Table 2.
Meta-analyses of studies linking polymorphisms of folate pathway genes to the maternal risk for having a birth with Down syndrome.
| References | MDS/MCa | Studied polymorphism/s | Overall findings (Significant data are in bold) | Subgroup analysis (Significant data are in bold) |
|---|---|---|---|---|
| Zintzaras, 2007 | 1.129/1.489 | MTHFR 677C>T | Allele contrast (OR = 1.18; 95% CI = 0.99–1.40) | Whitesb (OR = 1.04; 95% CI = 0.83–1.30) |
| 746/888 | MTHFR 1298A>C | Allele contrast (OR = 1.02; 95% CI = 0.80–1.29) | Whitesb (OR = 1.02; 95% CI = 0.68–1.52) | |
| 559/866 | MTRR 66A>G | Allele contrast (OR = 1.30; 95% CI = 0.97–1.74) | Whitesb (OR = 1.38; 95% CI = 0.94–2.01) | |
| Medica et al., 2009 | 1.545/2.052 | MTHFR 677C>T |
Dominant (OR = 1.40; 95% CI = 1.16–1.70) Recessive (OR = 1.35; 95% CI = 1.35–1.78) |
N.A. |
| 1.007/1.318 | MTHFR 1298A>C | Dominant (OR = 1.06; 95% CI = 0.85–1.31) Recessive (OR = 1.28; 95% CI = 0.78–2.11) |
||
| 623/936 | MTRR 66A>G | Dominant (OR = 1.54; 95% CI = 0.98–2.42) Recessive (OR = 1.57; 95% CI = 1.06–2.31) |
||
| 439/731 | MTR 2756A>G | Dominant (OR = 1.04; 95% CI = 0.80–1.35) Recessive (OR = 1.43; 95% CI = 0.65–3.13) |
||
| 354/644 | RFC1 80G>A | Dominant (OR = 1.32; 95% CI = 0.95–1.82) Recessive (OR = 1.24; 95% CI = 0.67–1.40) |
||
| 367/542 | CBS 844 ins68 | Dominant (OR = 0.97; 95% CI = 0.67–1.40) Recessive (N.A.) |
||
| Amorim and Lima, 2013 | 1.226/1.533 | MTRR 66 A>G | Allele contrast (OR = 1.23; 95% CI = 1.02–1.49) | N.A. |
| Costa-Lima et al., 2013 | 2.101/2.702 | MTHFR 677C>T | TT vs. CC (OR = 1.51; 95% CI = 1.22–1.87) |
Sub-Tropicalc (OR = 2.39; 95% CI = 1.62–3.54) Tropicalc (OR = 1.33; 95% CI = 0.81–2.18) Northernc (OR = 1.20; 95% CI = 0.89–1.62) |
| CT vs. CC (OR = 1.26; 95% CI = 1.10–1.43) |
Sub-Tropicalc (OR = 1.44; 95% CI = 1.17–1.77) Tropicalc (OR = 1.33; 95% CI = 1.01–1.76) Northernc (OR = 1.06; 95% CI = 0.86–1.30) |
|||
| Wu et al., 2013 | 2.806/4.597 | MTHFR 677C>T | Allele contrast (OR = 1.22; 95% CI = 1.09-1.38) | Caucasiansd (OR = 1.11; 95% CI = 0.99–1.25) Asiansd (OR = 1.53; 95% CI = 0.97–2.41) Othersd (OR = 1.24; 95% CI = 1.06–1.44) |
| Dominant (OR = 1.30; 95% CI = 1.12–1.51) | Caucasiansd (OR = 1.17; 95% CI = 0.98–1.40) Asiansd (OR = 1.75; 95% CI = 1.08–2.82) Othersd (OR = 1.34; 95% CI = 1.10–1.64) |
|||
| Recessive (OR = 1.26; 95% CI = 1.02–1.56) | Caucasiansd (OR = 1.12; 95% CI = 0.91–1.37) Asiansd (OR = 1.76; 95% CI = 0.66–4.67) Othersd (OR = 1.23; 95% CI = 0.88–1.74) |
|||
| 1.854/2.364 | MTHFR 1298A>C | Allele contrast (OR = 1.03; 95% CI = 0.90–1.17)h | Caucasiansd (OR = 0.98; 95% CI = 0.80–1.21) Asiansd (OR = 1.23; 95% CI = 0.60–2.53) Othersd (OR = 1.03; 95% CI = 0.90–1.17) |
|
