More than 50% of your patients are affected by genetic variations in the methylation pathway.1 Standard MTHFR genotyping only evaluates folic acid metabolism. The MethylDetox Profile makes it easy to understand the complicated methylation process by giving comprehensive insights into the functional status of the methylation pathway.
The MethylDetox Profile includes genetic markers involved in methylation and homocysteine metabolism provided in a detailed lab report with personalized commentary. Additionally, continued homocysteine testing enables easy monitoring of patient progress.
Genetic variations in this pathway are associated with elevated homocysteine levels, impaired methylation processes, and limited detoxification capacity. 1, 3 As a result, these SNPs (single nucleotide polymorphisms) may contribute to accelerated aging, certain chronic diseases like cardiovascular disease and neurodegenerative disorders, impaired gene-regulation, poor drug clearance, and impaired neurotransmitter metabolism. 1, 3-21Get Starter Test Kit
Methionine and homocysteine metabolism are areas of active scientific and medical investigation. In addition to the MTHFR gene, specific SNPs in other genes also affect individual methylation capacity and homocysteine levels. 1-3
Methionine and homocysteine balance is important for optimal health. Homocysteine is resynthesized from the amino acid methionine. In general, amino acids are supplied from a balanced diet or supplementation. However, a certain amount of methionine is recycled for methylation in the methionine/ homocysteine pathway.
Therefore, the primary purpose of methionine/ homocysteine balance is to ensure proper methylation by donating methyl groups for:
Elevated serum homocysteine is a widely accepted marker for methionine/homocysteine imbalance, which is a genetically controlled process.28 Elevated homocysteine levels can lead to accelerated aging, cardiovascular disease, neurodegenerative disorders, and other conditions. 20, 21, 29
Sequence Specific Real-Time Polymerase Chain Reaction (SSP-PCR) Enzyme
Individuals with a manifestation and/or family history of:
1. MTHFR (Methylenetetrahydrofolate reductase)
Folic acid (vitamin B9) passes through a complex metabolic pathway in order to be used in the methionine/homocysteine cycle. It is first converted to tetrahydrofolate (THF) then to 5,10-methylenetetrahydrofolate (5,10-CH2- THF).
MTHFR is needed to further convert 5,10-CH2-THF into active 5-methyltetrahydrofolate (5-MTHF), in order to convert methionine from homocysteine. This is where one genetic problem can occur. If the patient has particular genetic polymorphisms in the MTHFR gene, the conversion of folic acid into its active form, 5-MTHF, may be reduced. If the patient acquired the SNPs from both parents (homozygous positive), she/he probably has significantly reduced MTHFR activity and a marked deficiency in active 5-MTHF. If the patient received the SNP from only one parent (heterozygous positive) he/she may have suboptimal MTHFR function.
The SNPs investigated here are at position C677T and A1298C (Ala222Val and Glu429Ala). Testing these SNPs indicate how well homocysteine is cleared from the blood.30 Approximately 10% of Caucasian and Asian populations have 70% less activity (homozygote positive, diminished function). About 40% of the population (heterozygous appearance) have a diminished enzyme capacity to convert folic acid into (levomefolic acid) 5-MTHF.
Supplementation: When genetic variants are present, supplementation of 5-MTHF may be considered.
2. MTR (5-methyltetrahydrofolate-homocysteine methyltransferase)
The MTR gene encodes the methionine synthase (MS) enzyme. MS regenerates methionine from homocysteine using 5-MTHF as a methyl donor and vitamin B12 as the methyl transfer compound. In a first reaction, MS attaches the methyl group from 5-MTHF to vitamin B12, forming a MSmethylcobalamin complex. The MS-methylcobalamin complex then transfers this methyl group to the homocysteine, thus converting it into methionine.
During this process, MS becomes oxidized over time and has to be reduced again to maintain proper function. This step is performed by methionine synthase reductase (MSR) which is encoded by the MTRR gene (see MTRR). MTR gene mutations, C3518T and A2756G, affect function of the enzyme even in the heterozygous form. They are associated with higher homocysteine levels and may lead to hypomethylation. Reported prevalence of A2756G in the Caucasian population is 1.7% in the homozygous form.
Supplementation: When genetic mutations are present in the MTR gene, supplementation with methylcobalamin (methylated vitamin B12)) may be considered.
3. MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase)
The MTRR gene encodes the enzyme methionine synthase reductase (MSR). Its task is to support MS in the remethylation of homocysteine into methionine by keeping the MS enzyme in an active (reduced) form (see MTR). Over time, MS becomes oxidized and loses its ability to transfer methyl groups from the MS-methylcobalamin complex to homocysteine. The MS has to be activated (reduced) again by MSR in a so called “ping-pong” reaction that uses SAMe (S-adenosyl methionine) as the activating (reducing) agent.
The common MTRR polymorphism, A66G, has a prevalence of 26.58% (GG), 48.84 %(AG), 24.58% (AA) in the Caucasian population. In combination with the C677T polymorphism in MTHFR, MTRR genotypes AG, GG influence total plasma homocysteine levels. Additionally, the combination of the genetic polymorphisms in MTRR and MTHFR was linked to an increase in DNA damage as measured by micronucleus frequency (MN).
Supplementation: When genetic variants are present in teh MTRR gene, supplementation with methylated vitamin B12 may be considered.
4. COMT (Catechol-O-Methyltransferase)
COMT is the major enzyme involved in the methylation process. COMT catalyzes the transfer of the functional methyl group from S-adenosyl methionine (SAMe) to a substrate, which has to be methylated. Two SNPs, Val108/158Met and Ala52/102Thr, are known to alter COMT methylation capacity. 41
These 2 SNPs of the COMT gene are associated with:
Supplementation: When genetic mutations are present, supplementation with S-Adenosyl Methionine (SAMe) is often recommended. Attention should be paid to other medications being taken, including anti-depressants.
5. AHCY (S-Adenosylhomocysteine hydrolase)
The AHCY gene encodes an enzyme called S-adenosylhomocysteine hydrolase and is the only enzyme known to convert S-adenosylhomocysteine (AdoHcy) to homocysteine.
AdoHcy is an inhibitor of methylation processes. The ratio between AdoMet and AdoHcy is referred to as methylation potential. Therefore, it is crucial that AHCY immediately converts AdoHcy to homocysteine and adenine in order to maintain an optimal methylation potential. Several genetic polymorphisms (SNPs) in this gene are known to alter activity and expression of this enzyme, leading to elevated AdoHcy concentrations and impaired methylation potential. Recent studies show association between those variants resulting in poor methylation potentials, severe myopathies, developmental delays, and hypermethioninemia.
Supplementation: When genetic variants are present, addressing the need for the precursor to S-Adenosyl Methionine (SAMe), methionine, may be considered.
Monitoring of patient progress is done by testing homocysteine levels before, during, and after the implementation of personalized therapy or supplementation.
Patient test results are provided both in the context of the methylation pathway and personalized commentary including lifestyle and supplementation considerations. Throughout treatment, homocysteine testing is recommended to monitor patient outcomes.
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1 Sharp L, Little J. Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia: AHuGE Review. Am. J. Epidemiol. (2004) 159(5):423–443.
2 Figueiredo JC, Grau MV, Wallace K, Levine AJ, Shen L, Hamdan R, Chen X, Bresalier RS, McKeown-Eyssen G, Haile RW, Baron JA, Issa JP. Global DNA Hypomethylation (LINE-1) in the Normal Colon and Lifestyle Characteristics, Dietary and Genetic Factors. Cancer Epidemiol Biomarkers Prev. 2009 April; 18(4): 1041-1049
3 Watkins D, Rosenblatt DS. Update and new concepts in vitamin responsive disorders of folate transport and metabolism J Inherit Metab Dis. 2012 Jul;35(4):665-70.
4 Jacques PF, Rosenberg IH, Rogers G, Selhub J, Bowman BA, Gunter EW, Wright JD, Johnson CL. Serumotal homocysteine concentrations in adolescent and adult Americans:results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr.1999;69:482-489.
5 Brosnan JT, Jacobs RL, Stead LM, Brosnan ME. Methylation demand: a key determinant of homocysteine metabolism. Acta Biochim Pol. 2004;51:405-413.
6 Oterino A, Toriello M, Valle N, Castillo J, Alonso-Arranz A, Bravo Y, Ruiz-Alegria C, Quintela E, Pascual J.The relationship between homocysteine and genes of folate-related enzymes in migraine patients. Headache. 2010;50:99-168.
