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Homocysteine and Cardiovascular Risk

Effect of Lifestyle in Relation to MTHFR(C677T) Genotype

Lise Lotte Nystrup Husemoen


It has been hypothesized that total homocysteine (tHcy) is causally related to the development of cardiovascular disease (CVD). It is therefore important to identify modifiable factors such as lifestyle factors that influence tHcy.

The aims of the current PhD study consisted of three parts: 1) to examine the effects of sex, age and MTHFR(C677T) genotype on tHcy (descriptive study), 2) to examine the effects of various lifestyle factors – dietary habits, smoking, physical activity, coffee, tea, and alcohol – on tHcy in relation to MTHFR genotype (analytic study), and 3) to examine the effects of lifestyle changes and changes in lifestyle related biological CVD risk markers on tHcy in relation to MTHFR genotype (intervention study).

The study population comprised an age- and sex-stratified random sample (subsample of the Inter99 study) of 6,508 men and women aged 30-60 years invited to a health examination during November 1999 - January 2001. The health examination included a self-administered questionnaire, a physical examination, blood tests, and an individual IHD risk assessment using the computer program PRECARD®. Only participants assessed to be at increased CVD risk were invited to the re-examination after one year. A total of 2,788 participants at baseline and 915 participants at follow-up were eligible for statistical analyses (multiple regression).

Results of the descriptive study showed that men had higher tHcy than women. A statistical significant interaction was observed between age and MTHFR genotype. Older age was positively associated with tHcy in CC and CT individuals and negatively associated with tHcy in TT individuals. Accordingly the TT genotype was associated with higher tHcy especially at younger ages.
Results of the analytic study indicated that less healthy dietary habits, daily smoking, and coffee consumption were associated with elevated tHcy. Wine consumption was related to tHcy in a J-shaped fashion. Beer consumption was negatively associated with tHcy. No associations were observed between tHcy and physical activity, and tea consumption, respectively. A tendency toward a stronger effect in TT individuals compared with CC and CT individuals was observed. However, only the gene-lifestyle interaction between smoking and MTHFR genotype remained statistically significant after multiple adjustments.
In the intervention study none of the studied lifestyle changes was significantly associated with tHcy. However, changes in tHcy were related to changes in several biological CVD risk markers. Positive associations were observed between changes in tHcy and changes in total cholesterol, HDL cholesterol, LDL cholesterol, and systolic blood pressure. A negative association was observed between changes in tHcy and changes in weight. No associations were observed between changes in tHcy and changes in diastolic blood pressure, triglycerides, and waist circumference after multiple adjustments.

Methodological issues
Due to the observational design of the study methodological problems such as chance, bias and confounding cannot be excluded. Most importantly no information on supplement use, dietary intake, or blood concentrations of folate and the other B vitamins (B12, B6, and B2) was available. Since these vitamins are major determinants of tHcy and also related to lifestyle habits, they are important confounders, which may very well explain some of the observed results.

Male sex, older age, and the MTHFR TT genotype have consistently been associated with elevated tHcy in cross-sectional population based studies. The finding of an interaction effect between age and MTHFR genotype suggests that unknown regulatory mechanisms may lower tHcy in TT individuals as they age.
Review of the existing literature suggests that dietary habits, smoking, coffee, alcohol, and perhaps physical activity, and tea consumption may be important tHcy determinants in the general population. However, some inconsistencies have been observed, and residual confounding from vitamin intake cannot be excluded. In addition interaction effects between several lifestyle factors and MTHFR(C677T) genotype have been reported, suggesting that TT individuals may be genetically predisposed to elevated tHcy in response to an unhealthy lifestyle. 
The relation between biological markers and CVD are in general not very strong and are in many studies weakened upon adjustment for other tHcy determinants.

Several potential causal and non-causal pathways may link lifestyle, tHcy, and CVD. Rather than being a causal risk factor, elevated tHcy may just be an indicator of subclinical disease, or an innocent marker of unhealthy lifestyle and low vitamin status.