Table 2 Candidate gene association studies examining the association of SNPs with vitamin B12 concentrations. Candidate gene association studies testing the association between SNPs and vitamin B12 concentrations. The chromosome location, gene name, reference SNP cluster ID, sample size and ethnicity, study design, mean age, observed frequency of the minor allele in the population, effect size and P value are shown in the table. The order of SNPs reflects the order of the chromosome location
From: An update on vitamin B12-related gene polymorphisms and B12 status
| Chromosome location | Gene name (gene symbol) | Reference SNP cluster ID | Sample size and ethnicity | Study design | Age (years) | Minor allele frequency | Effect size | P value | References |
|---|---|---|---|---|---|---|---|---|---|
| 1p34.1 | Methylmalonic aciduria and homocystinuria type C protein (MMACHC) | rs10789465 | n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | C = 0.469† | Not available | 1.00 × 10−3 | Andrew et al. [13] |
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | rs1801131 |
n = 988 French women | Cross-sectional | 40–65 (range) | C = 0.290 | Not available | > 0.05 | De Batlle et al. [79] |
| 1p36.3 | Methylenetetrahydrofolate reductase (MTHFR) | Rs1801131 |
n = 6784 Danish | Cross-sectional | 30–60 (range) | C = 0.340 | Not available | > 0.05 | Thuesen et al. [57] |
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | Rs1801131 |
n = 220 Brazilian | Cross-sectional | 1–8 (range) | C = 0.240 | Not available | > 0.05 | Aléssio et al. [78] |
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | rs1801133 |
n = 988 French women | Cross-sectional | 40–65 (range) | T = 0.360 | Not available | > 0.05 | De Batlle et al. [79] |
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | rs1801133 |
n = 731 English (White Caucasian) | Cross-sectional | 85 | T = 0.330 | β = 5.00 × 10−5 pmol/l‡ | > 0.05 | Mendonca et al. [28] |
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | rs1801133 |
Elderly individuals: n = 262 Brazilian | Cross-sectional |
60–91 (range) | T = 0.370 | Not available | > 0.05 | Barnabe et al. [77] |
|
Children: n = 106 Brazilian |
0.5–6 (range) | T = 0.290 | Not available | > 0.05 | |||||
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | rs1801133 |
n = 6784 Danish | Cross-sectional |
30–60 (range) | T = 0.290 |
Effect allele: Not available Other allele: not available Low serum vitamin B12: OR 1·78 (95% CI 1.25, 2.54) pmol/l | 3.00 × 10−3 | Thuesen et al. [57] |
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | rs1801133 |
n = 153 Spanish | Cross-sectional |
13–19 (range) | T = 0.380 | Not available | > 0.05 | Al-Tahan et al. [81] |
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | rs1801133 |
n = 10,601 Norwegian | Cross-sectional | 56 | T = 0.280 | Not available | > 0.05 | Hustad et al. [80] |
| 1p36.3 | Methylenetetrahydrofolate Reductase (MTHFR) | rs1801133 |
n = 220 Brazilian | Cross-sectional |
1–8 (range) | T = 0.320 | Not available | > 0.05 | Aléssio et al. [78] |
| 1q43 | 5-Methyltetrahydrofolate-Homocysteine methyltransferase (MTR) | rs1805087 |
n = 731 English (White Caucasian) | Cross-sectional | 85 | G = 0.180 | β = 4.00 × 10−3 pmol/l‡ | > 0.05 | Mendonca et al. [28] |
| 1q43 | 5-Methyltetrahydrofolate-Homocysteine methyltransferase (MTR) | rs1805087 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.161† | Not available | > 0.05 | Andrew et al. [13] |
| 1q43 | 5-Methyltetrahydrofolate-Homocysteine methyltransferase (MTR) | rs1805087 |
n = 6784 Danish | Cross-sectional |
30–60 (range) | G = 0.200 | Not available | > 0.05 | Thuesen et al. [57] |
