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Common variants of FUT2 are associated with plasma vitamin B12 levels

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We identified a strong association (P = 5.36 x 10(-17)) between rs492602 in FUT2 and plasma vitamin B(12) levels in a genome-wide scan (n = 1,658) and an independent replication sample (n = 1,059) from the Nurses' Health Study. Women homozygous for the rs492602[G] allele had higher B(12) levels. This allele is in strong linkage disequilibrium with the FUT2 nonsecretor variant encoding W143X, suggesting a plausible mechanism for altered B(12) absorption and plasma levels.
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Common variants of FUT2 are associated with plasma vitamin
B12 levels
Aditi Hazra1,2, Peter Kraft1, Jacob Selhub3, Edward L. Giovannucci2,4, Gilles Thomas5,
Robert N. Hoover5, Stephen J. Chanock5, and David J. Hunter1,2,4,5
1Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public
Health, 677 Huntington Avenue, Boston, MA 02115, USA.
2Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical
School, 181 Longwood Avenue, Boston, MA 02115, USA.
3Vitamin Metabolism and Aging Laboratory, Jean Mayer US Department of Agriculture Human Nutrition
Research Center on Aging, Tufts University, Boston, MA 02111, USA.
4Department of Nutrition, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115,
USA.
5Division of Cancer Epidemiology and Genetics, National Cancer Institute(NCI), US National Institutes of
Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland 20892, USA.
Abstract
We identified a strong association (p=5.36×1017) between rs492602 in FUT2 and plasma vitamin
B12 levels in a genome-wide scan (n=1,658) and an independent replication sample (n=1,059) from
the Nurses' Health Study. Women homozygous for the rs492602 G allele had higher B12 levels. This
allele is in strong linkage disequilibrium with the FUT2 W143X nonsecretor variant, suggesting a
plausible mechanism for altered B12 absorption and plasma levels.
Keywords
one-carbon metabolism; plasma vitamin B12; genome-wide association; FUT2; secretor locus
Plasma levels of vitamin B12 are modifiable quantitative traits associated with certain
diseases1. Vitamin B12 found in meat (such as liver, shellfish, fish, poultry, and eggs) and milk
products2 is composed of corrin and cobalt rings and is necessary for the formation of red
blood cells, DNA synthesis during cell division, and maintenance of the myelin nerve sheath.
Deficiency in vitamin B12, clinically associated with pernicious anemia, cardiovascular
disease, cancer, and neurodegenerative disorders, is often related to poor intestinal B12
absorption2 rather than direct dietary deficiency (the recommended adult intake for vitamin
B12 is 2.4 µg/day). In the Nurses’ Health Study (NHS), we previously observed that women
in the lowest quartile of plasma vitamin B12 levels had marginally worse cognitive performance
(based on a global score averaging 6 cognitive tests) than women in the highest quartile of
plasma vitamin B12 and that combined folate and vitamin B12 deficiency was associated with
the lowest cognitive performance3.
To whom correspondence should be addressed: David J. Hunter, Department of Epidemiology, Harvard School of Public Health, 677
Huntington Ave, Boston, MA 02115, Phone: 617-525-2755; Fax: 617-525-2008, Email: E-mail: dhunter@hsph.harvard.edu.
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Published in final edited form as:
Nat Genet. 2008 October ; 40(10): 1160–1162. doi:10.1038/ng.210.
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Epidemiologic studies provide evidence for the association of genes and metabolites in the B-
vitamin-mediated plasma one-carbon metabolic pathway with chronic diseases2–4. Rare high
penetrance mutations in genes in this pathway affect the ability to digest, absorb5, and utilize
vitamin B122. However, common genetic variants in candidate genes have not been
consistently associated with plasma vitamin B12 levels. Therefore, we conducted a genome-
wide association study (GWAS) to identify novel loci that influence plasma vitamin B12 levels
in 1,658 women genotyped with the HumanHap500 as part of the Cancer Genetic Markers of
Susceptibility Project (CGEMS; Supplementary Methods). Participants were of self-reported
European ancestry6. Detailed methods have been previously reported, including quality control
assessment of genotypes with sample completion and SNP call rates, concordance rate,
deviation from Hardy–Weinberg proportions in control DNA, and final sample selection for
association analysis of the NHS CGEMS population6.
