Clin Chem Lab Med 2003; 41(8):1028 – 1032 © 2003 by Walter de Gruyter · Berlin · New York Charles E. Adjalla 1 *, Emile K. Amouzou 1, 2 *, Ambaliou Sanni 3 , Idrissia Abdelmouttaleb 1 , Nicodème W. Chabi 3 , Fares Namour 1 , Batoma Soussou 4 and Jean- Louis Guéant 1 ** 1 Laboratory of Cellular and Molecular Pathology in Nutrition, INSERM 00-14, Faculty of Medicine, Vandoeuvre lès Nancy, France 2 Laboratory of Biochemistry and Nutrition, Lome, Togo 3 Laboratory of Biochemistry and Molecular Biology, Benin 4 Department of Cardiology, CHU de Lome, Togo 5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key en- zymes in the folate/vitamin B 12 -dependent remethyla- tion of homocysteine to methionine. The frequencies of MTHFR single nucleotide polymorphisms (SNPs), 677C→T, 1298A→C, 1317T→C and of MTR, 2756A→G, have been widely studied in Caucasians, but they have never been reported simultaneously in a large popula- tion from Sub-Saharan Africa. Presently, we report the prevalence of these SNPs and their relationship to ho- mocysteine in 240 subjects recruited in West Africa. The frequencies of the mutant genotypes 677TT (0.8%) and 1298CC (2%) were lower than that usually observed in Caucasians, while the frequency of the mutant 1317CC was higher (16%). We formed a systematic association of the mutated MTHFR 677C→T SNP with a 1298A/ 1317T common haplotype. The MTHFR mutant geno- type 677TT was associated with an intermediate hyper- homocysteinemia (92.4 ± 6.0 μmol/l) higher than that described in Caucasians. The 2756A→G SNP in the MTR was similarly distributed in Africans compared to Caucasians. In conclusion, the MTHFR 677TT or 1298CC genotypes are much rarer in Africans than in Cau- casians. The 677TT low frequency may be related to the high effect of this mutation on homocysteine metabo- lism in the environmental conditions of this African re- gion. Clin Chem Lab Med 2003; 41(8):1028 – 1032 Key words: Homocysteine; Single nucleotide polymor- phism; Methylenetetrahydrofolate reductase; Methion- ine synthase. Abbreviations: MTHFR, 5,10-methylenetetrahydrofo- late reductase; MTR, methionine synthase; SNP, single nucleotide polymorphism. Introduction 5,10-Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are two of the key en- zymes in the folate/vitamin B 12 -dependent synthesis of methionine, an upstream reaction to both DNA synthesis and DNA methylation. Mutations in the MTR or MTHFR genes may result in decreased en- zyme activity and hyperhomocysteinemia (1, 2). Ho- mocysteine, a branch-point metabolite of methionine metabolism, can be remethylated to methionine by MTR or degraded to cysteine in the trans-sulfuration pathway. The remethylation of homocysteine, which occurs by the transfer of a methyl group from the 5-methyltetrahydrofolate (MeTHF) via vitamin B 12 to homocysteine, is intimately linked to the reduction of the 5,10-methylenetetrahydrofolate by the MTHFR. Three single nucleotide polymorphisms (SNPs), 677C→T, 1298A→C including one silent mutation, 1317T→C, have been identified in the MTHFR gene (3). The 677C→T mutation leads to a thermolabile enzyme that shows a reduced activity and results in a moder- ate hyperhomocysteinemia when associated with low plasma folate levels in patients with occlusive vascu- lar diseases (4 – 6). The 1298A→C SNP is known to re- sult in altered enzyme activity but was not shown to be related to hyperhomocysteinemia in the absence of association with the MTHFR 677CT genotype (7). Another SNP, 2756A→G, has been identified in the vicinity of the binding domain of vitamin B 12 to the apoenzyme MTR and seems to have no clear effect on homocysteine blood level (8). The percentage of individuals homozygous for the 677C→T mutation is between 14% to 18% among the Caucasian population, while this percentage is consid- erably lower in African-Americans, less than 2% (9, 10). This mutation is associated with a common haplotype that may confer a selective advantage (9). The frequen- cies of the MTHFR 1298A→C and 1317 T→C and the MTR 2756A→G mutations, and their influence on the plasma homocysteine levels, have never been evalu- ated in a large black population from Africa. The pre- sent study was therefore undertaken first to describe the frequency of the three mutations in the MTHFR gene and the one in the MTR gene in a population from two West African countries, and to look for the respec- tive influence of these genetic factors and of nutritional factors on the plasma homocysteine levels. *These authors contributed equally to this work. **E-mail of the corresponding author: Jean-Louis.Gueant@medecine.uhp-nancy.fr Low Frequency of Mutated Methylenetetrahydrofolate Reductase 677C→T and 1298A→C Genetics Single Nucleotide Polymorphisms (SNPs) in Sub-Saharan Populations Brought to you by | Karolinska Institute Authenticated Download Date | 5/26/15 7:24 PM