Association of methylenetetrahydrofolate reductase gene 677C > T polymorphism and Down syndrome

Abstract

The association between Down syndrome (DS) and maternal polymorphisms in genes encoding folic acid metabolizing enzymes remains a controversial issue. A meta-analysis was performed to evaluate the association of maternal MTHFR 677C > T polymorphism and the risk of having a child with DS. Case-control studies were screened from major literature databases. Twenty articles from 13 countries worldwide, with a total of 2,101 DS and 2,702 control mothers, attended the inclusion criteria. We found a 50 % increase for the association of maternal homozygous TT genotype and DS in both fixed (OR = 1.51; 95 % CI 1.22-1.87) and random effects models (OR 1.54; 95 % 1.15-2.05). Similarly, a significant pooled OR was found for the heterozygote CT, with an OR 1.26; 95 % CI 1.10-1.43 (fixed effects model) and OR 1.28; 95 % 1.08-1.51 (random effects model). As ultra-violet B solar radiation highly depends on latitude, and can promote, in less pigmented skin, intravascular folate photolysis, we stratified the analysis by latitude region, defining as Tropical (between 23.5(°) S and 23.5(°) N), Sub-Tropical (between 23.5(°) and 40(°) N and S), and Northern (≥ 40(o) N). Significant association was only found for Sub-Tropical area, both using fixed and random effect models. In conclusion, MTHFR 677C > T polymorphism is a moderate risk factor for DS for some populations, and populations located in Sub-Tropical region seem to be at greater risk. Latitude, ethnicity, skin pigmentation, and red blood cell folate are important variables to be considered in future studies.

A Pilot Study Evaluating the Contribution ofSLC19A1(RFC-1) 80G>A Polymorphism to Alzheimer’s Disease in Italian Caucasians

“…Dietary regimens rich in folate, such as the Mediterranean diet, could mask the effect of certain polymorphisms, as it happens for the MTHFR 677C>T one, the most studied polymorphism of the folate pathway, which is associated with increased risk of sporadic AD in Asians but not in Caucasians [16]. It was also suggested that geographic factors, such as the latitude, could interfere with ultraviolet B solar radiation and promote, in less pigmented skins, intravascular folate photolysis, thereby affecting circulating folate levels and folate metabolism [29]. In this regard, a recent literature meta-analysis reported a significant effect of the MTHFR 677C>T polymorphism on pregnancy outcome only in subtropical regions [29], and it is also of interest that the RFC-1 80G>A polymorphism was associated with increased chromosome damage in blood cells of healthy Australian individuals but not in those of healthy Italian ones [30, 31].…”

“…It was also suggested that geographic factors, such as the latitude, could interfere with ultraviolet B solar radiation and promote, in less pigmented skins, intravascular folate photolysis, thereby affecting circulating folate levels and folate metabolism [29]. In this regard, a recent literature meta-analysis reported a significant effect of the MTHFR 677C>T polymorphism on pregnancy outcome only in subtropical regions [29], and it is also of interest that the RFC-1 80G>A polymorphism was associated with increased chromosome damage in blood cells of healthy Australian individuals but not in those of healthy Italian ones [30, 31]. Moreover, the presence/absence of other polymorphisms of the pathway could mask or potentiate the effect of a single one [26].…”

Women with Methylenetetrahydrofolate Reductase Gene Polymorphism and the Need for Proper Periconceptional Folate Supplementation

“…DS (down syndrome) also known as trisomy 21 is a chromosomal disease that is associated with growth and mental retardation [50,51]. DS results from an over-expression of three extra copies of the gene on chromosome 21 causing failure of normal chromosomal separation during meiosis [21,51,52].…”

“…DS results from an over-expression of three extra copies of the gene on chromosome 21 causing failure of normal chromosomal separation during meiosis [21,51,52]. DS affects approximately 1 in 1000 to 1100 live births worldwide and 1 out of every 700 newborns in the US [53,54].…”

“…DS affects approximately 1 in 1000 to 1100 live births worldwide and 1 out of every 700 newborns in the US [53,54]. An important risk factor for DS is advanced maternal age at the time of conception [51,52]. Women who are 35 years or older are more at an increased risk of having a child with DS, however DS children have been born to younger mothers [55][56][57][58].…”