Meta-analysis of MTHFR 677C→ T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.38611.658947.55 (Published 03 November 2005) Cite this as: BMJ 2005;331:1053
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The meta-analysis by Lewis et al shows the MTHFR 677C->T variant associated with increased coronary heart disease [CHD] via a higher level of homocysteine [Hcy] (+2.24 �mol/L in table 1 in (1
)). This is important and plausible but the focus on folate alone is misplaced being but one of the many micro-nutrients reducing the life-long Hcy effects on artery architecture and structural integrity.
The MTHFR enzyme only remethylates Hcy in the presence of vitamin B12. Also, the level of Hcy, and thus of the putative damage to the 3 long-living structural artery components (collagens, proteo-glycans and elastin, the
fibrillin 'fiber reinforced elastomer' with a reported half-life of 40-70 years) is made possible by deficiencies in a host of additional micro-nutrients. These are: vitamins B2, B6 and C, copper, zinc, magnesium,
choline and betaine, the latter being the non MTHFR dependent Hcy remethylator found in liver and whole grain products.
Hcy is generated in all cell types from methylation reactions and its toxic thiolactone [HcyT] is formed in error-editing in protein synthesis. Hcy is also arguably our best biomarker for micro-nutrient status and geographical
variance (1) is explained by micro-nutrient intakes, with 15 year olds in the U.S. at mean levels of 6 �mol/L [NHANES] vs. ~22 �mol/L in mean 24 year olds in India (2),
countries with, respectively, declining and increasing CHD.
Dose-dependent Hcy damage is relentless and consists of altering cysteine disulfide bridges in long-living proteins and (OH)lysine generated linkages in collagen and elastin (desmosine). Hcy may affect the core protein of proteoglycans and their level of sulfation, and may thiolate (lysine in) any protein. Hcy has pleiotropic effects on atherogenesis, promoting oxidative stress, endothelial dysfunction, and procoagulant effects. HcyT promotes
aggregation of LDL and phagocytosis of LDL aggregates by vascular macrophages. HcyT is hydrolyzed by the paraoxonase activity of HDL.
We argue that CHD is rare when maintaining Hcy <_7 mol="mol" l="l" a="a" level="level" not="not" reported="reported" in="in" _1="_1" and="and" that="that" micro-nutrient="micro-nutrient" fortification="fortification" supplementation="supplementation" is="is" urgent="urgent" especially="especially" areas="areas" with="with" hcy="hcy" levels="levels"/>10 �mol/L, or with CHD; folate helps but is not enough.
1: Lewis SJ, Ebrahim S, Smith GD. Meta-analysis
of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? BMJ 10-10-2005. Medline 16216822.
2. Misra A, Vikram NK, Pandey RM, Dwivedi M, Ahmad FU et al. Hyperhomocysteinemia,
and low intakes of folic acid and vitamin B12 in urban North India. Eur J Nutr. 2002;41(2):68-77. Medline 12083316.
Competing interests:
None declared
Competing interests: No competing interests
Sir,
Lewis et al found little evidence for an association of the MTHFR 677
C->T polymorphism and coronary heart disease in Europe, North America,
or Australia, suggesting that the observed association between plasma
homocysteine and coronary heart disease risk might be due to a detrimental
effect of existing atherosclerosis on homocysteine concentrations (1).
The methionine synthase reaction, which converts homocysteine to
methionine, is extremely sensitive to redox changes, at least in vitro
(2). Vascular endothelium is particularly vulnerable to oxidative stress;
it lacks an intact transulfuration pathway, which diverts homocysteine
towards synthesis of the important intracellular antioxidant glutathione.
It also lacks the alternative betaine:homocysteine methyltransferase
pathway (3).
The surface area of vascular endothelial cells is equivalent to six
tennis courts in an average-sized man (4). Increased endothelial export
of homocysteine under conditions of oxidative stress might be the source
of moderately elevated serum levels found in association with vascular
disease. If confirmed, this mechanism has important implications for the
Polypill. The inclusion of antioxidants such as N-acetylcysteine (NAC)
might be considered. NAC also has beneficial angiotensin II antagonist
properties, and is capable of reducing atheroma progression (5) (6).