We tested association between each of the 528,134 SNP markers that passed quality control
filters and log-transformed plasma vitamin B12 using linear regression, adjusted for age, total
methyl intake (defined as total folate, dietary methionine, and alcohol intake), and assay batch.
We saw no evidence for systematic bias in the distribution of p-values for analyses with and
without further adjustment for residual population structure using the top four principal
components of genetic variation (Supplementary Fig. 1), compatible with no confounding of
SNP-metabolite associations due to population stratification.
In the initial GWAS, the SNPs on chromosome 19p13.3 accounted for the excess of p-values
<107 (Supplementary Fig. 1: Quantile-Quantile plot). The strongest association with plasma
vitamin B12 was rs602662 (Ptrend = 6.54×1010; Fig. 1, Table 1, Supplementary Fig. 2), a non-
synonymous SNP in FUT2 on chromosome 19p13.3, which has a minor allele frequency of
0.49 (Table 1). The association with plasma vitamin B12 and rs602662 was independently
replicated using Taqman allelic discrimination assays in 1,059 women from two nested case
control studies drawn from the same cohort (Table 1, Supplementary Table 2) with ptrend=1.13
× 10 06. The joint analysis of the CGEMS scan data and the replication dataset supports the
association of rs602662 with plasma vitamin B12 (ptrend = 3.51×1015). Results were similar
using untransformed plasma vitamin B12 values. A similar association was observed using the
non-parametric Kruskal-Wallis test (joint analysis Kruskal-Wallis p = 1.48×1021). Plasma
vitamin B12 has an inverse correlation in this data set with plasma homocysteine, an integrated
marker of the one-carbon metabolism pathway, (Spearman correlation coefficient 0.26,
p<0.0001). FUT2 rs602662 also has a modest association with plasma homocysteine,
(ptrend=0.0085 in the GWAS data and ptrend=0.0081 in the replication data). The pattern of
mean log-transformed plasma vitamin B12 levels by rs602662 genotype suggest a dominant
genetic effect, with lower B12 levels among variant carriers (test comparing mean log-
transformed vitamin B12 levels between variant carriers and non-carriers p = 1.35 × 1039).
The SNP rs602662 is in strong linkage disequilibrium (D’=1, r2=0.76) with the FUT2 nonsense
SNP W143X (rs601338; Fig. 1). We imputed the nonsense SNP in the initial GWAS samples
using the observed chromosome 19 genotyping data augmented by data from the densely-
genotyped CEPH European HapMap samples and found that it was strongly associated with
plasma vitamin B12 levels (ptrend=4.11×1010; Fig. 1, Table 1). Since the nonsense SNP
rs601338 could not be genotyped by Taqman because of a neighboring SNP (rs1800459)
located one nucleotide upstream, we genotyped a proxy SNP, rs492602 (which is in perfect
LD with rs601338 in HapMap data; Supplementary Table 1, Supplementary Fig. 3), in both
the initial GWAS and the replication data set. The association between rs492602 and plasma
vitamin B12 was stronger than the association for rs602662 and plasma vitamin B12 (Table 1:
rs492602 joint ptrend=5.36×1017; joint dominant model p =8.26×1045). The rs492602 SNP
explains 2.5% of the variance in log-transformed plasma vitamin B12 levels using the log-
additive genetic model and 3.5% of variance using the dominant genetic model.
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Fucosylated carbohydrate structures are involved in a range of biological processes7,8
including tissue development, angiogenesis, fertilization, cell adhesion, inflammation, and
tumor metastasis. The classic human secretor locus (Se) FUT2 encodes α(1,2)
fucosyltransferase, which regulates expression of the Lewis ABO(H) histo-blood group
antigens on the surface of epithelial cells and in body fluids and determines the secretion status
of the ABO antigens7. Secretor status of this polymorphic protein was used by Mohr to provide
the first autosomal linkage in humans between secretor factor and the Lutheran blood group;
subsequently secretor linkage was established with the APOE and myotonic dystrophy
locus7. The family of α-1,2-fucosyltransferases catalyze the addition of fucose in α-1,2-linkage
to the galactose of type 1(Galβ1,3GlcNAc-R) and type 2 Galβ1,4GlcNAc- R) disaccharide to
form H type 1 and H type 2 antigens7, respectively.
