteinemia is known as a risk factor for cardiovascular diseases.

CBS (Cystathionine β-synthase)
Genes	rs	Minor Allele	Minor Allele Explanation	Reference
CBS 360	rs1801181	C	High relative risk for homocysteine	(Li, Q. et al.,2013)
CBS 699	rs234706	G	High relative risk for homocysteine	(Li, Q. et al.,2013)
CBS	rs2851391	T	Increased relative risk for homocysteinemia	(Li Y. et al.2021)
CBS	rs5742905	C	Increased relative risk for homocysteinemia	(Saha T. et al.,2017), (Ding R. et al.2012)

The table above contains CBS genes and their polymorphisms. Polymorphisms that cause decreased CBS enzyme activity cause homocysteinemia.

CBS
Genes	rs	Minor Allele	Minor Allele Explanation	Reference
CBS 360	rs1801181	T	High relative risk for increased enzyme activity	(Li, Q. et al., 2013)
CBS 699	rs234706	A	High relative risk for increased enzyme activity	(Li, Q. et al., 2013)

The table above contains CBS genes and their polymorphisms. In a study on non-Hodgkin lymphoma (NHL) risk, the rs234706 homozygous TT genotype in CBS was associated with a reduced risk of NHL compared with CC. This decrease was observed with the intake of methionine, folate and vitamin B6 in the diet. The increase in the risk of NHL was observed in the homozygous variant genotype (TT versus CC) (C>T) in CBS (rs1801181) (Li, Q. et al., 2013). Increased homocysteine is observed in various psychological disorders such as depression, bipolar, and schizophrenia. In a study conducted on 120 bipolar patients, the CBS (rs5742905) gene was found to be related to bipolar (Permoda et al.,2014). In another study, CBS (rs5742905) TT was associated with hyperactivity and impulsivity (Saha T. et al.,2017). In a meta-analysis study, it was reported that the risk of stroke increased in those with CBS T833C (rs5742905) genetic polymorphism and that the C allele was a risk factor (Ding R. et al.2012). In a study examining CBS rs2851391 in terms of congenital heart diseases, an increased risk of CHD was observed in the offspring of mothers with TT genotype compared to the offspring of mothers with CC genotype. It has been observed that if mothers with the CBS rs2851391 risk genotype (CT/TT) consume fried, barbecued and similar foods, the risk of CHD in the offspring increases, and on the contrary, when mothers with the rs2851391 CC genotype consume foods such as fish, meat, eggs and fresh fruit, the risk of CHD in the offspring decreases. The rs2851391 mutant variant causes reduced enzyme activity and is associated with hyperhomocysteinemia and abnormal DNA methylation (Li Y. et al., 2021).

 

CHOLINE

Choline is an essential nutrient required for the structural integrity of cell membranes and signaling functions, methyl group metabolism and neurotransmitter synthesis. People fed diets deficient in choline develop fatty liver, liver damage, and muscle damage (Kozyreva, O. G. et al., 2006). It is also suggested that choline plays a critical role in fetal development and that pregnancy may represent a period when the mother's need for choline increases markedly (Ivanov, A. et al., 2009). The best dietary sources of choline include liver, eggs and wheat germ. In foods, choline is found free and as choline esters. It is not clear whether a normal diet provides the recommended amount of choline for all people. The only source of choline outside the diet is the de novo biosynthesis of phosphatidylcholine catalyzed by phosphatidylethanolamine- N -methyltransferase (PEMT) in the liver (Zeisel, S. H., 2007).

 

Methylenetetrahydrofolate Dehydrogenase (MTHFD1) Gene

5, 10-methylenetetrahydrofolate dehydrogenase (MTHFD1), a folate-dependent enzyme, has a central role in folate metabolism. In addition to its enzymatic activity, MTHFD1 has been shown to play a critical role in methionine synthesis and as a structural component in de novo purine and pyrimidine synthesis (Jiang, J. et al., 2014).

 

Phosphatidylethanolamine N-Methyltransferase (PEMT) Gene

Endogenous biosynthesis of choline in the liver occurs when phosphatidylethanolamine is methylated by phosphatidylethanolamine N -methyltransferase (PEMT) to form phosphatidylcholine. The PEMT enzyme is also encoded by the PEMT gene. PEMT activity is responsible for the endogenous biosynthesis of choline and this activity is increased by oestrogen treatment (Kozyreva, O. G. et al., 2006). Phosphatidylethanolamine N-methyltransferase ensures the secretion of hepatic triglycerides in the form of very low density lipoprotein. PEMT gene-related polymorphisms have been associated with non-alcoholic fatty liver disease (NAFLD) (Tan HL, et. al., 2016).

