The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation.
The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation.
复制标题
FUT2 分泌变体 p.Trp154Ter 通过 Holo-haptocorrin（而非 Holo-转钴胺素）影响血清维生素 B12 浓度，并且与 haptocorrin 糖基化相关。
DOI：
10.1093/hmg/ddx369
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发表时间：
2017
影响因子：
3.5
通讯作者：
Brody,LawrenceC
中科院分区：
文献类型：
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作者：
Velkova,Aneliya;Diaz,JenniferEL;Pangilinan,Faith;Molloy,AnneM;Mills,JamesL;Shane,Barry;Sanchez,Erica;Cunningham,Conal;McNulty,Helene;Cropp,CherylD;Bailey-Wilson,JoanE;Wilson,AlexanderF;Brody,LawrenceC
维生素 B12 缺乏症在老年人中很常见。循环维生素 B12 浓度可用于诊断缺乏症，但该测试具有很高的假阳性和假阴性率。我们进行了全基因组关联研究 (GWAS)，将总血清维生素 B12 分解为与转钴胺素和 haptocorrin 结合的部分：这两种载体蛋白具有非常不同的生物学特性。我们复制了已报告的总循环维生素 B12 浓度与 FUT2 中常见无效变异之间的关联。该等位基因决定了在非血液体液中发现血型抗原的分泌表型。与 haptocorrin (holoHC) 结合的维生素 B12 仍然与 FUT2rs601338 (p.Trp154Ter) 高度相关。转钴胺结合维生素 B12 (holoTC) 不受此变体的影响。 HoloTC 是具有生物活性的维生素形式，可被所有组织吸收。相比之下，holoHC 仅被肝脏吸收。使用具有已知 FUT2 基因型的个体的 HoloHC，我们证明 FUT2rs601338 基因型影响 haptocorrin 的糖基化。然后，我们开发了一个实验模型，证明 HoloHC 通过脱唾液酸糖蛋白受体 (ASGR) 转运到培养的肝细胞 (HepG2) 中。我们的数据挑战了目前发表的关于遗传变异对这一临床重要指标的影响的假设，并且与 FUT2rs601338 通过改变 haptocorrin 糖基化影响 HoloHC 的模型一致，而与非糖基化转钴胺素（即 HoloTC）结合的 B12 不受影响。我们的研究结果解释了使用总 B12 或 HoloTC 作为维生素 B12 状态的一线临床测试之间观察到的一些差异。
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 inFUT2. This allele determines thesecretorphenotype in which blood group antigens are found in non-blood body fluids. Vitamin B12 bound to haptocorrin (holoHC) remained highly associated withFUT2rs601338 (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 knownFUT2genotypes, we demonstrated thatFUT2rs601338 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 whichFUT2rs601338 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.