Association between MTHFR C677T
genotype and circulating folate levels
irrespective of folate intake: Data
from the IMMIDIET Project
To the Editor:
Low serum folate and the resultant high plasma homocysteine
(Hcy) levels are associated with neural tube defects in children,
neuropsychiatric conditions, cardiovascular diseases, and cancers
. The methylenetetrahydrofolate reductase (MTHFR) C677T
polymorphism is the most common genetic determinant of
increased Hcy levels, particularly in the presence of low circulating
levels of folate. The prevalence of the TT genotype usually varies in
the range of 8% to 14 % for the majority of white populations;
however, in Italian populations, a prevalence of approximately
18% or higher has been observed . The TT genotype also has
been associated with plasma or serum folate concentrations [3,4].
However, studies on dietary folate intake are relatively rare [5,6].
We studied the association between the MTHFR C677T geno-
type and circulating folate levels according to folate intakes in
Italian subjects from the IMMIDIET (Dietary Habit Proﬁle in
European Communities with Different Risk of Myocardial Infarc-
tion: the Impact of Migration as a Model of Gene-Environment
Interaction) study [7,8].
In brief, 542 Italian subjects were recruited randomly from
general practices in Abruzzo, a central-southern region of Italy.
Exclusion criteria included cardiovascular disease; diabetes;
familial hypercholesterolemia; malignancies; heart, liver, or renal
failure; hypo-/hyperthyroidism; and epilepsy. The study was
approved by the ethics committees of the participating institution.
Each participant gave written informed consent for the study.
Folic acid levels were determined by a chemoluminescence
assay at microparticle capture (CMIA, Axsym, Abbott, Abbot
Park, IL, USA; normal range of folate >3 ng/mL); the assay sensi-
tivity was lower than 0.8 ng/mL (interassay coefﬁcient of varia-
tion <10%). The Italian European Prospective Investigation into
Cancer and Nutrition (EPIC) semiquantitative food-frequency
questionnaire, containing questions on the average consumption
of 164 food items over the previous year, was used . Blood
folate levels were logarithmically transformed in statistical anal-
ysis; however, non-transformed adjusted means are reported in
Table 1. Mean characteristics of the population were as follows:
age 44.5 Æ 7.2 y, body mass index 27.2 Æ 4.4 kg/m
hip ratio 0.88 Æ 0.08, Hcy 11.8 Æ 5.7
mol/L, and folate 5.8 Æ
2.2 ng/mL (mean Æ SD). Because of missing data for serum folate
or MTHFR C677T genotype, 529 subjects only were included in
The prevalence of high, medium, and low circulating levels of
folate varied according to the MTHFR genotypes (Table 1), even
after adjustment for gender, age, and smoking status (P <
0.0001, PROC CATMOD in SAS; SAS Institute, Cary, NC, USA). In
particular, the percentage of subjects with folate levels of at least
6.4 ng/mL decreased from CC homozygotes to heterozygotes to
TT homozygotes. Similarly to the data by Gori et al. , we found
serum folate levels lower in MTHFR 677 TT homozygotes than in
subjects with CT or CC genotypes (Table 1). The observed associ-
ation remained signiﬁcant after adjusting further for folate
intake and was evident in all tertiles of folate intake.
Other studies have reported an association between serum
folate and MTHFR C677T while taking dietary folate intake into
account, with contrasting results, showing no effect  or
a stronger association in the lower or in the higher tertile of
folate intake .
The fact that the MTHFR C677T polymorphism, a major
genetic factor inﬂuencing Hcy levels, is, as conﬁrmed by our
study, related to circulating folate levels (itself a major determi-
nant of Hcy levels) stresses the complexity of Hcy and folate
metabolism and suggests the need for a more complex approach
in understanding this pathway. The relation between the MTHFR
C677T polymorphism and folate has not been yet clearly
explained, although a gene–nutrient interaction in determining
genomic DNA methylation has been suggested.
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Nutrition 27 (2011) 1209–1210