| 1q43 | 5-Methyltetrahydrofolate-Homocysteine methyltransferase (MTR) | rs2275568 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | A = 0.460† | Not available | > 0.05 | Andrew et al. [13] |
| 1q43 | 5-Methyltetrahydrofolate-Homocysteine methyltransferase (MTR) | rs2789352 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.381† | Not available | > 0.05 | Andrew et al. [13] |
| 1q43 | 5-Methyltetrahydrofolate-Homocysteine methyltransferase (MTR) | rs3768142 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.384† | Not available | > 0.05 | Andrew et al. [13] |
| 1q43 | 5-Methyltetrahydrofolate-homocysteine methyltransferase (MTR) | rs10733118 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.381† | Not available | > 0.05 | Andrew et al. [13] |
| 1q43 | 5-Methyltetrahydrofolate-Homocysteine methyltransferase (MTR) | rs10925257 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.155† | Not available | > 0.05 | Andrew et al. [13] |
| 1q43 | 5-Methyltetrahydrofolate-homocysteine methyltransferase (MTR) | rs11800413 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.431† | Not available | > 0.05 | Andrew et al. [13] |
| 1q43 | 5-Methyltetrahydrofolate-homocysteine methyltransferase (MTR) | rs12060264 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | A = 0.438† | Not available | > 0.05 | Andrew et al. [13] |
| 2q23.2 | Methylmalonic aciduria and homocystinuria,CblD type (MMADHC) | rs7580915 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.228† | Not available | > 0.05 | Andrew et al. [13] |
| 4p14 | Replication factor C subunit 1 (RFC1) | rs1051266 |
Elderly individuals: n = 262 Brazilian | Cross-sectional |
60–91 (range) | A = 0.430 | Not available | > 0.05 | Barnabe et al. [77] |
|
Children: n = 106 Brazilian |
1–6 (range) | A/G = 0.500 | Not available | > 0.05 | |||||
| 4q31.21 | Methylmalonic aciduria (cobalamin deficiency) cblA type (MMAA) | rs4835011 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.080† | Not available | > 0.05 | Andrew et al. [13] |
| 4q31.21 | Methylmalonic aciduria (cobalamin deficiency) cblA type (MMAA) | rs4835012 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.178† | Not available | 3.00 × 10−2 | Andrew et al. [13] |
| 4q31.21 | Methylmalonic aciduria (cobalamin deficiency) cblA type (MMAA) | rs4835014 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.031† | Not available | > 0.05 | Andrew et al. [13] |
| 4q31.21 | Methylmalonic aciduria (cobalamin deficiency) cblA type (MMAA) | rs11728906 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.235† | Not available | > 0.05 | Andrew et al. [13] |
| 5q14.1 | Betaine-homocysteine S-methyltransferase (BHMT) | rs3733890 |
n = 6784 Danish | Cross-sectional |
30–60 (range) | A = 0.290 | Not available | > 0.05 | Thuesen et al. [57] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs10380 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.156† | Not available | > 0.05 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs162031 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.205† | Not available | > 0.05 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs162036 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.186† | Not available | 4.00 × 10−2 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs162040 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | C = 0.124† | Not available | > 0.05 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs162048 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.164† | Not available | 5.00 × 10−2 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs326120 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.155† | Not available | > 0.05 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs1532268 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | A = 0.308† | Not available | 1.00 × 10−2 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs1801394 |