CHOLINE
Genler	rs	Minor Allele	Minor Allele Explanation	Reference
MTHFD1	rs2236225	T	High relative risk for Choline requirement, possibly due to decreased enzyme activity	(Ganz, A. B. et al., 2016)
PEMT	rs7946	T	High relative risk for Choline requirement, possibly due to decreased PEMT activity	(Song, J. et al., 2005)

The table above contains genes and polymorphisms related to choline metabolism. The MTHFD1 rs2236225 polymorphism encodes an enzyme with a ~50% reduction in enzymatic activity. This variant also increases susceptibility to choline deficiency in premenopausal women who are deficient in choline. It shows that MTHFD1 rs2236225 polymorphism may increase susceptibility to choline and phosphatidylcholine deficiency even at choline intakes consistent with current recommendations (Ganz, A. B. et al., 2016).

When the relationship between the PEMT gene and non-alcoholic fatty liver disease (NAFLD) is examined; The rs7946 A-allele has been shown to be significantly associated with increased risk of NAFLD (Tan HL, et. al., 2016). rs7946 polymorphism causes loss of function in the PEMT enzyme. With this variant, the risk of fatty liver disease increases when the diet is inadequate in choline (Song, J. et al., 2005).

 

Catechol-O-methyltransferase (COMT) Gene

Catechol-O-methyltransferase (COMT) is a ubiquitously expressed enzyme involved in the metabolism of a wide variety of catechol substrates, including catecholamines and catecholestrogens such as epinephrine, norepinephrine, and dopamine. Functional polymorphisms in the COMT gene are associated with dopamine and norepinephrine-dependent neuropsychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder, anxiety disorders, as well as neurodegenerative disorders such as attention deficit hyperactivity disorder, addiction, anorexia nervosa, and Parkinson's disease. It has also been associated with the development of disorders characterized by increased levels of catecholamines and their reactive products in peripheral tissues, such as cardiovascular disease and estrogen-induced hormonal cancers (Nackley, A. G. Et al., 2009).

COMT
Genes	rs	Minor Allele	Minor Allele Explanation	Reference
COMT	rs4633	C	High relative predisposition for COMT activity	(Mikołajczyk, E. Et al., 2010)
COMT	rs4680	G	High relative predisposition for COMT activity	(Fernández-de-Las-Peñas C. Et al., 2012)

The table above contains genes and polymorphisms related to the COMT gene. Comt rs 4680 (Val158Met), a genetic polymorphism leading to a G→A change at codon 158, causes differences in gene activity. The presence of GG genotype results in 3-4 higher enzymatic activity compared to GA and AA genotype. Therefore, G allele carriers cause more degradation of dopamine and less presence of this neurotransmitter in synaptic receptors. Additionally, individuals with the GG genotype have decreased pain sensitivity compared to those with the AA genotype, suggesting that the presence of the AA genotype may predispose to chronic pain (Fernández-de-Las-Peñas C. Et al., 2012). The C allele of the COMT rs4633 polymorphism is associated with low expression of COMT mRNA. It causes a decrease in enzyme activity (Mikołajczyk, E. Et al., 2010).

 

FOLATE

The folate structure is represented by the folate group derived from folic acid. It serves as an essential cofactor in methylation reactions and the synthesis of purines and pyrimidines, and the main sources of folate in the diet are especially green leafy vegetables, legumes and grains, apart from foods enriched with folic acid. However, folic acid is not active in the human body and must be converted by the liver into the active molecule, 5-methyltetrahydrofolate (5-MTHF). Folate deficiency is associated with hyperhomocysteinemia, megaloblastic anemia, cardiovascular disease, especially neural tube defects, and cognitive impairment (Ferrazzi E, Tiso G, Di Martino D., 2020).

 

Folate and Methylenetetrahydrofolate Reductase (MTHFR) Gene Interaction

The MTHFR gene encodes the information needed to produce an enzyme called methylenetetrahydrofolate reductase. This enzyme is important for processing amino acids and creating proteins. The MTHFR enzyme is also required to metabolize folate. Metabolized by the addition of a methyl group, folate is required for the conversion of homocysteine to methionine. Methionine is important for the production of protein and other compounds in the body. Genetic variations in the MTHFR gene result in decreased activity of the enzyme produced and are associated with a number of diseases and conditions, including cardiovascular disorders, neurological defects, certain types of cancer, psychiatric disorders, diabetes and pregnancy complications (W Boughrara et al., 2015).

