FOLSÄURE

Folsäure ist eines der am häufigsten eingenommenen Nahrungsergänzungsmittel und wird auch in vielen Beauty-Produkte verwendet. Der Wirkstoff hat eine Vielzahl von Effekten im Körper und hat auch eine Funktion bei der Zellteilung (EFSA Health Claims).

Allerdings gibt es bei Folsäure sogenannte NON-RSPONDER, Personen die nicht oder nur sehr schwach auf Folsäure ansprechen. Die European Food Safety Agency (EFSA) bestätigt, dass bei der Wirkung von Folsäure, genetische Faktoren eine Rolle spielen (Health Claims Verordnung).

EFSA:

Deficiencies of folate, vitamin B6 and vitamin B12 lead to impaired remethylation of homocysteine causing mild, moderate, or severe elevations in plasma homocysteine, depending on the severity of the deficiency, as well as coexistence of genetic or other factors that interfere with homocysteine metabolism (Miller, 2005). The Panel concludes that a cause and effect relationship has been established between the dietary intake of folate and normal homocysteine metabolism. The Panel considers that the following wording reflects the scientific evidence: “Folate contributes to normal homocysteine metabolism.”

https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2009.1213

DAS MTHFR-GEN

Folsäure ist im Körper nicht aktiv und muss erst vom MTHFR Gen in die aktive Form 5MTHF umgewandelt werden. Das MTHFR-Gen wird derzeit in mehr als 7200 Publikationen auf der Wissenschaftsdatenbank PUBMED erwähnt und gehört zu einem der am besten untersuchten Gene.

Studien haben gezeigt, dass es zwei entscheidende Versionen dieses Gens gibt: eine aktive Form die Folsäure gut umwandeln kann und eine beeinträchtigte Form die kaum in der Lage ist Folsäure zu aktivieren.

Etwa 13 % der EuropäerInnen haben nur beeinträchtigte MTHFR-Gene und können Folsäure nicht ausreichend in die aktive Form umwandeln. Die Folsäure bleibt somit meist wirkungslos.

Die Rolle des MTHFR Gens ist eine der am besten wissenschaftlich untersuchten genetischen Aspekte der Wissenschaft. Bis heute wurden bereits mehr als 297 unabhängige Studien publiziert, die insgesamt 227 903 Probanden untersucht haben. Sie alle kamen zu demselben Ergebnis: Ohne einem funktionierenden MTHFR-Gen bleibt Folsäure wirkungslos.

Eine Auflistung der größten Meta-Studien zu diesem Gen:

Reilly R (2014), 227 903 Probanden
Hiraoka (2017), 836 Probanden
Klerk (2002), 23 920 Probanden
Casas (2005), 13 928 Probanden
Holmes (2011), 59 995 Probanden
Tsang (2016), 9 224 Probanden (Kaukasier, Hispanier, Asiaten und Afrikaner)

Somit wurde an mehr als 230 000 Probanden immer dasselbe beobachtet: Personen mit der ungünstigen Version des MTHFR-Gens können Folsäure meist nicht ausreichend umwandeln.

Doch die Wissenschaft ging noch einen weiteren Schritt: in 11 sogenannten randomisierten Placebokontrollierten Doppelblindstudien (Gold-Standard), die insgesamt mehr als 6300 Teilnehmer untersucht haben zeigte sich, dass Personen mit unterschiedlichen MTHFR Genen unterschiedlich gut oder schlecht auf Folsäure reagiert haben.

Eine Auflistung der Plazebo-kontrollierten randomisierten Studien:

Fezeu (2018), 2381 Probanden
Wilson (2013), 1427 Probanden
McNulty (2006), 680 Probanden
Huang (2019), 769 Probanden
Mech (2016), 330 Probanden
Cabo (2015), 103 Probanden
Ebisch (2003), 190 Probanden
Fohr (2002), 160 Probanden
Strandhagen (2004), Probanden
Wilson (2012), 83 Probanden
Mottaghi (2019), 80 Probanden

Hier wurde an über 6300 Probanden in Goldstandard Placebo kontrollierten Studien nachgewiesen, dass Personen unterschiedlich gut auf Folsäure und andere Mikronährstoffe reagieren.