n = 6784 Danish | Cross-sectional |
30–60 (range) | A = 0.430 | Not available | > 0.05 | Thuesen et al. [57] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs1801394 |
n = 220 Brazilian | Cross-sectional | 1–8 (range) | A = 0.490 | Not available | > 0.05 | Aléssio et al. [78] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs2966952 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.167† | Not available | > 0.05 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs3776455 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.389† | Not available | 2.00 × 10−3 | Andrew et al. [13] |
| 5p15.31 | Methionine synthase reductase (MTRR) | rs6555501 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | C = 0.473† | Not available | > 0.05 | Andrew et al. [13] |
| 6p12.3 | Methylmalonyl-CoA mutase (MUT) | rs6458687 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.372† | Not available | > 0.05 | Andrew et al. [13] |
| 6p12.3 | Methylmalonyl-CoA mutase (MUT) | rs6458690 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.363† | Not available | 2.00 × 10− 4 | Andrew et al. [13] |
| 6p12.3 | Methylmalonyl-CoA mutase (MUT) | rs9381784 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.363† | Not available | 3.00 × 10−2 | Andrew et al. [13] |
| 6q13 | LMBR1 domain containing 1 (LMBRD1) | rs991974 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.044† | Not available | > 0.05 | Andrew et al. [13] |
| 6q13 | LMBR1 domain containing 1 (LMBRD1) | rs1457498 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.084† | Not available | > 0.05 | Andrew et al. [13] |
| 6q13 | LMBR1 domain containing 1 (LMBRD1) | rs3778241 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.398† | Not available | > 0.05 | Andrew et al. [13] |
| 6q13 | LMBR1 domain containing 1 (LMBRD1) | rs3799105 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | C = 0.384† | Not available | > 0.05 | Andrew et al. [13] |
| 6q13 | LMBR1 domain containing 1 (LMBRD1) | rs6455338 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | C = 0.387† | Not available | > 0.05 | Andrew et al. [13] |
| 6q13 | LMBR1 domain containing 1 (LMBRD1) | rs9294851 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | T = 0.384† | Not available | > 0.05 | Andrew et al. [13] |
| 11q12.1 | Transcobalamin 1 (TCN1) | rs526934 |
n = 731 English (White Caucasian) | Cross-sectional | 85 | G = 0.270 | β = 4.00 × 10−3 pmol/l‡ | > 0.05 | Mendonca et al. [28] |
| 12q24.11 | Methylmalonic aciduria (cobalamin deficiency) cblB type (MMAB) | rs2287182 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | A = 0.128† | Not available | > 0.05 | Andrew et al. [13] |
| 12q24.11 | Methylmalonic aciduria (cobalamin deficiency) cblB type (MMAB) | rs3759387 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | A = 0.235† | Not available | > 0.05 | Andrew et al. [13] |
| 12q24.11 | Methylmalonic aciduria (cobalamin deficiency) cblB type (MMAB) | rs7134594 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | C = 0.487† | Not available | > 0.05 | Andrew et al. [13] |
| 12q24.11 | Methylmalonic aciduria (cobalamin deficiency) cblB type (MMAB) | rs7957619 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | A = 0.110 † | Not available | > 0.05 | Andrew et al. [13] |
| 12q24.11 | Methylmalonic aciduria (cobalamin deficiency) cblB type (MMAB) | rs12314392 |
n = 262 Caucasian women of North European descent | Cross-sectional (Twin Study) | 48 ± 13 | G = 0.433 † | Not available | > 0.05 | Andrew et al. [13] |
