Homocysteine and Coronary Heart Disease: Meta-analysis of Case-Control Studies, Avoiding Publication Bias
Background:
Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality.
Methods and Findings:
Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases).
Conclusions:
The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
: Please see later in the article for the Editors' Summary
Vyšlo v časopise:
Homocysteine and Coronary Heart Disease: Meta-analysis of Case-Control Studies, Avoiding Publication Bias. PLoS Med 9(2): e32767. doi:10.1371/journal.pmed.1001177
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pmed.1001177
Souhrn
Background:
Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality.
Methods and Findings:
Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases).
Conclusions:
The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
: Please see later in the article for the Editors' Summary
Zdroje
1. McCullyKS 1969 Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56 111 128
2. MuddSHSkovbyFLevyHLPettigrewKDWilckenB 1985 The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37 1 31
3. ClarkeRDalyLRobinsonKNaughtonECahalaneS 1991 Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324 1149 1155
4. Homocysteine Studies Collaboration 2002 Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288 2015 2022
5. ClarkeRHalseyJLewingtonSLonnEArmitageJ 2010 Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 170 1622 1631
6. WaldDSMorrisJKWaldNJ 2011 Reconciling the evidence on serum homocysteine and ischaemic heart disease: a meta-analysis. PloS One 6 e16473 doi:10.1371/journal.pone.0016473
7. FrosstPBlomHJMilosRGoyettePSheppardCAMatthewsRG 1995 A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10 111 113
8. JacquesPFBostomAGWilliamsRREllisonRCEckfeldtJH 1996 Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93 7 9
9. Davey SmithGEbrahimS 2003 ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32 1 22
10. WaldDSLawMMorrisJK 2002 Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325 1202
11. KlerkMVerhoefPClarkeRBlomHJKokFJ 2002 MTHFR 677C->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288 2023 2031
12. LewisSJEbrahimSDavey SmithG 2005 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 331 1053
13. UK Department of Health Scientific Advisory Committee 2006 Folate and disease prevention London HMSO
14. WaldDSWaldNJMorrisJKLawM 2006 Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence. BMJ 333 1114 1117
15. PedenJFHopewellJCSaleheenDChambersJCHagerJ The Coronary Artery Disease (C4D) Genetics Consortium 2011 A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 43 339 344
16. SchunkertHKönigIRKathiresanSReillyMPAssimesTL 2011 Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43 333 338
17. ClarkeRXuPBennettDLewingtonSZondervanK 2006 Lymphotoxin-alpha gene (LTA) and risk of myocardial infarction in 6928 cases and 2712 controls in the ISIS case-control study. PloS Genetics 2 e107 doi:10.1371/journal.pgen.0020107
18. AnandSSXieCPareGMontpetitARangarajanS 2009 INTERHEART Investigators. Genetic variants associated with myocardial infarction risk factors in over 8000 individuals from five ethnic groups: the INTERHEART Genetics Study. Circ Cardiovasc Genet 2 16 2519
19. Tunstall-PedoeHKuulasmaaKAmouyelPArveilerDRajakangasAM 1994 Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 90 583 612
20. BrattstromLWilckenDEOhrvikJBrudinL 1998 Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 98 2520 2526
21. ClarkeRFrostCSherlikerPLewingtonSCollinsR for the Homocysteine-Lowering Trialists' Collaboration 2005 Dose-dependent effects of folic acid on plasma homocysteine concentrations. A meta-analysis of the randomised trials. Am J Clin Nutr 82 806 812
22. VITATOPS Trial Study Group 2010 B vitamins in patients with recent transient ischaemic attack or stroke in the vitamins to prevent stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol 9 855 865
23. GalanPKesse-GuyotECzernichowSBrianconSBlacherJ 2010 Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: randomised placebo controlled trial. BMJ 341 c6273
24. BostomAGCarpenterMAKusekJWLeveyASHunsickerL 2011 Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant participants: primary results from the folic acid for vascular outcome reduction in transplantation trial. Circulation 123 1763 1770
25. PooleCGreenlandS 1999 Random-effects meta-analyses are not always conservative. Am J Epidemiol 150 469 475
26. GreenlandS 1987 Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 9 1 30
27. CheneGThompsonSG 1996 Methods for summarizing the risk associations of quantitative variables in epidemiologic studies in a consistent form. Am J Epidemiol 144 610 621
28. CochranW 1954 The combination of estimates from different experiments. Biometrics 10 101 129
29. HigginsJPThompsonSGDeeksJJAltmanDG 2003 Measuring inconsistency in meta-analyses. BMJ 327 557 560
30. EasterbrookPJBerlinJAGopalanRMatthewsDR 1991 Publication bias in clinical research. Lancet 337 867 872
31. Yamaguchi-KabataYNakazonoKTakahashiASaitoSHosonoN 2008 Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am J Hum Genet 83 445 456
32. HolmesMVNewcombePHubacekJASofatRRickettsSL 2011 et al. 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. Lancet 378 584 594
33. Davey SmithGEbrahimS 2005 What can mendelian randomisation tell us about modifiable behavioural and environmental exposures? BMJ 330 1076 1079
34. NitschDMolokhiaMSmeethLDeStavolaBLWhittakerJC 2006 Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol 163 397 403
35. BagleyPJSelhubJ 1998 A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci U S A 95 13217 13220
Štítky
Interné lekárstvoČlánok vyšiel v časopise
PLOS Medicine
2012 Číslo 2
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Pleiotropní účinky statinů na kardiovaskulární systém
- Statiny indukovaná myopatie: Jak na diferenciální diagnostiku?
- Zástava srdce u pacienta se střelnými ranami – kazuistika
- Statinová intolerance
Najčítanejšie v tomto čísle
- The Activities of Current Antimalarial Drugs on the Life Cycle Stages of : A Comparative Study with Human and Rodent Parasites
- Association between Clean Delivery Kit Use, Clean Delivery Practices, and Neonatal Survival: Pooled Analysis of Data from Three Sites in South Asia
- Prevalence, Distribution, and Impact of Mild Cognitive Impairment in Latin America, China, and India: A 10/66 Population-Based Study
- Characterisation of Hospital Ward–Based Transmission Using Extensive Epidemiological Data and Molecular Typing