Homocysteine, the MTHFR 677 C→T polymorphism and family history of premature cardiovascular disease

Abstract

Background: Cardiovascular disease (CVD) is the main cause of premature death in the UK and accounts for 36% of all premature male deaths and 27% of female deaths every year (British Heart Foundation, 2006). Although many risk factors for CVD are known, family history has been identified as being of particular importance in premature CVD (Lloyd‐Jones et al., 2004). Recently, it was suggested that an elevated homocysteine (tHcy) may be associated with premature CVD (Homocystiene Studies Collaboration, 2002). The main genetic determinant of tHcy is the common 677 C→T polymorphism, in the enzyme methylenetetrahydrofolate reductase (MTHFR), which is prevalent in approximately 10% of the UK population. Relatively few studies have examined the association between tHcy and premature CVD and hardly any have considered the role of this polymorphism. The aim of this study therefore was to examine the relationships between the MTHFR 677 C→T polymorphism, tHcy and a family history of CVD in patients with established premature CVD.Methods: An analysis was conducted on medical, lifestyle and family history data collected from patients and age‐sex matched controls, recruited through the GENOVIT study in 2003. This case–control study involved n = 404 premature CVD patients and a similar number of age‐sex matched controls, all of whom were screened for the TT genotype. A subset of patients (n = 196) and controls (n = 167) provided a blood sample, from which the tHcy concentration was established. Independent sample t‐tests were used to determine differences between patients and controls and differences among genotype groups were examined using a one‐way analysis of variance, followed by a Tukey's post hoc test.Results: Plasma tHcy was significantly elevated in patients with a family history of CVD (compared to those without) (P = 0.013). A nonsignificant trend towards higher tHcy (compared to those without) was observed in patients with the TT genotype (P = 0.419). Furthermore, specifically in those with the TT genotype, those with a family history of CVD (compared to those without) showed significantly higher tHcy concentrations (P < 0.005). Those with the TT genotype who smoked had significantly higher tHcy (P < 0.05) than the CC and CT genotypes.Discussion: The findings presented provide evidence to support an association between the MTHFR 677C→T polymorphism, elevated homocysteine and family history of premature CVD. Given that dietary levels of riboflavin have been shown to lower homocysteine specifically in individuals with the TT genotype (McNulty et al., 2006), these results have implications for the dietary management of premature CVD in those individuals with a genetic predisposition for elevated tHcy. In conclusion, further research in larger cohort numbers, regarding the correlation between family history, tHcy and the MTHFR polymorphism, would be beneficial for establishing their cause and effect relationship.References British Heart Foundation (2006) All Deaths and Deaths Under 75 by Cause and Sex, 2005, England, Wales, Scotland, N Ireland and United Kingdom. Available at http://www.bhf.org.uk/research_health_professionals/resources/heart_statistics.aspx.Homocystine Studies Collaboration (2002) Homocysteine and the risk of ishaemic heart disease and stroke. JAMA288, 2015–2022.Llyod‐Jones, D.M., Nam, B.H., D’Agostino, R.B., Levy, D., Murabito, J.M., Wang, T.J., Wilson, P.W. & O’Donnell, C.J. (2004) Parental cardiovascular disease as a risk factor for cardiovascular disease in middle‐aged adults, a prospective study of parents and offspring. JAMA291, 2204–2211.McNulty, H., Dowey le, R.C., Strain, J.J., Dunne, A., Ward, M., Molloy, A.M., McAnena. L.B., Hughes, J.P., Hannon‐Fletcher, M. & Scott, J.M. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C‐>T polymorphism. Circulation113, 74–80.