Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

Clarke, Robert; Bennett, Derrick; Parish, Sarah; Verhoef, Petra; Dötsch-Klerk, Mariska; Lathrop, Mark; Xu, Peng; Nordestgaard, Børge G.; Hólm, Hilma; Hopewell, Jemma C.; Saleheen, Danish; Tanaka, Toshihiro; Anand, Sonia S.; Chambers, John C.; Kleber, Marcus E.; Ouwehand, Willem H.; Yamada, Yoshiji; Elbers, Clara C.; Peters, Bas J M; Stewart, Alexandre F.R.; Reilly, Mary M.; Thorand, Barbara; Yusuf, Salim; Engert, James C.; Assimes, Themistocles L.; Kooner, Jaspal S.; Danesh, John; Watkins, Hugh; Samani, Nilesh J.; Collins, Rory; Pető, Richárd

doi:10.1371/journal.pmed.1001177

Cited by 178 publications

(140 citation statements)

References 32 publications

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“…A patient who is homozygous for the c.665C→T "thermolabile" variant but also has elevated homocysteine, however, may be at mildly increased risk for both of these events (venous thromboembolism odds ratio 1.27 and recurrent pregnancy loss pooled risk 2.7). 20,32 The patient can also be reassured that there is no evidence of any association with MTHFR "thermolabile" variant homozygosity and mortality, from cardiovascular disease or otherwise. 67,68 Once it is known that an individual is homozygous for the "thermolabile" variant, it is appropriate to review some of the known associations and possible risks.…”

Section: Acmg Practice Guidelinesmentioning

confidence: 99%

“…19 Furthermore, a more recent meta-analysis of unpublished data sets has cast doubts on the hypothesis that lifelong moderate homocysteine elevation has any effect on cardiovascular disease, raising the possibility that publication bias accounted for the previously observed aggregate association. 20 The potential associations between MTHFR genotype status and a number of medical complications have been evaluated using methodologies such as case-control, cohort, Mendelian randomization, and meta-analysis. A modest positive association has been found between the MTHFR "thermolabile" polymorphism and many different medical complications, including, but not limited to, thromboembolic disease (in non-North-American populations only), 21,22 stroke, [23][24][25][26][27] aneurysm, 28 peripheral artery disease, 29 migraine, 30 hypertension, 31,32 recurrent pregnancy loss, 33,34 male infertility, 35,36 risk for offspring with neural tube defects, 37,38 certain cancers, [39][40][41] neuropsychiatric disease, 42 and chemotherapy toxicity.…”

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confidence: 99%

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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%

mentioning

confidence: 99%

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

Hickey

Curry

Toriello

2013

Genetics in Medicine

134

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“…The public health importance of the impact of applying these cut‐off values is not fully understood (De Benoist, 2008). Elevated concentrations of circulating homocysteine were once considered as a functional indicator of folate deficiency because of their association with cardiovascular disease, but the causality of this association is now highly doubtful (Miller et al , 2010; Clarke et al , 2012). …”

Section: Evidence Of Folate Deficiencymentioning

confidence: 99%

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

et al. 2017

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SummaryFor decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine‐pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria‐endemic countries. We conclude that formal cost‐benefit analyses are required.

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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) . Of note, these meta-analyses have identified important geographical influences on the extent of excess CVD risk due to this polymorphism, strongly suggesting that environmental factors may have a modulating effect on the phenotype and thus CVD risk.…”

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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Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

Cited by 178 publications

References 32 publications

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

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

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