Reference List
1. Lewis, S. J., Ebrahim, S., and Smith, G. D. Meta-Analysis of
MTHFR 677C->T Polymorphism and Coronary Heart Disease: Does Totality of
Evidence Support Causal Role for Homocysteine and Preventive Potential of
Folate? BMJ 10-10-2005.
2. Drummond, J. T., Huang, S., Blumenthal, R. M., and Matthews, R.
G. Assignment of Enzymatic Function to Specific Protein Regions of
Cobalamin-Dependent Methionine Synthase From Escherichia Coli.
Biochemistry 14-9-1993;32(36):9290-5.
3. Jacobsen, D. W. Cellular mechanisms of homocysteine pathogenesis
in atheroscleroris. Carmel, R. and Jacobsen, D. W. Homocysteine in Health
and Disease. 1 ed. Cambridge: Cambridge University Press; 2001. pp.425-40.
4. Henderson, A. H. St Cyres Lecture. Endothelium in Control.
Br.Heart J 1991;65(3):116-25.
5. Ullian, M. E., Gelasco, A. K., Fitzgibbon, W. R., Beck, C. N.,
and Morinelli, T. A. N-Acetylcysteine Decreases Angiotensin II Receptor
Binding in Vascular Smooth Muscle Cells. J Am Soc.Nephrol. 2005;16(8):2346
-53.
6. Ivanovski, O., Szumilak, D., Nguyen-Khoa, T., Ruellan, N., Phan,
O., Lacour, B., Descamps-Latscha, B., Drueke, T. B., and Massy, Z. A. The
Antioxidant N-Acetylcysteine Prevents Accelerated Atherosclerosis in
Uremic Apolipoprotein E Knockout Mice. Kidney Int. 2005;67(6):2288-94.
Competing interests:
AMc and PH are scientific advisors for, and shareholders of, COBALZ Limited, a UK-based company with IP relating to the treatment and prevention of functional vitamin B12 deficiency.
Competing interests: No competing interests
to perish, to publish, to haste, too...
SIR
I admire authors' conciseness in their report [1]-- they did not
appear to include any other data than a general list of refereces to the
studies they analyzed. I also admire their courage to report just another
negative finding without providing any factual background nor any actual
proof to the reader.
Meta-analyses are, typically, done by collecting all of the
publication data into on large table and then by analyzing all of the
interactions of interest. In many cases, authors are normally provide this
intermediate table (slang: 'meta-table') allowing the reader to judge how
accurate their analysis actually was (for instance, see [2] and the
supplementary table there). In the present study [1] , which appears to
report a negative association, no evidence of a careful analysis being
done is presented to the interested reader.
Thus, in [2], the authors were very kind to provide most of the meta-
table they used in their meta-analysis. This allowed me, among other
readers, to find several strong confounders and to re-analyze again their
thorough, albeit incomplete work [3]. After the analysis, it became clear
that the authors'
1. neglect of the considerable bias from the very small studies,
2. neglect of the accurate ethnicity report and
3. neglect of the type of the study (case control vs
nested vs prospective etc)
resulted in reporting of 4 negative associations [2] where as, in
facts, these were statistically strong associations with P well below
0.001 [3].
Unfortunately, the daring courage of the authors of the present study
[1] entirely prevents me (or any other interested reader of BMJ, for that
matter) to take a better look on the problem.
Although it may seem a bit foolhardy, I would recommend BMJ editorial
staff to require supplementary tables (of the kind given in [2]) for all
meta-analyses accepted for publication in the journal. Otherwise, we are
dealing with sheer opinions, biases, wrangling and not with scientific
research.
REFERENCES
[1] Sarah J Lewis, Shah Ebrahim, and George Davey Smith
Meta-analysis of MTHFR 677CT polymorphism and coronary heart disease: does
totality of evidence support causal role for homocysteine and preventive
potential of folate?
BMJ 2005; 331: 1053
[2] Ye Z, Liu EH, Higgins JP, Keavney BD, Lowe GD, Collins R, Danesh
J. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis
of 66,155 cases and 91,307 controls. Lancet. 2006 Feb 25;367(9511):651-8.
See the web-extras at
http://www.thelancet.com/journals/lancet/article/PIIS0140673606682639/ab...,
especially the table mmc2.pdf
[3] Torshin I.Y. Bioinformatics in post-genomic biology: physiology
and medicine, Nova Sci, NY, in press (2007-2008).
Competing interests:
None declared
Competing interests: No competing interests