Personalisierung der Auswahl der Mikronährstoffe auf Basis der Genetik

Aus diesem Grund ist es hilfreich den Status des individuellen MTHFR Gens zu kennen und dementsprechend die richtigen und geeigneten Formen des Wirkstoffes zu verwenden. Funktioniert die Umwandlung verwenden wir die Folsäure, funktionieren die Gene nicht richtig verwenden wir die bereits aktivierte Form.

Die wissenschaftliche Validität von genetisch personalisierter Auswahl der richtigen Nährstoffe wurde auch von Autor der bisher größten Meta-Studie (Reilly 2014) bestätigt:

“Overall, there is convincing evidence of the potential for a personalised approach to disease prevention or treatment, whereby B-vitamin intervention may be targeted at those individuals sharing this common genetic factor.”

Für interessierte Experten liegt auch ein internationales Gutachten von Europas führendem Nutrigenetik-Wissenschaftler vor, das bei Interesse bei uns angefordert werden kann.

Literaturquellen und relevante Text-Auszüge

REILLY (2014)

Meta-Study
227 903 Subjects
106 Studies

Proc Nutr Soc. 2014 Feb;73(1):47-56. doi: 10.1017/S0029665113003613. Epub 2013 Oct 17. MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins? Reilly R1, McNulty H1, Pentieva K1, Strain JJ1, Ward M1.

“Overall, there is convincing evidence of the potential for a personalised approach to disease prevention or treatment, whereby B-vitamin intervention may be targeted at those individuals sharing this common genetic factor.”

Hiraoka (2017)

Review & Study
836 Subjects

Hiraoka, Mami, and Yasuo Kagawa. “Genetic polymorphisms and folate status.” Congenital anomalies vol. 57,5 (2017): 142-149. doi:10.1111/cga.12232

“Intervention of folate status based on personalized nutrition by notifying individuals of their genotype could be effective in motivating individuals to change their lifestyle and improve their nutrition status, particularly in individuals with the TT genotype. “

Valentin (2018)

Review

Ann Endocrinol (Paris). 2018 Apr;79(2):91-94. doi: 10.1016/j.ando.2017.10.001. Epub 2018 Feb 9. Acid folic and pregnancy: A mandatory supplementation. Valentin M1, Coste Mazeau P2, Zerah M3, Ceccaldi PF4, Benachi A2, Luton D4.

“The alternative suggested by some studies to overcome this resistance, would be the administration of the 5methyltetrahydrofolate (5-méthylTHF) molecule that does not need to be metabolized. “

KLERK (2002)

Meta Study
23 920 Subjects
40 Studies

JAMA. 2002 Oct 23-30;288(16):2023-31. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. Klerk M1, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG; MTHFR Studies Collaboration Group.

“Individuals with the MTHFR 677 TT genotype had a significantly higher risk of CHD, particularly in the setting of low folate status. These results support the hypothesis that impaired folate metabolism, resulting in high homocysteine levels, is causally related to increased risk of CHD”

CASAS (2005)

Meta Study
13 928 Subjects
111 studies

Lancet. 2005 Jan 15-21;365(9455):224-32. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Casas JP1, Bautista LE, Smeeth L, Sharma P, Hingorani AD.

“The observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant.“

HOLMES (2011)

Meta Study
59 995 Subjects
237 Studies

Lancet. 2011 Aug 13;378(9791):584-94. doi: 10.1016/S0140-6736(11)60872-6. Epub 2011 Jul 29. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Holmes MV

“The effects of MTHFR 677C→T on homocysteine decreased as the prevailing level of folic acid increased.“

TSANG (2015)

Meta Study
9 224 Subjects
40 Studies

Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies. Becky L Tsang , The American Journal of Clinical Nutrition, Volume 101, Issue 6, June 2015

“Meta-analysis results (limited to the MA, the recommended population assessment method) indicated a consistent percentage difference in S/P and RBC folate concentrations across MTHFR C677T genotypes. The countries represented in the included studies were Australia, Brazil, Canada, China, Costa Rica, the Czech Republic, Finland, France, Germany, Ghana, Greece, India, Ireland, Italy, Japan, Malaysia, Mexico, The Netherlands, New Zealand, Pakistan, Portugal, Spain, Taiwan, the United Kingdom, and the United States. ”