| Coppedè et al., 2013a | 1.171/1.402 | MTR 2756A>G | Allele contrast (OR = 1.08; 95% CI = 0.93–1.25)h | Caucasianse (OR = 1.05; 95% CI = 0.83–1.31) Brazilianse (OR = 1.20; 95% CI = 0.94–1.54) |
| Coppedè et al., 2013c | 930/1.240 | RFC1 80G>A | Allele contrast (OR = 1.14; 95% CI = 1.01–1.30) | N.A. |
| Dominant (OR = 1.09; 95% CI = 0.83–1.43) | N.A. | |||
| Recessive (OR = 1.27; 95% CI = 1.04–1.57) | N.A. | |||
| Yang et al., 2013 | 2.458/3.144 | MTHFR 677C>T | Allele contrast (OR = 1.28; 95% CI =1.11–1.47) |
Caucasiansf (OR = 1.15; 95% CI = 1.03–1.29) Asiansf (OR = 1.68; 95% CI = 1.08–2.63) Othersf (OR = 1.02; 95% CI = 1.02–1.43) |
| 1.664/2.027 | MTHFR 1298A>C | Allele contrast (OR = 1.16; 95% CI = 0.98–1.38) | Caucasiansf (OR = 1.03; 95% CI = 0.83–1.29) Asiansf (OR = 1.41; 95% CI = 0.88–2.27) Othersf (OR = 1.28; 95% CI = 0.94–1.74) |
|
| 1.478/2.037 | MTRR 66A>G | Allele contrast (OR = 1.22; 95% CI = 1.02–1.46) | Caucasiansf (OR = 1.24; 95% CI = 0.98–1.58) Asiansf (OR = 1.57; 95% CI = 0.94–2.60) Othersf (OR = 1.01; 95% CI = 0.86–1.19) |
|
| 1.038/1.286 | MTR 2756A>G | Allele contrast (OR = 1.07; 95% CI = 0.91–1.25) | Caucasiansf (OR = 0.99; 95% CI = 0.77–1.29) Asiansf (OR = 0.74; 95% CI = 0.29–1.87) Othersf (OR = 1.13; 95% CI = 0.92–1.38) |
|
| 897/1.249 | RFC1 80G>A | Allele contrast (OR = 1.16; 95% CI = 1.02–1.31) | Caucasiansf (OR = 1.21; 95% CI = 0.98–1.58) Asiansf (OR = 0.99; 95% CI = 0.43–2.33) Othersf (OR = 1.14; 95% CI = 0.95–1.38) |
|
| 825/1.034 | CBS 844 ins68 | Allele contrast (OR = 1.03; 95% CI = 0.82–1.29) | Caucasiansf (OR = 0.78; 95% CI = 0.46–1.33) Asiansf N.A. Othersf (OR = 1.09; 95% CI = 0.85–1.40) |
|
| Coppedè et al., 2014 | 1.171/1.402 | MTRR 66A>G | Allele contrast (OR = 1.26; 95% CI = 1.04–1.51) | Europeansg (OR = 1.22; 95% CI = 0.96–1.55) Not Europeansg (OR = 1.36; 95% CI = 0.94–1.96) Mediterraneansg (OR = 1.10; 95% CI = 0.94–1.29) |
| Dominant (OR = 1.36; 95% CI = 1.10–1.68) |
Europeansg (OR = 1.31; 95% CI = 1.01–1.70) Not Europeansg (OR = 1.47; 95% CI = 1.02–2.11) Mediterraneansg (OR = 1.19; 95% CI = 0.91–1.55) |
|||
| Recessive (OR = 1.32; 95% CI = 1.09–1.62) | Europeansg (OR = 1.25; 95% CI = 0.97–1.59) Not Europeansg (OR = 1.48; 95% CI = 1.06–2.07) Mediterraneansg (OR = 1.11; 95% CI = 0.85–1.46) |
|||
| The study was restricted to Caucasians | ||||
| Victorino et al., 2014 | 2.223/2.807 | MTHFR 677C>T | Allele contrast (OR = 1.25; 95% CI = 1.09–1.44) |
Caucasiansf (OR = 1.17; 95% CI = 1.04–1.31) Asiansf (OR = 1.95; 95% CI = 1.04–1.43) Braziliansf (OR = 1.22; 95% CI = 1.05–1.64) |
| TT vs. CC (OR = 1.46; 95% CI = 1.10–1.94) |
Caucasiansf (OR = 1.28; 95% CI = 1.00–1.65) Asiansf (OR = 2.49; 95% CI = 0.24–25.8) Braziliansf (OR = 1.38; 95% CI = 0.95–2.02) |
|||
| CT vs. CC (OR = 1.27; 95% CI = 1.07–1.52) | Caucasiansf (OR = 1.20; 95% CI = 0.93–1.54) Asiansf (OR = 1.46; 95% CI = 1.05–2.03) Braziliansf (OR = 1.30; 95% CI = 1.04–1.62) |