In the highly polymorphic FUT2 gene7, three SNPs, rs602662, rs492602 and rs601338
(W143X; nucleotide position 428), are in strong LD, we note that W143X is a nonsense
mutation7 and is plausibly the causal variant for the association with plasma B12 levels. The
143X variant is characteristic for the nonsecretor allele in Europeans and has an allele frequency
of 0.46 in populations of European ancestry7. In Europeans, Africans, and Iranians, the FUT2
W143X nonsense mutation is the primary nonsecretor allele, with a frequency of approximately
50 percent. In contrast, in Asian populations, the FUT2 I129F (nucleotide position 385)
missense mutation is the primary nonsecretor allele8. In non-Asian populations, nonsecretors
are frequently homozygous for the FUT2 W143X polymorphism, resulting in an inactive
FUT2. Individuals homozygous for the FUT2 nonsecretor genotype appear to be resistant to
infection with Norovirus9, suggesting that individuals homozygous for nonsecretor status may
be unable to mediate host-microbe interactions9.
Absorption of B12 requires the secretion of the glycoprotein intrinsic factor (IF) from the gastric
cells, binding of IF to vitamin B12 and a functional gastrointestinal absorption system2. The
H-antigen synthesized by FUT2, Lewis ABO antigens, and FUT2 genotypes have all been
reported to mediate H. pylori attachment to human gastric mucosa10. Atrophic gastritis is a
consequence of H. pylori infection11 and leads to reduced secretion of IF12,14. The FUT2
secretor status has been associated with both H. pylori infection and gastritis10; patients with
vitamin B12 malabsorption and low levels of serum vitamin B12 have higher seroprevalence
of H. pylori infection10. These data suggest a potential mechanism by which vitamin B12
absorption12–15 may be reduced in carriers of the secretor genotype due to the sequelae of
susceptibility to H. pylori infection compared to individuals with the nonsecretor genotype.
In summary, among generally well-nourished women, we found that common variation in the
FUT2 secretor gene is associated with plasma vitamin B12 at high levels of statistical
confidence. Although the participants included in these analyses are a selected subset of women
who had plasma vitamin B12 levels measured, numerous demographic and lifestyle factors are
comparable between this sample and the overall NHS cohort. Insights gained from the study
of plasma vitamin B12 are likely to have implications for the study of complex diseases such
as cognitive decline, cancer, and cardiovascular disease. Further study is required to investigate
the biological basis of our reported association findings.
The commonly used abbreviations are
FUT2, Fucosyltransferase; GWAS, genome-wide association study; H. pylori, Helicobacter
pylori; NHS, Nurses’ Health Study; CI, confidence interval; SNPs, single nucleotide
polymorphisms.
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Acknowledgements
We thank Hardeep Ranu, Constance Chen, and the staff at the Core Genotyping Facility at the National Cancer Institute
for their expertise.
This research is supported by the National Institutes of Health Research Grants U54 CA100971, P01 CA87969, P01
CA55075, U01 CA098233, R01 CA 065725 and CA070817.
A.H. is supported in part by training grant NIH T-32 CA 09001-30.