FOLATE (Tetrahydrofolate)
Genes	rs	Minor Allele	Minor Allele Explanation	Reference
MTHFR A1298C	rs1801131	C	High relative risk for folate deficiency	(Tisato, V. et al., 2021)
MTHFR C677T	rs1801133	T	High relative risk for folate deficiency	(Yang, Q. et al., 2008)

Individuals with the MTHFR 677 TT genotype had lower serum folate and higher homocysteine concentrations compared to individuals with the CC genotype. Moderate daily folic acid intake (mean: 150 μg/day) significantly reduced the difference in mean homocysteine concentrations between those with MTHFR 677 CC and TT genotypes (Yang, Q. et al., 2008). MTHFR A1298C variant, CC genotype also causes a decrease in enzyme activity. Combined heterozygosity of two MTHFR variants leads to lower MTHFR enzyme activity than two single heterozygosity individually and causes high homocysteine and low folate levels comparable to 677TT homozygotes (Tisato, V. et al., 2021).

 

VITAMIN B2 (Riboflavin)

Vitamin B2 (riboflavin) is a water-soluble vitamin and is heat stable. It is especially found in foods such as milk, offal (mostly calf liver), eggs, fish, nuts, some fruits and legumes, wild rice, mushrooms, dark green leafy vegetables, yeast, and beer. It is phosphorylated intracellularly to flavin mononucleotide (FMN) and further metabolized to flavin adenine dinucleotide (FAD). Both FMN and FAD play an important role as cofactors in energy metabolism and are required for co-enzyme function in numerous oxidation and reduction reactions in all aerobic life forms (Suwannasom, N. et al., 2020).

 

Riboflavin and Methylenetetrahydrofolate Reductase (MTHFR) Gene Interaction

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme required to catalyze the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a key process in folate metabolism and the remethylation of homocysteine to methionine, and its cofactor is riboflavin. (Candrasatria RM. et al., 2020).

VITAMIN B2
Genes	rs	Minor Allele	Minor Allele Explanation	Reference
MTHFR	rs1801133	T	Increased relative risk for hyperhomocysteinemia and increased riboflavin requirement	(Candrasatria RM. et al., 2020)

The table above contains the genes and their polymorphisms that play a role in riboflavin metabolism. In individuals with the rs1801133 TT allele, MTHFR enzymatic activity is reduced, and the reduced activity of the MTHFR enzyme is associated with a decrease in the concentration of its cofactor riboflavin or vitamin B2 (Candrasatria RM. et al., 2020).

 

VITAMIN B12

Vitamin B12, also known as cobalamin, is an important water-soluble micronutrient that must be taken by humans to maintain health. B12 deficiency is clinically associated with megaloblastic anemia and neurodegenerative disorders, and is also linked to cardiovascular diseases thought to be mediated through hyperhomocysteinemia (Surendran, S. et al., 2018). Due to low B12 levels, weakness, fatigue and forgetfulness can be seen (Jatoi et al., 2020). Vitamin B12 is found in animal products such as meat, eggs and shellfish (“Vitamin B12 - Health Professional Fact Sheet,” n.d.; Watanabe, Yabuta, Bito, & Teng, 2014).

 

Vitamin B12 and TCN1/TCN2 Gene Interaction

The transcobalamin 1 (TCN1) gene encodes transcobalamin I, a vitamin B12-binding protein. TCI plays a role in facilitating the entry of vitamin B12 into cells via receptor-mediated endocytosis. The TCN2 gene, also known as transcobalamin 2, has the function of making the vitamin B12-binding protein called transcobalamin II (TC), which is found in human serum. TC plays a role in the absorption and transport of vitamin B12 into the cell. Only 10-20% of vitamin B12 binds to TC; the remainder binds to holo-haptocorrin (transcobalamin 1) (Surendran, S. et al., 2018).

 

Vitamin B12 and MTRR Gene Interaction

The MTRR (Methionine synthase reductase) enzyme is encoded by the MTRR gene. It is responsible for maintaining adequate levels of active vitamin B12 (methylcobalamin), which keeps the methionine synthase enzyme active (Surendran, S. et al., 2018).

 

Vitamin B12 and MTHFR Gene Interaction

The MTHFR gene encodes the information needed to produce an enzyme called methylenetetrahydrofolate reductase. This enzyme is important for processing amino acids and creating proteins. Genetic variations in the MTHFR gene result in decreased activity of the enzyme produced and are associated with a number of diseases and conditions, including cardiovascular disorders, neurological defects, certain types of cancer, psychiatric disorders, diabetes and pregnancy complications (W Boughrara et al., 2015).

