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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]
  1. All studies have a cross-sectional design
  2. SNP single-nucleotide polymorphism
  3. *NORwegian Colorectal CAncer Prevention (NORCCAP) cohort
  4. Data refers to HapMap European population, with data collected from Utah Residents (CEPH) with Northern and Western European Ancestry
  5. The specific data available is not published elsewhere and was obtained by contacting the corresponding authors