Introduction
Hyperhomocysteinemia (HHcy) is a medical condition characterized by high concentrations of plasma homocysteine (Hcy) and it has been associated with increased risk for many disorders, including vascular and neurodegenerative diseases, pregnancy complications, male infertility, birth defects, diabetes, renal diseases, osteoporosis, neuropsychiatric disorders and cancers [1]–[3].
Plasma levels of Hcy are influenced by both environmental and genetic factors. The main environmental factors include vitamins folate, B12, B6, and B2 [4]–[7]. The major genetic factors are polymorphisms in genes encoding homocysteine metabolizing enzymes, such as methylenetetrahydrofolate reductase (MTHFR) C677T, A1298C and methionine synthase reductase (MTRR) A66G polymorphisms.
MTHFR plays a critical role in catalyzing the irreversible reduction of 5,10-methylenetrahydrofolate to 5-methyltetrahydrofolate, which serves as the methyl donor for the vitamin-B12-depedent remethylation of homocysteine to methionine and for the synthesis of purine, DNA, and RNA. Several polymorphisms in the MTHFR have been identified, however, only the C677T and A1298C polymorphisms have been expressed and confirmed to affect the enzyme activity [8], [9]. The C677T polymorphism is a C to T transition at base pair 677 resulting in an alanine to valine substitution.
This polymorphism encodes for a thermolabile variant that decreases enzyme activity by 65% and increases plasma total homocysteine (tHcy) levels especially under the conditions of low dietary folate [10]. The A1298C polymorphism is an A to C transition at base pair 1298 leading to a glutamate to alanine substitution. The polymorphism results in the reduction of the enzyme activity, although to lesser extent than the C677T polymorphism [11]. Neither the homozygous nor the heterozygous state for the A1298C polymorphism is associated with increased plasma homocysteine and/or lower blood folate concentrations. However, combined heterozygosity for the A1298C and C677T polymorphisms is associated with decreased enzyme activity, elevated plasma homocysteine concentrations and reduced plasma folate levels [9].
MTRR is another key enzyme involved in homocysteine metabolism, which is responsible for the remethylation of Hcy to methionine via a vitamin-B12-dependent reaction. The MTRR restores methionine synthase (MTR) activity and is consequently a critical determinant of Hcy levels [12]. The most common polymorphism in the MTRR gene is the substitution of A for G at nucleotide 66 (A66G), which decreases the enzyme activity and the rate of Hcy remethylation [13].
Many epidemiological studies have indicated that the MTHFR C677T, A1298C and MTRR A66G polymorphisms are associated with increased risk for several disorders aforementioned [1], [14]–[20]. The prevalence of the three polymorphisms varies in different geographical regions and ethnic groups. For example, the MTHFR 677T allele frequency is often reported to be high in Europe (24.1–64.3%), and low in Africa (0–35.5%). The MTHFR 1298C allele frequency is approximately 20–70% in Asia, 24–46% in Europe, and 0–15% in America, although it has not been more extensively studied than the C677T [21], [22]. The highest and the lowest MTRR 66G allele frequencies are reported among Hispanics (28.65%) and Caucasians (54.4%), respectively [23]. Additionally, it is of interest that a north-to-south incline of increase in the MTHFR 677T allele frequency has been observed among Europeans and North Americans [24], [25], but a reverse trend has also been reported among Pakistanis, Indians, and Chinese minority groups [26]–[28]. The reasons for these distributional differences are still unclear and can involve both genetic and environmental factors. Nevertheless, accurate information on the prevalence of these polymorphisms may be beneficial to studies of gene-disease associations, population genetics and health impact evaluation.
Heretofore, the studies on the three polymorphisms are performed mainly among European and North American populations, and the data on the distributions of these polymorphisms among Chinese population are limited. The Han nationality is the largest among the 56 nationalities in China, making up 92% of the total population. The Han population are distributed widely from north to south of China. Due to high geographical, social and dietary diversity in China, we hypothesized a varied prevalence of these polymorphisms among the Chinese Han populations residing in different regions. In addition, due to the changing of life styles and dietary habits, like in any other developing countries the rates of Hcy-related diseases, such as stroke, coronary heart disease, hypertension, are markedly increasing in China [29]. It is therefore essential to investigate the heterogeneity in the prevalence of these polymorphisms among the Chinese Han population and compare the genetic markers with other published data of different populations around the world. In this study, we showed the prevalence of the MTHFR C677T, A1298C and MTRR A66G polymorphisms among 15357 Chinese Han adults from 10 geographical regions.
Materials and Methods
Ethics Statement
The study was conducted in accordance with the principles stipulated by the Declaration of Helsinki and all procedures were approved by the ethics review committee of the China Medical University. All specimens and survey data were obtained with written informed consents from all participants prior to study entry and subsequently anonymised.
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