 

Vitamin B12 and FUT2 Gene Interaction

Common variants in exon 2 of FUT2 (rs602662, rs492602, and FUT2 haplotype) have been associated with higher vitamin B-12 status. There are two hypotheses to explain the relationship between FUT2 and vitamin B-12 status. In the first, FUT2 variants reduce the risk of Helicobacter pylori infection and associated gastritis-induced vitamin B-12 malabsorption by reducing H-type antigen production and function, and in the second hypothesis, FUT2 variants reduce the risk of vitamin B-12 malabsorption, a fucosylated glycoprotein required for vitamin B-12 absorption. It has been suggested that it increases the secretion of factor (Zinck, J. W. et al., 2015).

VITAMIN B12
Genes	rs	Minor Allele	Minor Allele Explanation	Reference
MTHFR	rs1801133	T	Increased relative risk for vitamin B12 deficiency and hyperhomocysteinemia	(Al-Batayneh, K. M. et al., 2018)
MTRR	rs1801394	G	Increased relative risk for hyperhomocysteinemia associated with B12 and folate deficiency	(Miasko, M. H. et al., 2020)
TCN1	rs526934	G	Increased relative risk for low plasma B12 level.	(Nongmaithem SS, et al., 2017)
TCN2	rs9606756	G	Increased relative risk for low plasma B12 level.	(Lahner, E. et al., 2015)
FUT2	rs602662	G	Reduced relative risk for low plasma B12 level	(Hazra, A. ve diğerleri, 2008)

The table above contains genes and polymorphisms that play a role in vitamin B12 metabolism. According to studies, individuals with the TT genotype of the MTHFR 677C>T variant are highly prone to vitamin B12 deficiency. TT genotype and T allele were found to be significantly associated with low vitamin B12 levels (Al-Batayneh, K. M. et al., 2018).

Carriers of the 'G' allele of the TCN1 rs526934 variant were found to have lower circulating vitamin B12 concentrations compared to carriers of the 'A' allele (Nongmaithem SS, et al., 2017). TCN2 rs9606756 polymorphism is more common in patients with pernicious anemia, associated with low vitamin B12 levels (Lahner, E. et al., 2015).

The most common polymorphism of the MTRR enzyme, rs1801394 (A66G), which ensures that B12 is kept in an active state, reduces the activity of the enzyme. Therefore, individuals with the GG allele were associated with lower levels of B12 (Miasko, M. H. et al., 2020). A strong association was found between FUT2 rs602662 polymorphism and plasma vitamin B12. Individuals carrying this variant have been shown to have lower B12 levels (Hazra, A. et al. 2008).

 

VITAMIN B6

Vitamin B6 is an enzymatic cofactor that plays a critical role in many biochemical and physiological processes in the human body, such as amino acid and homocysteine metabolism, glucose and lipid metabolism, neurotransmitter production and DNA/RNA synthesis. Vitamin B6 is also involved in the methylation cycle, which has an important role in gene expression. The most biologically active form is pyridoxal 5'-phosphate. Clinically evident vitamin B6 deficiency is not common (Hellmann, H., & Mooney, S. 2009). In the diet, for food resources of vitamin B6, red and white meat, fish and other seafoods, eggs, carrots, spinach, cauliflower, bananas, avocados and hazelnuts can be preferred (“Vitamin B6 - Health Professional Fact Sheet,” n.d.).

 

Vitamin B6 and ALPL Gene Interaction

Alkaline phosphatase (ALPL) is associated with vitamin B6. Its indispensable role in vitamin B6 intake is to ensure the hydrolysis of PLP to PL. Pyridoxine can also be found in different forms called pyridoxal and pyridoxamine in the structure of foods. It requires cofactors such as magnesium and riboflavin (vitamin B2) to convert pyridoxine into its active form, pyridoxal phosphate (PLF) (Loohuis, L. M., et. al., 2018).

VITAMIN B6
Genes	rs	Minor Allele	Minor Allele Explanation	Reference
ALPL	rs4654748	C	High relative risk for vitamin B6 level.	(Tanaka, T. et al., 2009)

The table above contains the gene (ALPL) and its polymorphism (rs4654748) that play a role in vitamin B6 metabolism. Mutations in the ALPL gene are characterized by low or complete absence of alkaline phosphatase (ALP) activity. ALP is the main enzyme involved in the clearance of vitamin B6, and therefore the lower vitamin B6 in C allele carriers is most likely due to more effective clearance of the vitamin (Tanaka, T. et al., 2009).

 

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