Heterogenous Distribution of MTHFR Gene Variants among Mestizos and Diverse Amerindian Groups from Mexico.

Cecilia Contreras-Cubas,Lorena Orozco,Elvia C Mendoza-Caamal,José Concepción Jiménez-López,Beatríz E Sánchez-Hernández,Osvaldo M Mutchinick,Yolanda Saldaña-Alvarez,Gabriela Ortiz-Cruz,Eva Gabriela Salas-Bautista,Angélica Martínez-Hernández,Emilio J Córdova,Francisco Barajas-Olmos,Miguel Cid,Juan Carlos Fernández-López,Humberto García-Ortiz,Federico Centeno-Cruz,Zoha Kibar

doi:10.1371/journal.pone.0163248

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Folate deficiency has been related to several conditions, including neural tube defects (NTDs) and cardiovascular diseases. Hence, MTHFR genetic variants have been studied worldwide, particularly the C677T and A1298C. We genotyped the C677T and A1298C MTHFR polymorphisms in Mexican Amerindians (MAs), from the largest sample included in a genetic study (n = 2026, from 62 ethnic groups), and in a geographically-matched Mexican Mestizo population (MEZ, n = 638). The 677T allele was most frequent in Mexican individuals, particularly in MAs. The frequency of this allele in both MAs and MEZs was clearly enriched in the South region of the country, followed by the Central East and South East regions. In contrast, the frequency of the 1298C risk allele in Mexicans was one of the lowest in the world. Both in MAs and MEZs the variants 677T and 1298C displayed opposite allele frequency gradients from southern to northern Mexico. Our findings suggest that in Mestizos the 677T allele was derived from Amerindians while the 1298C allele was a European contribution. Some subgroups showed an allele frequency distribution that highlighted their genetic diversity. Notably, the distribution of the frequency of the 677T allele was consistent with that of the high incidence of NTDs reported in MEZ.

Highlights

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway
To gain global insight into the frequency of the C677T and A1298C polymorphisms in the Mexican population, we compared the genotype and allele frequencies observed in the Mexican Amerindians (MAs) (n = 2026) and MEZ (n = 638) populations with those reported for continental populations, such as Africans (AFR), Asians (CHB), and Europeans (EUR), as well as the Mexican Ancestry individuals from Los Angeles, CA, USA (MXL) from the 1000 genome database [31]
The frequencies observed in MAs were significantly different from those observed in the MEZ population from this study and from those observed in populations reported in the 1000 genomes database (S1 Table) [31]

Summary

Introduction

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway. The C677T polymorphism changes an alanine to valine (A222V), and the A1298C variant changes a glutamic acid to alanine (E429A) Both polymorphisms have been associated with reduced enzyme activity, the C677T polymorphism, which imparts thermolability to the enzyme [2, 3]. Despite the relevance of the MTHFR C677T variant in populations with an Amerindian origin, genetic studies have explored only about 10% of the ethnic groups recognized by the Mexican Indigenous Languages Institute (INALI) [7, 8, 13, 16, 20]. We investigated the allele and genotype frequencies of the MTHFR C677T and A1298C variants and their geographic distributions in the largest cohort of Mexican Amerindians (MAs) included in a genetic study. We included a sample of Mexican Mestizo (MEZ) individuals geographically-matched

Ethics Statement

Results

Discussion