rs3760775 — FUT6

Near-gene regulatory variant near FUT6 that lowers circulating vitamin B12

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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.

The Mechanism

FUT6 encodes alpha-(1,3)-fucosyltransferase 6, a Golgi enzyme that synthesises sialyl-Lewis X11 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 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 HNF4α22 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 haptocorrin33 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.44 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 inverse normal 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.

Practical Actions

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.

Nutrient Interactions

vitamin B12 reduced_absorption

Genotype Interpretations

What each possible genotype means for this variant.

TT Full FUT6 Activity Beneficial

Both copies of the higher-B12 allele — optimal FUT6 expression

You carry two copies of the T allele, the variant associated with the highest circulating B12 levels at this locus. This genotype is rare in Europeans (about 0.4%) but found in roughly 7% of Indians. This does not guarantee B12 sufficiency — diet, FUT2 status, and other absorption-related factors still matter — but this locus is working in your favour.

GT Partial FUT6 Activity Intermediate

One copy of the low-B12 allele — moderately reduced FUT6 expression

The GWAS discovery by Nongmaithem et al. (2017) showed an additive effect of the T allele on B12 levels (beta = 0.25 per allele on inverse normal transformed B12). GT carriers sit in the middle of this distribution.

Holo-transcobalamin (active B12) provides a cleaner readout of tissue-available B12. Methylmalonic acid (MMA) — a metabolite that accumulates when cellular B12 is insufficient — is the most sensitive functional marker.

GG Reduced FUT6 Activity Decreased

Both copies of the low-B12 allele — lowest circulating B12 in this gene

Conditional analysis by Nongmaithem et al. (2017) confirmed rs3760775 as the primary signal in this chromosomal region, with the T allele raising inverse normal transformed B12 by ~0.25 units per copy. GG individuals lack both T alleles and thus show the lowest B12 at this locus.

The clinically actionable fraction is holo-transcobalamin (active B12), which represents B12 bound to transcobalamin and available to all tissues. Elevated methylmalonic acid is the downstream functional marker of cellular insufficiency.

Note that this variant acts additively with FUT2 secretor variants (rs601338, rs602662) — carrying risk alleles at both genes produces a compounded effect on B12 regulation.