7 Papatheodorou L, Weiss N. Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxid Redox Signal. 2007;9:1941-1958.
8 Osanai T, Fujiwara N, Sasaki S, Metoki N, Saitoh G, Tomita H, Nishimura T, Shibutani S, Yokoyama H, Konta Y, Magota K, Okumura K.Novel pro-atherogenic molecule coupling factor 6 is elevated in patients With stroke: a possible linkage to homocysteine. Ann Med. 2010;42:79-86.
9 Seshadri, N., Robinson, K. Homocysteine and coronary risk, Curr Cardiol Rep 1999; 1, 91-98.
10 Vasan RS, Beiser A, D'Agostino RB, Levy D, Selhub J, Jacques PF, Rosenberg IH, Wilson PW. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA. 2003;289:1251-1257.
11 Kurth T, Ridker PM, Buring JE. Migraine and biomarkers of cardiovascular disease in women. Cephalalgia. 2008;28:49-56.
12 Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83.
13 Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, McArdle JJ, Willis RJ, Wallace RB.Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008;148:427-434
14 Lee SH, Kim MJ, Kim BJ, Kim SR, Chun S, Kim HK, Ryu JS, Kim GS, Lee MC, Chung SJ, Koh JM. Hyperhomocysteinemia due to levodopa treatment as a risk factor for osteoporosis in patients with Parkinson’s disease. Calcif Tissue Int. 2010;86:132-141.
15 Rochtchina E1, Wang JJ, Flood VM, Mitchell P. Elevated serum homocysteine, low serum vitamin B12, folate, and age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol. 2007;143:344-346.
16 Christen WG1, Glynn RJ, Chew EY, Albert CM, Manson JE. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study. Arch Intern Med. 2009;169:335-341.
17 Haagsma CJ, Blom HJ, van Riel PL, van't Hof MA, Giesendorf BA, van Oppenraaij-Emmerzaal D, van de Putte LB. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis.1999;58:79-84.
18 Desouza C1, Keebler M, McNamara DB, Fonseca V. Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs. 2002;62:605-616.
19 Foucher C, Brugère L, Ansquer JC. Fenofibrate, homocysteine, and renal function. Curr Vasc Pharmacol. 2010;8:589-603.
20 Cavalieri EL, Li KM, Balu N, Saeed M, Devanesan P, Higginbotham S, Zhao J, Gross ML, Rogan EG.. Catechol ortho-quinones: the electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases. Carcinogenesis. 2002 Jun;23(6):1071-7.
21 Yager JD. Catechol-O-methyltransferase: characteristics, polymorphisms and role in breast cancer. Drug Discov Today Dis Mech. 2012 June 1; 9(1-2).
22 Brustolin S, Giuglian R, et al. Genetics of homocysteine metabolism and associated disorders. Braz J Med. Biol Res. 2010 January ; 43(1): 1–7.
23 Bautista LE, Arenas IA, Peñuela A, Martínez LX. Total plasma homocysteine level and risk of cardiovascular disease: a meta-analysis of prospective cohort studies. J Clin Epidemiol. 2002 Sep;55(9):8827.
24 Meleady R, Ueland PM, Bloom H et al.: Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: The European Concerted Action Project. Am J Clin Nutr 2003; 77: 63–70.
25 Gokcen C1, Kocak N, Pekgor A. Methylenetetrahydrofolate reductase gene polymorphisms in children with attention deficit hyperactivity disorder. Int J Med Sci. 2011;8(7):523-8.
26 Sener EF, Oztop DB, Ozkul Y. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders. Genet Res Int. 2014;2014:698574.
27 Beydoun MA, Gamaldo AA, Canas JA, Beydoun HA, Shah MT, McNeely JM, Zonderman AB. Serum nutritional biomarkers and their associations with sleep among US adults in recent national surveys. PLoS One. 2014 Aug 19;9(8):e103490.
28 Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, Gottfries CG. Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. PLoS One. 2015 Apr 22;10(4):e0124648.
29 Di Renzo L, Marsella LT, Sarlo F, Soldati L, Gratteri S, Abenavoli L, De Lorenzo A. C677T gene polymorphism of MTHFR and metabolic syndrome: response to dietary intervention. J Transl Med. 2014 Nov 29;12(1):329.
