Type

Journal Article

Authors

Lawrence C Brody
Alexander F Wilson
Joan E Bailey-Wilson
Cheryl D Cropp
Helene McNulty
Conal Cunningham
Erica Sanchez
Barry Shane
James L Mills
Anne M Molloy
and 3 others

Subjects

Biochemistry

Topics
carrier proteins vitamin b12 blood group antigens genetic variation asialoglycoprotein receptor cells cultured genome wide association studies body fluids

The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation. (2017)

Abstract Vitamin B12 deficiency is common in older individuals. Circulating vitamin B12 concentration can be used to diagnose deficiency, but this test has substantial false positive and false negative rates. We conducted genome-wide association studies (GWAS) in which we resolved total serum vitamin B12 into the fractions bound to transcobalamin and haptocorrin: two carrier proteins with very different biological properties. We replicated reported associations between total circulating vitamin B12 concentrations and a common null variant in FUT2. This allele determines the secretor phenotype in which blood group antigens are found in non-blood body fluids. Vitamin B12 bound to haptocorrin (holoHC) remained highly associated with FUT2 rs601338 (p.Trp154Ter). Transcobalamin bound vitamin B12 (holoTC) was not influenced by this variant. HoloTC is the bioactive the form of the vitamin and is taken up by all tissues. In contrast, holoHC is only taken up by the liver. Using holoHC from individuals with known FUT2 genotypes, we demonstrated that FUT2 rs601338 genotype influences the glycosylation of haptocorrin. We then developed an experimental model demonstrating that holoHC is transported into cultured hepatic cells (HepG2) via the asialoglycoprotein receptor (ASGR). Our data challenge current published hypotheses on the influence of genetic variation on this clinically important measure and are consistent with a model in which FUT2 rs601338 influences holoHC by altering haptocorrin glycosylation, whereas B12 bound to non-glycosylated transcobalamin (i.e. holoTC) is not affected. Our findings explain some of the observed disparity between use of total B12 or holoTC as first-line clinical tests of vitamin B12 status.
Collections Ireland -> Trinity College Dublin -> PubMed

Full list of authors on original publication

Lawrence C Brody, Alexander F Wilson, Joan E Bailey-Wilson, Cheryl D Cropp, Helene McNulty, Conal Cunningham, Erica Sanchez, Barry Shane, James L Mills, Anne M Molloy and 3 others

Experts in our system

1
Lawrence C. Brody
Trinity College Dublin
Total Publications: 33
 
2
Joan E Bailey-Wilson
Trinity College Dublin
Total Publications: 3
 
3
Helene McNulty
Trinity College Dublin
Total Publications: 14
 
4
Conal Cunningham
Trinity College Dublin
Total Publications: 22
 
5
Barry Shane
Trinity College Dublin
Total Publications: 11
 
6
James L. Mills
Trinity College Dublin
Total Publications: 37
 
7
Anne M. Molloy
Trinity College Dublin
Total Publications: 124