|||
| 1.601/1.849 | MTHFR 1298A>C | Allele contrast (OR = 1.06; 95% CI = 0.91–1.24)h | Caucasiansf (OR = 1.04; 95% CI = 0.81–1.33) Asiansf (OR = 1.32; 95% CI = 0.92–1.90) Braziliansf (OR = 1.02; 95% CI = 0.86–1.22) |
|
| Rai et al., 2014 | 3.098/4.852 | MTHFR 677C>T | Allele contrast (OR = 1.22; 95% CI = 1.13–1.31)h |
Asians (OR = 1.53; 95% CI = 1.29–1.82) Americans (OR = 1.23; 95% CI = 1.07–1.39) Europeans (OR = 1.04; 95% CI = 0.93–1.16) |
| Balduino Victorino et al., 2014 | 1.311/1.674 | MTR 2756A>G | Allele contrast (OR = 1.11; 95% CI = 0.97–1.26)h | Caucasiansf (OR = 1.04; 95% CI = 0.83–1.31) Braziliansf (OR = 1.14; 95% CI = 0.96–1.34) |
| 1.486/2.163 | MTRR 66 A>G | Allele contrast (OR = 1.18; 95% CI = 0.99–1.40) | Caucasiansf (OR = 1.26; 95% CI = 0.96–1.66) Braziliansf (OR = 1.00; 95% CI = 0.88–1.14) |
|
| Dominant (OR = 1.29; 95% CI = 1.09–1.53) |
Caucasiansf (OR = 1.42; 95% CI = 1.08–1.88) Braziliansf (OR = 1.14; 95% CI = 0.91–1.42) |
|||
| Recessive (OR = 1.33; 95% CI = 1.03–1.71) |
Caucasiansf (OR = 1.43; 95% CI = 1.13–1.83) Braziliansf (OR = 1.02; 95% CI = 0.86–1.22) |
|||
| 825/1034 | CBS 844ins68 | Allele contrast (OR = 1.07; 95% CI = 0.86–1.34)h | Braziliansf (OR = 1.07; 95% CI = 0.83–1.37) | |
| 497/930 | MTHFD1 1958G>A | GA vs. GG (OR = 1.33; 95% CI = 1.01–1.75) | N.A. | |
| 495/743 | TCN2 776C>G | Allele contrast (OR =1.27; 95% CI =0.83–1.93)h | N.A. |
a
MDS, mothers of Down syndrome individuals; MC, control mothers.
b
Caucasian inhabitants of Europe and North America. Studies in Asian populations, in mixed Brazilian populations, or in inhabitants of the Middle East were scarce for subgrouping.
c
Tropical Regions: between 23.5°Noth (N) and 23.5° South (S); Sub-Tropical Regions: between 23.5° and 40° N/S; Northern Region: ≥40° N.
d
The authors included in the “Caucasians” subgroup both Europeans, North Americans and inhabitants of the Middle East. Brazilian studies conducted either in mixed Brazilian populations or in individuals of European descent were subgrouped as “Others.”
e
The “Caucasian” subgroup was composed by studies performed in Europeans; The Brazilian subgroup was composed by studies performed in mixed Brazilian populations.
f
The authors included in the “Caucasians” subgroup both Europeans, North Americans and inhabitants of the Middle East. Brazilian studies conducted either in mixed Brazilian populations or in individuals of European descent were subgrouped as “Brazilians.”
g
This study was restricted to Caucasians that were subgrouped as follows: Europeans, all the Europeans; Not Europeans, Americans of European descent; Mediterraneans, European inhabitants of Mediterranean regions.
h
Similar results observed for dominant, recessive, and/or co-dominant models.