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PAPERS: 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 [Abstract] [Full text]

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Homocysteine and endothelial oxidative stress

Andrew McCaddon, MD, Peter Hudson, PhD   (19 October 2005)

Homocysteine: Folate is Not Enough.

Eddie Vos, Kilmer McCully MD, Veterans Affairs Boston Health Care System   (22 October 2005)

to perish, to publish, to haste, too...

Ivan Y. Torshin   (25 May 2006)

Homocysteine and endothelial oxidative stress 19 October 2005
Andrew McCaddon, MD, General Practitioner Gardden Road Surgery, Rhosllanerchrugog, Wrexham, North Wales, LL14 2EN, Peter Hudson, PhD Send response to journal: Re: Homocysteine and endothelial oxidative stress	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.
Homocysteine: Folate is Not Enough. 22 October 2005
Eddie Vos, maintains health-heart.org Sutton (Qc) Canada J0E 2K0, Kilmer McCully MD, Veterans Affairs Boston Health Care System Send response to journal: Re: Homocysteine: Folate is Not Enough.	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 µmol/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 µmol/L [NHANES] vs. ~22 µmol/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 µmol/L, a level not reported in (1), and that micro-nutrient fortification and supplementation is urgent, especially in areas with Hcy levels >10 µmol/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
to perish, to publish, to haste, too... 25 May 2006
Ivan Y. Torshin, Dir of Bioinformatics Consulting, LLC 125239, Moscow, Russia Send response to journal: Re: 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/abstract, 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