rs3760775 — FUT6

FUT6 and Vitamin B12 — A Hidden Genetic Lever Common in South Asians

Vitamin B12 is essential for DNA synthesis, myelin formation, and one-carbon metabolism, yet a striking proportion of Indians — estimated at 47–70% of adults — have clinically low circulating B12 levels even when their diets are not severely restricted. Part of this disparity has a genetic explanation: a regulatory variant near the FUT6 gene that subtly suppresses fucosyltransferase¹¹ fucosyltransferase
An enzyme that attaches fucose sugar molecules to glycoproteins and glycolipids, influencing cell-surface signalling and microbial interactions activity and, through that, lowers circulating B12.

The Mechanism

FUT6 encodes alpha-(1,3)-fucosyltransferase 6, a Golgi enzyme that synthesises sialyl-Lewis X²² sialyl-Lewis X
A carbohydrate structure on cell surfaces that serves as a ligand for E-selectin and controls cell-cell adhesion, immune trafficking, and gut microbial colonisation glycan structures. These fucosylated glycans line the intestinal epithelium and serve as a biological interface between host cells and gut microbiota.

rs3760775 sits in a regulatory region near the FUT6 promoter/enhancer cluster on chromosome 19p13.3. The G allele (the common allele in Europeans, the risk allele here) is associated with lower FUT6 expression, while the T allele preserves higher expression. The companion variant rs78060698 at the same locus has been shown through luciferase reporter assays and electrophoretic mobility shift assays to exhibit allele-specific promoter and enhancer activity, affecting binding of HNF4α³³ HNF4α
Hepatocyte Nuclear Factor 4α — a transcription factor that regulates expression of multiple fucosyltransferases and is highly expressed in the gut and liver, a key regulator of fucosyltransferase expression in the gut.

The functional pathway linking FUT6 to B12 most likely runs through two routes: first, altered intestinal fucosylation changes the gut microbiome composition, affecting microbial B12 synthesis and uptake; second, fucosylation of haptocorrin⁴⁴ haptocorrin
Also called transcobalamin I — a glycoprotein that binds ~80% of circulating B12 but is metabolically inert; only the liver can extract B12 from it, the dominant B12-binding protein in serum, may affect its hepatic clearance rate, altering how much B12 remains in circulation.

The Evidence

The primary evidence comes from a 2017 GWAS by Nongmaithem et al.⁵⁵ Nongmaithem et al.
Nongmaithem SS et al. GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians. Hum Mol Genet, 2017 conducted in 1,001 healthy participants from the Pune Maternal Nutrition Study with replication in 3,418 Indians from independent cohorts (total n = 4,419). The T allele at rs3760775 was associated with higher B12 levels at genome-wide significance (meta-analysis beta = 0.25, P = 1.2×10⁻²³ on log-transformed B12). The effect allele frequency was 0.27 in Indians versus only 0.06 in Europeans (CEU), indicating the variant and its population impact are substantially higher in South Asians.

Conditional analysis showed that rs3760775 captures the primary signal at this locus, with rs3760776 and rs78060698 tagging the same or overlapping signals in the FUT6 region. The association was replicated consistently across sex, age, pregnancy status, and ethnicity subgroups.

A large PLOS Genetics meta-analysis⁶⁶ PLOS Genetics meta-analysis
Grarup N et al. Genetic Architecture of Vitamin B12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets. PLoS Genet, 2013 confirmed the FUT6/FUT3 cluster as one of 11 B12-associated loci across European and Icelandic populations. All identified loci together explain about 6.3% of B12 variance, consistent with polygenic architecture.

The mechanism was further illuminated by studies of the related FUT2 gene: Rogne et al. 2017⁷⁷ Rogne et al. 2017
Rogne S et al. FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin. Hum Mol Genet, 2017 demonstrated that FUT2 non-secretors have 16–22% higher total B12 but unchanged active B12 (holo-transcobalamin), because fucosylation affects haptocorrin glycosylation and hepatic clearance, not intestinal uptake per se. A similar mechanism likely operates at FUT6 — meaning the effect on total circulating B12 is real, but the clinically relevant fraction (active B12 delivered to tissues) may differ from what total serum B12 tests show.

Practical Actions

If you carry two G alleles at rs3760775 (GG), your FUT6 expression is likely somewhat lower, reducing the fucosylation-dependent mechanisms that support B12 metabolism. Given that Indians already have high background rates of B12 deficiency partly explained by vegetarian diets, this genetic variant can compound dietary inadequacy. The most direct action is to ensure adequate B12 intake and to use the most bioavailable supplemental forms when needed.

For monitoring: serum total B12 may not fully reflect cellular B12 status when fucosylation-dependent haptocorrin clearance is altered. Holo-transcobalamin (active B12) or methylmalonic acid (MMA) testing provides a more accurate picture of functional B12 sufficiency.

Interactions

FUT6 rs3760775 acts additively with FUT2 rs601338 and rs602662 — both affect fucosylation in overlapping pathways. Carrying risk alleles at multiple FUT loci compounds the effect on B12 regulation. Additionally, B12 metabolism intersects with the folate-methylation cycle: low B12 elevates homocysteine, which in turn amplifies risks from MTHFR C677T (rs1801133) heterozygosity. The FUT3-FUT5-FUT6 gene cluster on 19p13.3 shows distinct linkage disequilibrium patterns across ethnicities, which is why this variant's impact is most pronounced in South Asian populations.