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Figure 1. LD Structure of Chromosome 19
This panel shows the trend P values for association testing with plasma vitamin B12 from 25
observed ( ) and 44 imputed ( ) SNPs from the GWA study displaying SNPs on chromosome
19p13.3. All known genes are shown (National Center for Biotechnology Information build
36.1)
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Hazra et al. Page 6
Table 1
Association of plasma vitamin B12 levels with FUT2 genotypes in women participants from GWAS and replication studies
SNP Association by
Study Age N Allele Freq Estimate (S.E.)cP-valued
Geometric Mean (95% CI), pg/ml
rs602662 GWAS G (Gly)=0.49 Ser/Ser Ser/Gly Gly/Gly
NHS CGEMS 59 1,658 489.82 418.67 417.05 0.08 (0.01) 6.54 × 1010
(472.24–508.06) (407.74–429.90) (401.29–433.43)
Replication
Combined NHS 63 1,056 483.68 406.96 409.60 0.08 (0.02) 1.13 × 1006
Colorectal (CR e)(461.78–506.63) (393.69–420.67) (390.22–429.93)
Adenoma and CR
Cancer
Case-control Datasets
TOTAL (GWAS and
Replication) e487.72 413.35 413.52 0.08 (0.01) 3.52 × 1015
(473.80–502.06) (404.83–422.06) (401.14–426.27)
rs601338b aA (Trp)=0.51 Nonsecretor Secretor Secretor
(X/X) (X/Trp) (Trp/Trp)
GWAS
NHS CGEMS 59 1,658 496.60 418.69 418.32 0.08 (0.01) 4.11 × 1010
(477.89–516.04) (407.76–429.92) (403.36–433.84)
rs492602 GWAS a A=0.51 GG/GG AG/AG AA/AA
NHS CGEMS 59 1,637 496.02 419.95 416.97 0.08 (0.01) 2.68 × 1010
(477.32–515.45) (408.88–431.31) (402.14–432.35)
Replication
Combined NHS CR 63 1,059 491.13 407.67 406.61 0.10 (0.02) 5.60 × 1009
Adenoma and CR
Cancer (469.03–514.26) (394.34–421.45) (389.46–424.53)
Case-control Datasets
TOTAL (GWAS and
Replication)f493.89 414.27 412.70 0.09 (0.01) 5.36 × 1017
(479.42–508.81) (405.69–423.04) (401.33–424.40)
Nat Genet. Author manuscript; available in PMC 2009 April 27.
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Hazra et al. Page 7
aMajor allele according to HapMap CEU data
bImputed distribution for nonsense polymorphism, rs601338 (also known as W143X)
cEstimates (regression coefficients) calculated from linear regression adjusted for age using log-transformed plasma vitamin B12 (same estimates obtained when adjusting for age, assay batch and total
dietary methyl status)
dP-values: GWAS and replication p-values are calculated from linear regression adjusted for age
ecolorectal is abbreviated as CR
fDominant model p-value for the joint analysis: rs602662 = 1.35 × 1039; rs492602= 8.26 × 1045
Nat Genet. Author manuscript; available in PMC 2009 April 27.
... ABO secretor status has some purported clinical significance as "non-secretors" exhibit reduced risk of norovirus infection, the lead cause of gastroenteritis [86]. The lead SNP of this signal is in relatively strong LD with the FUT2 nonsense SNP W143X (rs601338)likely the causal variant for its impact on B 12 concentrations that is quite common (>30%) in all global ancestral superpopulations with the exception of East Asian ancestry populations for which a different "secretor" allele in FUT2 occurs at a similar common frequency (rs1047781) [87]. One proposed explanation for the relationship between secretor status and circulating vitamin B 12 relates to infection with H. pylori and its impact on vitamin B 12 absorption that is modulated by this signal [87]; however, this was challenged by later work that suggested that haptocorrin bound B 12 (only hepatic uptake) is associated with the FUT2 secretor allele but transcobalamin bound B 12 (bioactive form taken by all tissues) was not [88]. ...
... The lead SNP of this signal is in relatively strong LD with the FUT2 nonsense SNP W143X (rs601338)likely the causal variant for its impact on B 12 concentrations that is quite common (>30%) in all global ancestral superpopulations with the exception of East Asian ancestry populations for which a different "secretor" allele in FUT2 occurs at a similar common frequency (rs1047781) [87]. One proposed explanation for the relationship between secretor status and circulating vitamin B 12 relates to infection with H. pylori and its impact on vitamin B 12 absorption that is modulated by this signal [87]; however, this was challenged by later work that suggested that haptocorrin bound B 12 (only hepatic uptake) is associated with the FUT2 secretor allele but transcobalamin bound B 12 (bioactive form taken by all tissues) was not [88]. In that study, Velkova et al. [88] instead propose that this effect on haptocorrin bound B 12 is because of an impact on hepatic uptake arising from altered glycosylation of haptocorrin bound B 12 . ...
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... Moreover, it has been shown that the fructosyltransferase 2 (FUT2) is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 levels in the body [15][16][17]. Variants of this gene have been linked to low blood levels of vitamin B12, especially when following a vegetarian diet. Vitamin B12 deficiency is also associated with a diet low in meat and dairy products, total or partial resection of the stomach, resection of the ileum, the use of metformin, drugs blocking the secretion of gastric acid, and others [18]. ...
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