| 19p13.2 | CD320 molecule (CD320)/transcobalamin II receptor (TcblR) | rs2336573 |
n = 591 Caucasian women | Cross-sectional | 77 ± 7 | A = 0.050 | Not available | > 0.05 | Kurnat-Thoma et al. [59] |
|
n = 198 African American women | 75 ± 6 | A = 0.330 | Not available | 4.0 × 10−2 | |||||
|
n = 797 Combined total | Not available | 2.0 × 10−2 | |||||||
| 19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs492602 |
n = 731 English (White Caucasian) | Cross-sectional | 85 | A = 0.450 | β = 0.05 pmol/l‡ | < 0.001 | Mendonca et al. [28] |
| 19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs602662 |
Vegetarian: n = 553 North Indian | Cross-sectional |
50 (41–59) Median (interquartile range) | A = 0.310 |
Effect: A allele Other: G allele β = 0.12 pmol/l | 5.0 × 10−3 | Tanwar et al. [27] |
|
Non-vegetarian: n = 593 North Indian | Cross-sectional |
47 (37–55) Median (interquartile range) |
Effect: A allele Other: G allele β = 0.12 pmol/l | 4.0 × 10−3 | |||||
|
Combined total: n = 1146 North Indian | Cross-sectional |
49 (40–57) Median (interquartile range) |
Effect: A allele Other: G allele β = 0.12 pmol/l | 4.0 × 10−5 | |||||
| 22q12.2 | Transcobalamin 2 (TCN2) | rs1801198 |
NORCAP cohort*: n = 2411 Norwegian Serum holoTC could be analysed in only 2379 individuals | Cross-sectional |
50–64 (range) | G = 0.440 |
Effect: C allele Other: G allele Total holo-TC: β = 0.02 pmol/l‡ | > 0.05‡ | Riedel et al. [55] |
|
Effect: C allele Other: G allele Plasma Cbl: β = 0.03 pmol/l‡ | > 0.05‡ | ||||||||
| 22q12.2 | Transcobalamin 2 (TCN2) | rs1801198 |
n = 122 Portuguese | Cross-sectional | 46 ± 13 | G = 0.480 | Not available |
Vitamin B12: > 0.05 Holo-TC: < 0.05 | Castro et al. [52] |
| 22q12.2 | Transcobalamin 2 (TCN2) | rs1801198 |
n = 554 Participants of Latino ancestry residing in USA | Cross-sectional | 69 ± 6 | G = 0.350 | Not available |
Vitamin B12: > 0.05 Total holo TC: > 0.05 | Garrod et al. [56] |
| 22q12.2 | Transcobalamin 2 (TCN2) | rs1801198 |
n = 613 Northern Irish Men (Caucasian) | Cross-sectional |
30–49 (range) | G = 0.450 | Not available | 1.00 × 10−2 | Stanislawska-Sachadyn et al. [54] |
| 22q12.2 | Transcobalamin 2 (TCN2) | rs1801198 |
n = 6784 Danish | Cross-sectional |
30–60 (range) | G = 0.440 | Not available | > 0.05 | Thuesen et al. [57] |
| 22q12.2 | Transcobalamin 2 (TCN2) | rs1801198 |
n = 207 Brazillian | Cross-sectional |
1–8 (range) | G = 0.360 | Not available | > 0.05 | Alessio et al. [58] |
| 22q12.2 | Transcobalamin 2 (TCN2) | rs4820888 |
n = 591 Caucasian women | Cross-sectional | 77 ± 7 | G = 0.430 | Not available | > 0.05 | Kurnat-Thoma et al. [59] |
|
n = 198 African American women | 75 ± 6 | G = 0.450 | Not available | > 0.05 | |||||
|
n = 797 Combined total | Not available | 2.0 × 10−2 | |||||||
| 22q12.2 |
Transcobalamin 2 (TCN2) | rs9606756 |
NORCAP cohort*: n = 2411 Norwegian Serum holoTC could be analysed in only 2379 individuals | Cross-sectional |
50–64 (range) | G = 0.120 |
Effect: A allele Other: G allele Total holo-TC: β = − 0.21 pmol/l‡ | < 0.001‡ | Riedel et al. [55] |
|
Effect: A allele Other: G allele Plasma Cbl: β = −0.02 pmol/l‡ | > 0.05‡ | ||||||||
| 22q12.2 | Transcobalamin 2 (TCN2) | rs9606756 |
n = 6784 Danish | Cross-sectional |
30–60 (range) | G = 0.120 | Not available | > 0.05 | Thuesen et al. [57] |
|
1p36.3 19q13.33 | Methylenetetrahydrofolate Reductase (MTHFR) + Fucosyl transferase 2 gene (FUT2) |
rs180133 rs180131 rs492602 |
n = 988 Brazillian | Cross-sectional | 5 ± 3 |
rs180133 T = 0.320 rs180131 C = 0.220 rs492602 G = 0.390 | β for GRS = − 0·11 pmol/l | < 0·001 | Cobayashi et al. [105] |