30 Kang SS, Zhou J, Wong PW, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet. 1988 Oct;43(4):414-21.
31 Tonstad F, Refsum H, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine. J Pediatr. 1998;132: 365-368.
32 Wilcken B, Bamforth F, Li Z, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003;40(8):619-625.
33 Lea R, Colson N, et al. The effects of vitamin supplementation and MTHFR (C677T) genotype on homocysteine-lowering and migraine disability. Pharmacogenet Genomics. 2009;19:422-428.
34 Yan L, Zhao L, Long Y, et al. Association of the maternal MTHFR C677T polymorphism with susceptibility to neural tube defects in offsprings: evidence from 25 case-control studies. PLoS One. 2012;7(10):e41689.
35 Yin M, Dong L, Zheng J, Zhang H, Liu J, Xu Z. Meta analysis of the association between MTHFR C677T polymorphism and the risk of congenital heart defects. Ann Hum Genet. 2012;76(1):9-16.
36 Ocal IT, Sadeghi A, Press RD. Risk of venous thrombosis in carriers of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase. Mol Diagn 1997; 2: 61–68.
37 Nelen WL, Blom HJ, Thomas CM, Steegers EA, Boers GH, Eskes TK. Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages. J Nutr. 1998 Aug;128(8):1336-41.
38 Kelly PJ, Rosand J, Kistler JP, Shih VE, Silveira S, Plomaritoglou A, Furie KL. Homocysteine, MTHFR 677C— >T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology. 2002 Aug 27;59(4):529-36.
39 Ulvik A, Ueland PM, Fredriksen A, Meyer K, Vollset SE, Hoff G, Schneede J. Functional inference of the methylenetetrahydrofolate reductase 677C > T and 1298A > C polymorphisms from a large-scale epidemiological study. Hum Genet. 2007 Mar;121(1):57-64.
40 Watkins D, Ru M, Hwang HY, Kim CD, Murray A, Philip NS, Kim W, Legakis H, Wai T, Hilton JF, Ge B, Doré C, Hosack A, Wilson A, Gravel RA, Shane B,Hudson TJ, Rosenblatt DS. Hyperhomocysteinemia due to Methionine Synthase Deficiency, cblG: Structure of the MTR Gene, Genotype Diversity, and Recognition of a Common Mutation, P1173L. Am J Hum Genet. 2002 Jul;71(1):143-53.
41 Männistö PT, Kaakkola S. Catechol-O-methyltransferase (COMT): Biochemistry, Molecular Biology, Pharmacology, and Clinical Efficacy of the New Selective COMT Inhibitors. Pharmacological Reviews December 1, 1999 vol. 51 no. 4 593-628.
42 Dawling S, Roodi N, Mernaugh RL, Wang X, Parl FF. Catechol-O-Methyltransferase (COMT)-mediated Metabolism of Catechol Estrogens Comparison of Wild-Type and Variant COMT Isoforms. Cancer Res September 15, 2001 61; 6716.
43 Shield AJ, Thomae BA, Eckloff BW, Wieben ED, Weinshilboum RM. Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Molecular Psychiatry (2004) 9, 151–160
44 Åberg E, Fandiño-Losada A, Sjöholm LK, Forsell Y, Lavebratt C. The functional Val158Met polymorphism in catechol-O-methyltransferase (COMT) is associated with depression and motivation in men from a Swedish population-based study. J Affect Disord. 2011 Mar;129(1-3):158-66.
45 Htun NC, Miyaki K, Song Y, Ikeda S, Shimbo T, Muramatsu M. Association of the catechol-O-methyl transferase gene Val158Met polymorphism with blood pressure and prevalence of hypertension: interaction with dietary energy intake. Am J Hypertens. 2011 Sep;24(9):1022-6.
46 Schalinske KL, Smazal AL. Homocysteine Imbalance: a Pathological Metabolic Marker. Adv Nutr November 2012 Adv Nutr vol. 3: 755-762, 2012.
47 Ziegler DA, Ashourian P, Wonderlick JS, Sarokhan AK, Prelec D, Scherzer CR, Corkin S. Motor impulsivity in Parkinson disease: associations with COMT and DRD2 polymorphisms. Scand J Psychol. 2014 Jun;55(3):278-86.