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Homocysteïne: uitgemeten?
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Drie stellingen en twee vragen
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1.Hoe hoger de plasmaspiegel Hcy, des te hoger het risico op hartvaatziekten
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Marfan-like stature
Scoliosis and osteoporosis
Mental retardation
Lens dislocation
High incidence of venous
thromboembolism and atherothrombosis
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‘Mild’ Hyperhomocysteinaemia Is Common
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High Plasma Hcy Is Associated with a Greater Risk of Cardiovascular Disease
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Two meta-analyses
(Clarke, JAMA 2002; Wald, BMJ 2002)
3 mol/L (~25%) Hcy increase
ischaemic heart disease (%) 11 (4-17) 15 (10-20)
stroke (%) 19 (5-31) 22 (14-30)
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2.Het verband tussen Hcy en hartvaatziekten is waarschijnlijk causaal
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Causaal of niet? Rothman, 1976; Rothman and Greenland, 1998
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Two meta-analyses
(Clarke, JAMA 2002; Wald, BMJ 2002)
3 mol/L (~25%) Hcy increase
ischaemic heart disease (%) 11 (4-17) 15 (10-20)
stroke (%) 19 (5-31) 22 (14-30)
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diet
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Vascular Outcomes in Cystathionine Beta Synthase Deficiency ATVB 2001;21:2080
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Associated Treatment Potential
with CVD? effective? bias?
Severe yes yes natural history
HHcy
(>100 µM)
Mild yes residual confounding,
HHcy eg by lifestyle
(12-30 µM) factors
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Mendelian Randomisation
The random assortment of genes transferred
from parent to offspring at the time of
gamete formation
Akin to an RCT of genetic variants
Depends on genetic variant resulting in the
intermediate phenotype of interest
Potential biases include population stratification
and linkage disequilibrium (the association of
genetic polymorphisms because the polymorphisms
are close together on the genome)
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Diet
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MTHFR, TT vs CC
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MTHFR, TT vs CC
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Associated Treatment Potential
with CVD? effective? bias?
Severe yes yes natural history
HHcy
(>100 µM)
Mild yes residual confounding,
HHcy eg by lifestyle
(12-30 µM) factors
MTHFR yes - linkage disequilibrium,
Polymorphism other
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The assumption that the association between hyperhomocysteinaemia and cardiovascular disease is indeed causal is the simplest explanation of the totality of the observations
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Associated Treatment Potential
with CVD? effective? bias?
Severe yes yes natural history
HHcy
(>100 µM)
Mild yes residual confounding,
HHcy eg by lifestyle
(12-30 µM) factors
MTHFR yes - linkage disequilibrium,
Polymorphism other
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3.Verlaging van ‘milde’ Hcy met B-vitaminen verlaagt het risico op HVZ niet
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‘Mild’ HHcy Can Be Lowered with Folic Acid
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Wald, BMJ 2006
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Verlaging van ‘milde’ HHcy: RCT’s Cochrane, 2009
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Cochrane 2009
n=24210
Coronaire hartziekten 1,03 (0,94-1,13)
Herseninfarct 0,89 (0,73-1,08)
Sterfte 1,00 (0,92-1,09)
Kanker 1,06 (0,90-1,25)
(n=12361)
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Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine Jama 2010;303:2486
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Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine Jama 2010;303:2486
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Dia 28
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Associated Treatment Potential
with CVD? effective? bias?
Severe yes yes natural history
HHcy
(>100 µM)
Mild yes no residual confounding,
HHcy eg by lifestyle
(12-30 µM) factors
MTHFR yes - linkage disequilibrium,
Polymorphism other
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4.Er klopt iets niet, maar wat?
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Foliumzuur (>200 µg/d) is niet hetzelfde als 5-methyltetrahydrofolaat
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Hoge dosis foliumzuur (>1 mg/d) is niet hetzelfde als natuurlijke folaatinname (~400 µg/d)
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5.Wat nu?
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MTHFR - FAD binding is weakened in the TT genotype and is strengthened by 5-CH3-THF
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Low folate status impairs DNA methylation
in individuals with the TT genotype
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Hcy may cause cardiovascular disease through multiple mechanisms
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Dia 37
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2. Many types of folate species exist, with different functions
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… the redox state …
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… many types of intracellular folates …
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High folate during disease process:
Stimulation inflammatory cells (eg macrophages)
Stimulatie proliferating cells (eg vsmc)
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Geen verband gen en confounders
Geen verband gen en ziekte los van risicofactor
Risicofactor is werkelijk dé causale factor
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Cochrane 2009 Cochrane + Search
n=24210 n=37845
CHZ 1,03 (0,94-1,13)
Stroke 0,89 (0,73-1,08)
MACE . . . 1,01 (0,97-1,05)
Sterfte 1,00 (0,92-1,09)
Kanker 1,06 (0,90-1,25)
(n=12361)
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