FEZEU (2018)

Placebo, Randomized
2381 Subjects

Fezeu LK, Ducros V, Guéant JL, et al. MTHFR 677C → T genotype modulates the effect of a 5-year supplementation with B-vitamins on homocysteine concentration: The SU.FOL.OM3 randomized controlled trial. PLoS One. 2018;13(5):e0193352. Published 2018 May 29. doi:10.1371/journal.pone.0193352

“Participants with the TT genotype exhibited a lower 5-year decrease in tHcy concentrations following a B-vitamin supplementation than did participants with the CC or CT genotype”

WILSON (2013)

Placebo, Randomized
1 427 Subjects

Hypertension. 2013 Jun;61(6):1302-8. doi: 10.1161/HYPERTENSIONAHA.111.01047. Epub 2013 Apr 22. Blood pressure in treated hypertensive individuals with the MTHFR 677TT genotype is responsive to intervention with riboflavin: findings of a targeted randomized trial. Wilson CP1, McNulty H, Ward M, Strain JJ, Trouton TG, Hoeft BA, Weber P, Roos FF, Horigan G, McAnena L, Scott JM.

“In conclusion, these results show that riboflavin supplementation targeted at hypertensive individuals with the MTHFR 677TT genotype can decrease BP more effectively than treatment with current antihypertensive drugs only and indicate the potential for a personalized approach to the management of hypertension in this genetically at-risk group.“

MCNULTY (2006)

Placebo, Randomized
680 Subjects

Circulation. 2006 Jan 3;113(1):74-80. Epub 2005 Dec 27. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. McNulty H

“homocysteine is highly responsive to riboflavin, specifically in individuals with the MTHFR 677 TT genotype. ”

HUANG (2019)

Placebo, Randomized
769 Subjects

Andrology. 2019 May 24. doi: 10.1111/andr.12652. Effects of folic acid on oligozoospermia with MTHFR polymorphisms in term of seminal parameters, DNA fragmentation, and live birth rate: a double-blind, randomized, placebo-controlled trial. Huang WJ

“In summary, the present experiment shows that [very high] folic acid supplementation has a beneficial effect on oligozoospermia with MTHFR 677 TT genotype in term of seminal parameters, seminal MDA, sperm DNA fragmentation, and pregnancy outcome.”

MECH (2016)

Placebo, Randomized
1 427 Subjects

J Clin Psychiatry. 2016 May;77(5):668-71. doi: 10.4088/JCP.15m10166. Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study. Mech AW1, Farah A.

“A combination of reduced B vitamins and micronutrients, when used in the treatment of MDD in patients with MTHFR polymorphism, resulted in a separation from placebo by week 2, and 42% of the treatment arm achieved remission by week 8. Further, clinical improvement correlated with a significant reduction in homocysteine levels in a majority of responders. These results support the homocysteine theory of depression and the safety and therapeutic benefit of reduced B vitamins as monotherapy for MDD, particularly in patients with MTHFR polymorphism.“

CABO (2015)

Placebo, Randomized
103 Subjects

Effect of polymorphisms in endothelial nitric oxide synthase and folate metabolizing genes on the concentration of serum nitrate, folate and plasma total homocysteine after folic acid supplementation. A double-blind cross-over study. Rona Cabo, Nutrition August 2014

“Polymorphisms in ….. folate genes affect the concentration of serum folate and ptHcy ”

EBISH (2003)

Placebo, Randomized
190 Subjects

Fertil Steril. 2003 Nov;80(5):1190-4. C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Ebisch IM1, van Heerde WL, Thomas CM, van der Put N, Wong WY, Steegers-Theunissen RP.

“In contrast to heterozygotes and homozygotes for C677T MTHFR polymorphism, sperm concentration in wild-types significantly improved after folic acid and zinc sulfate intervention.”

FOHR (2002)

Placebo, Randomized
160 Subjects

Am J Clin Nutr. 2002 Feb;75(2):275-82. 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Fohr IP1, Prinz-Langenohl R, Brönstrup A, Bohlmann AM, Nau H, Berthold HK, Pietrzik K.

