Environmental influence on the world-wide prevalence of a 776C>G variant in the transcobalamin gene (TCN2)

Jean-Louis Guéant ^1*, Nicodème Chabi ², Rosa-Maria Guéant-Rodriguez ¹, Osvaldo Mutchinick ³, Renée Debard ¹, Corinne Payet ¹, Xiaohong Lu ¹, Christian Villaume ¹, Jean-Pierre Bronowicki ¹, Edward Quadros ⁴, Ambaliou Sanni ⁵, Emile Amouzou ⁶, Bing Xia ⁷, Min Chen ⁷, Guido Anello ⁸, Paolo Bosco ⁸, Corrado Romano ⁸, Heidy Arrieta ³, Beatriz Sánchez ³, Antonino Romano ⁹, Bernard Herbeth ¹⁰, Wafaa Anwar ¹ and Fares Namour ¹

¹ INSERM U724, France
² Université de Cotonou, Benin
³ Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico
⁴ SUNY-Downstate Medical Center, United States
⁵ Univesité de Cotonou, Benin
⁶ University of Lomé, Togo
⁷ Wuhan University Medical School, China
⁸ IRCCS, Oasi Maria S.S, Italy
⁹ UCSC, CI Colombus Roma, Italy
¹⁰ INSERM U525, France

^* To whom correspondence should be addressed. E-mail: jl.gueant{at}chu-nancy.fr.

Accepted 4 January 2007

Abstract

Background: A 776C>G 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 B12. Objective: To evaluate the world-wide 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 subjects with severe malaria. Results: The frequencies of 776G allele were the highest in China (0.607 [95% confidence interval:0.554-0.659]), low in West Africa (Benin and Togo, 0.178 [0.154-0.206]) and intermediate in France (0.445 [0.408-0.481]), Italy (0.352 [0.299-0.409]), Marocco (0.370 [0.300-0.447]) and Mexico (0.374 [0.392-0.41.9]). The 776GG genotype was more frequent in Afro-Americans from New York (16.7 [8.4-30.7]) and in Afro-African patients with severe malaria (6.0% [95%CI: 3.7-9.6]) than in healthy Afro-African volunteers (p=0.0004 and p=0.0329, respectively), while no difference was observed for MTHFR 677TT and 677T allele. A disequilibrium of TCN2 genotype distribution was recorded in the patients with severe malaria, with a 2-fold higher GG genotypes 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: Our results suggest therefore that, 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 being malaria.

Keywords: Transcobalamin, homocysteine, malaria, nutrigenetics

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