Table 3.

Analysis of markers of one-carbon metabolism and gene-nutrient interactions.

References	Country	MDS/MCa	Studied markers of one-carbon metabolism	Studied polymorphism/s	Main findings
James et al., 1999	USA/Canada	57/50	Plasma hcy Plasma methionine Folate intakeb Alcohol intakeb	MTHFR 677C>T	Increased hcy levels in MDS. Increased hcy/methionine ratio in MDS. Increased hcy levels in MDS carriers of the MTHFR 677CT or TT genotype. Folate intake from foods was significantly lower than the recommended daily allowance in MDS at conception. Increased reported alcohol intake at conception in MDS.
O'Leary et al., 2002	Ireland	48/192	Plasma hcy Plasma folate Plasma vitamin B12	MTHFR 677C>T MTRR 66A>G	No difference in hcy levels between MDS and control mothers. Increased hcy levels in control mothers carriers of the MTHFR 677TT genotype. Plasma folate and vitamin B12 levels resulted significant predictors of hcy levels.
Chadefaux-Vekemans et al., 2002	France	85/107	Plasma hcy	MTHFR 677C>T	No difference in hcy levels between MDS and control mothers. No difference in hcy levels according to MTHFR 677C>T genotypes.
Bosco et al., 2003	Italy	63/72	Plasma hcy Plasma folate Plasma vitamin B12	MTHFR 677C>T MTHFR 1298A>C MTRR 66A>G MTR 2756A>G	Increased hcy levels in MDS. No difference in folate or vitamin B12 levels between MDS and control mothers. No interaction between hcy, folate or vitamin B12 levels and the studied polymorphisms.
Takamura et al., 2004	Japan	31/60	Plasma hcy Serum folate Serum vitamin B6 Serum vitamin B12	MTHFR 677C>T	Increased hcy levels in MDS. Decreased serum folate levels in MDS. No difference in vitamin B6 or B12 levels between MDS and control mothers. No interaction between the MTHFR 677C>T polymorphism and markers of one-carbon metabolism.
da Silva et al., 2005	Brazil	154/158	Plasma hcy	MTHFR 677C>T MTHFR 1298A>C MTRR 66A>G MTR 2756A>G CBS 844 ins68	Increased hcy levels in MDS. Increased hcy levels in MDS carriers of the MTHFR 677TT genotype.
Scala et al., 2006	Italy	94/264	Plasma hcy	MTHFR 677C>T MTHFR 1298A>C MTRR 66A>G MTR 2756A>G CBS 844 ins68 RFC1 80G>A MTHFD1 1958G>A	No difference in hcy levels between MDS and control mothers. No interaction between hcy levels and the studied polymorphisms.
Martínez-Frías et al., 2006	Spain	91/90	Plasma hcy	MTHFR 677C>T MTHFR 1298A>C MTRR 66A>G	Increased hcy levels in MDS. The MTHFR 1298A>C polymorphism was associated with hcy levels. Interactions between MTHFR 1298A>C and MTRR 66A>G polymorphisms affect hcy levels, but in different ways in MDS than in control mothers.
Wang et al., 2007	China	100/100	Plasma hcy	MTHFR 677C>T	Increased hcy levels in MDS. Increased hcy levels in carriers of MTHFR 677CT or TT genotypes.
Meguid et al., 2008	Egypt	42/48	Folate intakeb	MTHFR 677C>T MTHFR 1298A>C	Folate intake from foods was significantly lower than the recommended daily allowance in MDS.
Biselli et al., 2008b	Brazil	58/49	Plasma hcy	MTHFR 677C>T MTHFR 1298A>C MTR 2756A>G RFC1 80A>G	Increased hcy levels in MDS. Interaction between hcy levels and the MTHFR 1298A>C polymorphism: hcy levels were higher in MDS carriers of the MTHFR 1298CC genotype, but the same genotype resulted in lower hcy levels in control mothers.
Kohli et al., 2008	India	92/91	Plasma hcy Folate intakeb	MTHFR 677C>T	Decreased hcy levels in MDS.
Santos-Rebouças et al., 2008	Brazil	103/108	Folate intakeb Methionineb Zincb Vitamin B6b Vitamin B12b	MTHFR 677C>T MTHFR 1298A>C MTRR 66A>G	Folate intake from foods was significantly lower than the recommended daily allowance in both MDS and control mothers. MDS had an estimate lower intake of zinc and methionine respect to control mothers.
Mohanty et al., 2012	India	52/52	Plasma hcy Serum folate Vitamin B12 RBC folatec	MTHFR 677C>T	Decreased serum folate levels and trend for decreased RBC folate in MDS.
Mendes et al., 2010; Marucci et al., 2012; Zampieri et al., 2012a,b	Brazil (São Paulo)	105/185	Plasma hcy Serum folate Plasma MMAd	MTHFR 677C>T MTHFR 1298A>C MTHFR 1317T>C MTR 2756A>G MTRR 66A>G RFC1 80G>A TCN2 67A>G TCN2 776C>G CBS 844ins68 CBS 833T>C MTHFD1 1958G>A BHMT 742G>A DHFR 19bp ins/del SHMT 1420C>T	MTHFR 677CT or TT genotypes were associated with plasma folate levels below the 25th percentile. RFC1 80GG genotype was associated with plasma folate levels below the 25th percentile only in women aged ≤ 35 years at conception. MTRR 66AG or GG genotypes were associated with MMA concentrations above the 75th percentile.
Wang et al., 2013a	China	104/184	Plasma hcy Serum folate	MTRR 524C>T	Increased hcy levels in MDS. The MTRR 524TT genotype was associated with low hcy levels in MDS.
Pandey et al., 2013	India	80/100	Plasma hcy Serum folate RBC folatec	MTHFR 677C>T MTHFR 1298A>C	Decreased serum folate and RBC folate, and increased hcy levels in MDS, but no association with the genotype.
Coppedè et al., 2013a, 2014	Italy	172/187	Plasma hcy Plasma folate Plasma vitamin B12	MTR 2756A>G MTRR 66A>G	No difference in hcy, folate or vitamin B12 levels between groups. The MTRR 66GG genotype was associated with increased folate levels. The combined MTR 2756AA/MTRR 66GG genotype was associated with increased folate levels. The combined MTR 2756 GG/MTRR 66AA genotype was associated with reduced folate and hcy levels.

^aMDS, mothers of Down syndrome individuals; MC, control mothers.

^bIntake estimated from food frequency questionnaire.

^cRBC folate, Red blood cell folate.

^dMMA, methylmalonic acid, an indicator of the vitamin B12 status.