“The response to tHcy-lowering therapy is influenced by MTHFR genotype. Women with the TT genotype seem to benefit the most from supplementation with [high dose] FA or MTHF. In women with the CT or CC genotype, FA is more effective than MTHF in lowering plasma tHcy.”

WILSON (2012)

Placebo, Randomized
82 Subjects

Am J Clin Nutr. 2012 Mar;95(3):766-72. doi: 10.3945/ajcn.111.026245. Epub 2012 Jan 25. Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR 677TT genotype: a 4-y follow-up. Wilson CP1, Ward M, McNulty H, Strain JJ, Trouton TG, Horigan G, Purvis J, Scott JM.

“Specifically in this genotype group [TT], we confirmed that the elevated BP observed was responsive to riboflavin and, relative to riboflavin intervention, conventional antihypertensive therapy appeared largely ineffective over the 4-y period. Thus, riboflavin could offer a low-cost strategy for managing elevated BP in this genetically predisposed group. ”

CRIDER (2011)

Intervention
932 Subjects

Am J Clin Nutr. 2011 Jun;93(6):1365-72. doi: 10.3945/ajcn.110.004671. Epub 2011 Apr 20. MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation. Crider KS1, Zhu JH, Hao L, Yang QH, Yang TP, Gindler J, Maneval DR, Quinlivan EP, Li Z, Bailey LB, Berry RJ.

“MTHFR TT was associated with lower folate concentrations, and the trend of TT < CC was maintained at even the highest doses …… MTHFR genotype was an independent predictor of plasma and RBC folate and plasma homocysteine concentrations and did not have a significant interaction with folic acid dose during supplementation.”

NAKAMURA (2002)

Intervention Study
534 Subjects

Am J Kidney Dis. 2002 May;39(5):1032-9. Methylenetetrahydrofolate reductase genotype, vitamin B12, and folate influence plasma homocysteine in hemodialysis patients. Nakamura T1, Saionji K, Hiejima Y, Hirayama H, Tago K, Takano H, Tajiri M, Hayashi K, Kawabata M, Funamizu M, Makita Y, Hata A.

“Functional vitamin B12 deficiency may exist, even in HD patients with normal vitamin B12 concentrations. The efficacy of vitamin B12 and folate supplementation on plasma Hcy levels may depend on MTHFR genotype.”

HUSTAD (2000)

Observational Cohort
423 Subjects

“The riboflavin-tHcy relationship was modified by genotype (P = 0.004) and was essentially confined to subjects with the C677T transition of the MTHFR gene.”

MCNULTY (2002)

Observational Study
286 Subjects

Am J Clin Nutr. 2002 Aug;76(2):436-41. Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. McNulty H1, McKinley MC, Wilson B, McPartlin J, Strain JJ, Weir DG, Scott JM.

“However, these expected relations in the total sample were driven by the TT group with the lowest riboflavin status, whose mean tHcy concentration (18.09 micromol/L) was almost twice that of the CC or CT group. By contrast, adequate riboflavin status rendered the TT group neutral with respect to tHcy metabolism.”

MCNULTY (2012)

Review

Int J Vitam Nutr Res. 2012 Oct;82(5):348-54. doi: 10.1024/0300-9831/a000130. Nutrition throughout life: folate. McNulty H1, Pentieva K, Hoey L, Strain J, Ward M.

“Intervention with supplemental riboflavin targeted specifically at individuals with the MTHFR 677TT genotype was shown to result in significant lowering of blood pressure in hypertensive people and in patients with CVD.”

MOTTAGHI (2019)

Placebo, randomized
80 Subjects

J Res Med Sci. 2019 Apr 26;24:36. doi: 10.4103/jrms.JRMS_774_18. eCollection 2019. The MTHFR C677T polymorphism influences the efficacy of folic acid supplementation on the nerve conduction studies in patients with diabetic polyneuropathy; A randomized, double blind, placebo-controlled study. Mottaghi T1, Khorvash F2, Kheirollahi M3, Maracy M4, Askari G1,5.

“The study determined that MTHFR C677T polymorphism effects the efficacy of folic acid supplementation on serum folic acid, homocysteine levels”