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, Michael V.; Newcombe, Paul; Hubacek, Jaroslav A.; Sofat, Reecha; Ricketts, Sally L.; Cooper, Jackie A.; Breteler, Monique M.B.; Bautista, Leonelo E.; Sharma, Pankaj; Whittaker, John C.; Smeeth, Liam; Fowkes, F. G. R.; Algra, Ale; Шмелева, В М; Szolnoki, Zoltán; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A.; Singleton, Andrew B.; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B.; Rich, Stephen S.; Matarı́n, Mar; Norman, Paul; Flicker, Leon; Almeida, Osvaldo P.; Bockxmeer, Frank M. van; Shimokata, Hiroshi; Khaw, Kay‐Tee; Wareham, Nicholas J.; Bobák, Martin; Sterne, Jonathan A C; Smith, George Davey; Talmud, Philippa J.; Duijn, Cornelia M. van; Humphries, Steve E.; Price, Jackie F.; Ebrahim, Shah; Lawlor, Debbie A.; Hankey, Graeme J.; Meschia, James F.; Sandhu, Manjinder S.; Hingorani, Aroon D.; Casas, Juan P.

doi:10.1016/s0140-6736(11)60872-6

Cited by 293 publications

(232 citation statements)

References 58 publications

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“…59 This public health initiative may be incidentally reducing some of the perceived risk associated with MTHFR polymorphisms. 60,61 This is hypothesized to be one reason that an association between the "thermolabile" variant and venous thromboembolism is no longer observed in the North-American population. 21 The American Congress of Obstetricians and Gynecologists does not recommend the measurement of homocysteine or MTHFR polymorphisms in the evaluation of the etiology of venous thromboembolism.…”

Section: Acmg Practice Guidelinesmentioning

confidence: 99%

See 1 more Smart Citation

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

Hickey

Curry

Toriello

2013

Genetics in Medicine

134

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Section: Acmg Practice Guidelinesmentioning

confidence: 99%

“…61 There is no known contraindication to taking oral contraceptives. Neonates who have had strokes are underrepresented in current studies, so the interpretation of MTHFR genotyping in this setting is particularly challenging.…”

Section: Box 1: Acmg Recommendationsmentioning

confidence: 99%

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

Hickey

Curry

Toriello

2013

Genetics in Medicine

134

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“…Of particular interest, extensive evidence has led to a number of meta-analyses reporting a strong association between this polymorphism and CVD, particularly stroke (73)(74)(75)(76) . It has been estimated that individuals with the MTHFR 677TT polymorphism have a 14-21 % increased risk of CHD (75,77,78) .…”

Section: Riboflavin C 1 Metabolism and Cvd Riskmentioning

confidence: 99%

Riboflavin status, MTHFR genotype and blood pressure: current evidence and implications for personalised nutrition

et al. 2016

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Clinical deficiency of the B-vitamin riboflavin (vitamin B 2 ) is largely confined to developing countries; however accumulating evidence indicates that suboptimal riboflavin status is a widespread problem across the developed world. Few international data are available on riboflavin status as measured by the functional biomarker, erythrocyte glutathione reductase activation coefficient, considered to be the gold standard index. One important role of riboflavin in the form of flavin dinucleotide is as a co-factor for the folate-metabolising enzyme methylenetetrahydrofolate reductase (MTHFR). Homozygosity for the common C677T polymorphism in MTHFR, affecting over 10 % of the UK and Irish populations and up to 32 % of other populations worldwide, has been associated with an increased risk of CVD, and more recently with hypertension. This review will explore available studies reporting riboflavin status worldwide, the interaction of riboflavin with the MTHFR C677T polymorphism and the potential role of riboflavin in personalised nutrition. Evidence is accumulating for a novel role of riboflavin as an important modulator of blood pressure (BP) specifically in individuals with the MTHFR 677TT genotype, with results from a number of recent randomised controlled trials demonstrating that riboflavin supplementation can significantly reduce systolic BP by 5-13 mmHg in these genetically at risk adults. Studies are however required to investigate the BP-lowering effect of riboflavin in different populations and in response to doses higher than 1·6 mg/d. Furthermore, work focusing on the translation of this research to health professionals and patients is also required.Riboflavin: Methylenetetrahydrofolate reductase: MTHFR C677T: Blood pressure:Personalised nutrition Riboflavin (vitamin B 2 ) is a water-soluble B-vitamin defined chemically as 7,8-dimethyl-10-1′-D-ribityl isoalloxazine. It acts as a precursor for FMN and FAD (1) . Clinical riboflavin deficiency is not generally considered to be a problem in the developed world but in recent years evidence has shown that sub-optimal status may be more widespread than generally perceived based on studies reporting the functional biomarker, erythrocyte glutathione reductase activation coefficient (EGRac) generally considered as the gold standard index of status. Few international data are however available based on EGRac and reports on riboflavin status are more commonly based solely on dietary intake data. Although riboflavin is required for numerous metabolic reactions its role (in the form of FAD) as a cofactor for the folatemetabolising enzyme, methylenetetrahydrofolate reductase (MTHFR) has recently received particular attention. Homozygosity (MTHFR 677TT genotype) for a common polymorphism in MTHFR, affecting over 10 % of the UK and Irish populations and up to 32 % of other populations worldwide (2) , has been associated with an increased risk of CVD (3) and more recently with hypertension (4) . Emerging evidence from intervention trials supports a novel role for riboflav...

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“…Several meta-analyses to date have demonstrated an increased risk of CVD in individuals with the TT genotype compared to those without this genetic variant (1,2,(20)(21)(22) (Table 1). Those studies which assessed the risk of CHD events estimated a 14-16% higher risk in individuals with the TT genotype compared to those with the CC genotype (20,23) .…”

Section: Association Between the Mthfr 677c T Polymorphism And Cvd Riskmentioning

confidence: 99%

MTHFR677TT genotype and disease risk: is there a modulating role for B-vitamins?

et al. 2013

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Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme which requires riboflavin as its co-factor. A common polymorphism (677C→T) in the MTHFR gene results in reduced MTHFR activity in vivo which in turn leads to impaired folate metabolism and elevated homocysteine concentrations. Homozygosity for this polymorphism (TT genotype) is associated with an increased risk of a number of conditions including heart disease and stroke, but there is considerable variability in the extent of excess risk in various reports. The present review will explore the evidence which supports a role for this polymorphism as a risk factor for a number of adverse health outcomes, and the potential modulating roles for B-vitamins in alleviating disease risk. The evidence is convincing in the case which links this polymorphism with hypertension and hypertensive disorders of pregnancy, particularly preeclampsia. Furthermore, elevated blood pressure was found to be highly responsive to riboflavin intervention specifically in individuals with the MTHFR 677TT genotype. Future intervention studies targeted at these genetically predisposed individuals are required to further investigate this novel gene–nutrient interaction. This polymorphism has also been associated with an increased risk of neural tube defects (NTD) and other adverse pregnancy outcomes; however, the evidence in this area has been inconsistent. Preliminary evidence has suggested that there may be a much greater need for women with the MTHFR 677TT genotype to adhere to the specific recommendation of commencing folic acid prior to conception for the prevention of NTD, but this requires further investigation.

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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

Cited by 293 publications

References 58 publications

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

Riboflavin status, MTHFR genotype and blood pressure: current evidence and implications for personalised nutrition

MTHFR677TT genotype and disease risk: is there a modulating role for B-vitamins?

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