The Frequent 5,10-Methylenetetrahydrofolate Reductase C677T Polymorphism Is Associated with a Common Haplotype in Whites, Japanese, and Africans

Abstract

The common 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism causes decreased activity of this enzyme and can be associated with mild-to-moderate hyperhomocysteinemia in homozygotes, particularly when there is folic acid deficiency, as well as with vascular dementia, arterial thrombosis, venous thrombosis, neural-tube defects, and fetal loss. When folic acid intake is sufficient, homozygotes for MTHFR 677T appear to be protected against colon cancer and acute lymphatic leukemia, and fetuses bearing this genotype have an augmented survival. The distribution of MTHFR 677T is worldwide, but its frequency in different populations varies extensively. In the present study, we addressed the question of whether the MTHFR 677T alteration has an ancestral origin or has occurred repeatedly. We analyzed the frequency distribution of the previously described polymorphism A1298C in exon 7 and of three intronic dimorphisms, in white Israelis (Jews and Arabs), Japanese, and Ghanaian Africans. The 677T allele was, remarkably, associated with one haplotype, G-T-A-C, in white and Japanese homozygotes. Among the Africans, analysis of maximum likelihood also disclosed an association with the G-T-A-C haplotype, although none of the 174 subjects examined was homozygous for MTHFR 677T. These results suggest that the MTHFR 677T alteration occurred on a founder haplotype that may have had a selective advantage.

Ethnic variation of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate-reductase (MTHFR) gene in southwestern Mexico

“…Different studies have been conducted to determine the frequency of the C677T and A1298C polymorphisms in various populations around the world, and the results are as varied as the populations studied (Rosenberg et al, 2002;Rady et al, 2002;Esfahani et al, 2003). For the 677TT genotype, the highest frequency (40%) was found in Mexico and the lowest (10%) was observed in African populations (Wilcken et al, 2003;Guéant-Rodriguez et al, 2006).…”

Increase in the prevalence of the MTHFR 677 TT polymorphism in women born since 1959: potential implications for folate requirements

“…Previous studies have suggested that the MTHFR TT homozygosity may confer a survival advantage in populations with adequate dietary folate consumption (MunozMoran et al, 1998;Rosenberg et al, 2002;Guéant-Rodriguez et al, 2006). The T allele is associated with a greater risk of neural tube defects in those geographical areas or ethnic groups with a high frequency of this genotype, but that risk seems to be neutralized by a diet rich in folate, such as the Mediterranean diet (Zetterberg, 2004).…”

Methylenetetrahydrofolate reductase polymorphisms and risk of squamous cell carcinoma of the head and neck: A case‐control analysis

“…Previous studies have shown that MTHFR C677T and A1298C are in linkage disequilibrium. 39,47,48 Rosenberg et al 49 investigated the linkage disequilibrium of the C677T, A1298C and 3 other intronic dimorphisms among white Israelis, Japanese and Ghanaian Africans and found that the 677T allele was associated with one haplotype, G-T-A-C, in white Israelis and Japanese homozygotes. Our results provide evidence for linkage disequilibrium between the C677T and A1298C polymorphisms and are the first to suggest that the 1793A allele is also in linkage disequilibrium with both C677T and A1298C polymorphisms.…”