Apolipoprotein E and methylenetetrahydrofolate reductase genetic polymorphisms in relation to other risk factors for cardiovascular disease in UK Caucasians and Black South Africans
Introduction
Coronary heart disease (CHD) risk depends on multiple factors including an important genetic component [1]. Lipid metabolism in humans is known to be strongly affected by polymorphisms of a number of genes [1], [2], [3]. The apolipoprotein E (apo E) gene, which belongs to this group, is located on chromosome 19 and has three common allelic variants known as apo E*2 (ε2), apo E*3 (ε3), and apo E*4 (ε4) [4], [5]. The corresponding apo E protein isoforms differ by their functional properties and, thus the ε4 allele is associated with increased levels of total and LDL cholesterol, while the opposite pattern is characteristic of the presence of ε2 [3], [4], [6]. There are reports linking the ε4 allele with CHD [6], [7], [8] and cerebrovascular disease [9], [10]. The presence of ε4 has recently been found to be closely associated with both increased risk and earlier onset of Alzheimer's disease [11].
Apo E is involved in lipoprotein metabolism and generation of hyperlipidemia, which until recently was believed to be the leading cause of CHD. However it has now become clear that hyperhomocysteinemia is an independent CHD risk factor [12], [13] and serves as a strong predictor of mortality in patients with coronary artery disease [14]. Increased plasma homocysteine concentration in humans was shown to be associated with the presence of a common 677C→T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene [15], [16], [17], [18]. This mutation is believed to cause thermolability and decreased activity of the enzyme, thus potentially impairing homocysteine remethylation and causing hyperhomocysteinemia in homozygous subjects, especially if their plasma folate levels are low [19]. Although the effect of the thermolabile MTHFR variant at the level of plasma homocysteine is well documented [15], [16], [17], [18], [20], there are conflicting reports regarding its impact on CHD risk. Some authors observed an increased CHD risk in the MTHFR 677TT homozygotes [15], [16], [17], [18], [21], whereas others failed to reveal any effect of the thermolabile allele [22], [23], [24], [25].
Although potentially important, unfavourable variants of polymorphic genes do not directly cause CHD. Their impact is subject to variation due to the involvement of numerous factors including other components of genetic background, environmental influences, life style, diet, etc., which may substantially differ between human populations. Interestingly, it has recently been reported that there may be ethnicity-dependent deviations from the generally observed pattern of association between apo E alleles, blood lipid concentrations and CHD risk [26], [27]. Similarly, several studies performed in Caucasian populations failed to reveal any significant association of the MTHFR 677T allele with an increased CHD risk [22], [23], [24], [25], while the latest reports from Japan show the variant to be strongly overrepresented in CHD patients [21], [28]. These findings indicate that further analysis of the distribution of CHD-related genetic polymorphisms and their role in different human populations and ethnicities is needed.
Studies of apo E allele distributions in different ethnic groups have shown similar patterns for most Caucasian populations. Allele ε3 is the most common one, with frequencies between 0.70 and 0.85, ε4 is less frequent, 0.10–0.20, and ε2 is the rarest one at 0.05–0.10 [29], [30], [31]. Substantial shifts in apo E allele distributions were observed in relatively small and isolated ethnicities like New Guinea Natives [32] or Khoi San Bushmen [33] and Aka pygmies [34] who display very high frequencies of ε4 allele or groups such as Alaska Natives [35] and Mayans of the Yucatan Peninsula [30], in which ε2 is extremely rare. Increased proportion of ε4 allele was found to be relatively common among ethnicities of sub-Saharan Africa [34], [36].
There are fewer MTHFR allele frequency studies in different ethnic groups, but it is known that the 677T allele frequency varies between 0.21 and 0.38 with 5–16% of homozygous carriers in Caucasian [20], [37] and Japanese [21], [28], [38] populations. Exceptionally low frequencies of the mutant allele have been found in Black Americans (0.11, no homozygotes) [39] and Canadian Innuit (0.06 with 1.2% of homozygotes) [40].
In the present study we compared distributions of the apo E and MTHFR alleles in the populations of Black South Africans and UK Caucasians from the Cambridge area and related these to concentrations of blood lipids, fibrinogen and blood pressure. Differences in morbidity and the main causes of mortality in South African Blacks, Whites and Asians are well known [41]. Black South Africans have a very low incidence of coronary heart disease [41], [42], although it is unknown whether this results from their mainly rural life style and dietary habits or from genetic mechanisms protecting this population from heart disease.
Section snippets
Subjects
The subjects were 207 clinically healthy volunteers including 107 UK Caucasians from the Cambridge area and 100 Black South Africans from the North West province. Most of the South African volunteers were Tswana-speaking people. Caucasian volunteers in Cambridge were recruited by the Dunn Clinical Nutrition Centre. The South African subjects were part of the Transition and Health during Urbanization of South Africans (THUSA) Study. All volunteers attended medical examinations, which included a
Apo E genotype and allele distribution
All three common alleles of apo E were detected among the study subjects. Genotype frequencies are presented in Fig. 1. Allele frequencies of 0.051 for ε2, 0.837 for ε3, and 0.112 for ε4 were found among Caucasians. Among Black South Africans these frequencies were: 0.145 for ε2, 0.570 for ε3, and 0.285 for ε4. In both groups, the observed genotype frequencies were not significantly different from Hardy–Weinberg equilibrium expected frequencies (results not shown). The presence of relatively
Discussion
It is well established that different populations often have very different distributions of alleles of polymorphic genes. Analysis of these polymorphisms may provide valuable clues for better understanding disease risk and morbidity structures in these populations. The main purpose of this study was to assess whether distributions of apo E and MTHFR genetic polymorphisms contribute to the apparently low incidence of CHD observed in Black South Africans [41], [42]. Both genes were shown to have
Acknowledgements
The volunteers who took part in this study are thanked for their enthusiastic participation. This study was supported by the Medical Research Council. The South African material was part of the Transition and Health during Urbanization of South Africans Study.
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