Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism

Abstract

BackgroundThe polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA probes homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533 G>A, c.1068C>T and IVS10 262C>G.FindingsHaplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262 G than expected from normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele.ConclusionGiven that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage.

Frecuencia del polimorfismo c677t (rs1801133) del gen MTFHR en individuos colombianos

“…Some reports suggest that the T allele can produce resistance to infections such as malaria and cytomegalovirus and may also protect against hypertension 32 , 33 . Similarly, the C allele protects against birth defects and cancer and is associated with higher fertility and relatively late onset of neurological diseases 34 . These findings allow postulating that the frequencies of the C and T alleles may be conditioned locally in different populations by environmental selective pressures in different regions of Colombia and the world.…”

Methylenetetrahydrofolate reductase polymorphisms as possible risk factors of venous thrombosis – too weak to take care, too frequent to be ignored…

“…The frequency of 677T allele was reported as being low in Africans (6-10%), relatively high in Caucasians (17-50%), and highest in the Mexican population (over the 50%) ( Fig. 2) [27]. Interestingly, there is a north-to-south increase in the frequency of this allele in Europe and North America, whereas a reverse trend has been observed in China, India, and Pakistan [28].…”

“…In contrast to the above-mentioned C677T polymorphism, the distribution of A1298C SNP is poorly recognised, mainly due to its less pronounced effect on enzyme activity. However, the prevalence of 1298C variant in Central Europe seems to be higher than in West Africa, and also, contrary to 677T allele, in Mexico [27,35]. According to a hypothesis concerning the origin of the observed frequency of MTHFR SNPs among the global population, such a distribution pattern may result from specific gene-nutrient interactions (including different nutritional habits, various exposure to UV radiation, etc.)…”

“…According to a hypothesis concerning the origin of the observed frequency of MTHFR SNPs among the global population, such a distribution pattern may result from specific gene-nutrient interactions (including different nutritional habits, various exposure to UV radiation, etc.) [27,36].…”