Environmental influence on the worldwide prevalence of a 776C→G variant in the transcobalamin gene (TCN2)

Background: A 776CRG variant ( dbSNP ID: rs1801198) in the transcobalamin gene ( TCN2; MIM# 275350) decreases the cellular and plasma concentration of transcobalamin and thereby influences the cellular availability of vitamin B-12. Objective: To evaluate the worldwide prevalence of this variant and its association with homocysteine plasma level. Methods: The study was performed in 1433 apparently healthy subjects, including Afro-Americans and Afro-Africans and in 251 Afro-Africans participants with severe malaria. Results: The frequencies of the 776G allele were the highest in China ( 0.607; 95% CI 0.554 to 0.659), low in West Africa ( Benin and Togo, 0.178; 0.154 to 0.206), and intermediate in France ( 0.445; 0.408 to 0.481), Italy ( 0.352; 0.299 to 0.409), Morocco ( 0.370; 0.300 to 0.447) and Mexico ( 0.374; 0.392 to 0.419). The 776G genotype was more frequent in Afro-Americans from New York ( 16.7; 8.4 to 30.7) and in AfroAfrican patients with severe malaria ( 6.0%; 95% CI 3.7 to 9.6) than in healthy Afro- African volunteers ( p = 0.0004 and p = 0.033, respectively), while no difference was observed for MTHFR 677TT and 677T alleles. A disequilibrium of TCN2 genotype distribution was recorded in patients with severe malaria, with a twofold higher GG genotype than expected ( p = 0.010). An association between the TCN2 polymorphism and homocysteine was observed only in Mexico and France, the two countries with the highest rate of low plasma concentration of vitamin B12 (< 100 pmol/ l). Conclusion: Given the dramatic heterogeneity of the 776G allele frequency worldwide, this polymorphism may be prone to a selective pressure or confers an evolutionary advantage in confronting environmental factors, one of which is malaria.