rs601338 — FUT2 W143X (Trp143Ter)

FUT2 W143X — Secretor Status and the Gateway to Your Gut

The FUT2 gene encodes fucosyltransferase 2¹¹ fucosyltransferase 2
An enzyme that adds fucose sugar residues to glycan chains on cell surfaces and in secreted mucus, an enzyme that determines one of the most fundamental divisions in human biology: whether you are a "secretor" or a "non-secretor." Secretors express ABO blood group antigens²² ABO blood group antigens
The same A, B, and H antigens that define your blood type (A, B, AB, O), but expressed on mucosal surfaces and in saliva, tears, breast milk, and intestinal mucus rather than just on red blood cells on their mucosal surfaces and in bodily fluids like saliva and intestinal mucus. Non-secretors do not.

A single G-to-A change at position 428 of the FUT2 coding sequence creates a premature stop codon (Trp143Ter), completely inactivating the enzyme. People with two copies of the A allele — about 20% of Europeans — produce no functional FUT2 and are non-secretors. This is one of the most pleiotropic³³ pleiotropic
Affecting multiple, seemingly unrelated traits from a single genetic variant common variants in the human genome, influencing gut microbiome composition, vitamin B12 metabolism, susceptibility to viral infections, and risk of autoimmune disease.

The Mechanism

FUT2 adds fucose⁴⁴ fucose
A six-carbon sugar (6-deoxy-L-galactose) that serves as a building block for complex sugar chains on cell surfaces to glycan structures on the intestinal epithelium and in mucosal secretions, creating the H antigen — the precursor to A and B blood group antigens. In secretors, these fucosylated glycans coat the gut lining and are shed into the intestinal lumen, where they serve two critical functions.

First, they act as attachment points for certain pathogens. Norovirus and rotavirus bind to H-type and Lewis blood group antigens on intestinal cells to initiate infection. Without these glycans, the viruses literally cannot gain a foothold. Second, the shed fucosylated glycans serve as a carbon source for beneficial gut bacteria, particularly Bifidobacterium⁵⁵ Bifidobacterium
A genus of beneficial bacteria that are among the first colonizers of the infant gut and remain important for intestinal health throughout life species, which have evolved specialized enzymes to harvest fucose from host glycans.

The W143X nonsense mutation truncates the FUT2 protein at amino acid 143 (of 332 total), eliminating the catalytic domain entirely. Heterozygous carriers (AG) retain secretor status because one functional copy produces sufficient enzyme, though possibly at somewhat reduced levels.

The Evidence

The landmark norovirus study⁶⁶ landmark norovirus study
Thorven M et al. A homozygous nonsense mutation (428G→A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (GGII) infections. J Virol, 2005 demonstrated that among 115 Swedish adults exposed to norovirus outbreaks, not a single non-secretor (AA genotype) developed symptomatic infection, while 49% of GG homozygotes and 51% of AG heterozygotes were affected. A 2021 meta-analysis of 20 studies⁷⁷ 2021 meta-analysis of 20 studies
Bustamante M et al. FUT2 and norovirus: a systematic review and meta-analysis confirmed that non-secretors are approximately 3 times more likely to remain uninfected during norovirus exposure.

For vitamin B12, a genome-wide association study⁸⁸ genome-wide association study
Hazra A et al. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet, 2008 identified FUT2 as the strongest genetic determinant of plasma B12 levels (p = 5.36 x 10^-17). Paradoxically, non-secretors have 16-18% higher measured serum B12⁹⁹ 16-18% higher measured serum B12
Velkova A et al. The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin. Hum Mol Genet, 2017. However, this elevation is in haptocorrin-bound B12¹⁰¹⁰ haptocorrin-bound B12
Haptocorrin (also called transcobalamin I) is a B12 carrier protein in blood that is not readily taken up by cells. It is distinct from transcobalamin II, which delivers B12 to tissues — a biologically inactive fraction — rather than in holotranscobalamin¹¹¹¹ holotranscobalamin
The portion of blood B12 bound to transcobalamin II, which is the only form that can be actively taken up by cells and used for metabolic reactions, the bioavailable form. This means standard total B12 blood tests may overestimate functional B12 status in non-secretors.

The Crohn's disease link¹²¹² Crohn's disease link
McGovern DPB et al. Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. Hum Mol Genet, 2010 was established through GWAS, with non-secretors showing increased susceptibility (OR ~1.64 for AA genotype). A separate study¹³¹³ separate study
Smyth DJ et al. FUT2 nonsecretor status links type 1 diabetes susceptibility and resistance to infection. Diabetes, 2011 found that the AA genotype also confers susceptibility to type 1 diabetes (OR 1.29, 95% CI 1.20-1.37, p = 4.3 x 10^-18). The proposed mechanism links altered gut microbiome composition to immune dysregulation.

The gut microbiome connection¹⁴¹⁴ gut microbiome connection
Wacklin P et al. Secretor genotype (FUT2 gene) is strongly associated with the composition of bifidobacteria in the human intestine. PLoS One, 2011 showed that non-secretors harbor significantly lower diversity and abundance of Bifidobacterium species. Without fucosylated glycans lining the gut, these beneficial bacteria lose a primary food source, potentially contributing to the gut dysbiosis that underlies the increased Crohn's and autoimmune risk.

Practical Implications

The effects of FUT2 secretor status are a striking example of evolutionary trade-offs. Non-secretors gain robust protection against norovirus (and likely rotavirus and some bacterial pathogens) at the cost of a less diverse gut microbiome and modestly increased risk of certain autoimmune conditions.

For non-secretors (AA), the most actionable implications involve gut health maintenance and vitamin B12 monitoring. Since standard serum B12 tests may be misleadingly normal, requesting a holotranscobalamin (active B12) or methylmalonic acid test provides a more accurate picture of functional B12 status. Supporting gut bifidobacterial populations through targeted probiotics and prebiotic fiber is also worth considering, given the reduced diversity seen in non-secretors.

For heterozygous carriers (AG), secretor function is preserved and no specific action is typically needed, though being aware of this variant's role in B12 metabolism can inform supplement choices.

Interactions

FUT2 secretor status interacts with ABO blood type. The A and B antigens are built on top of the H antigen that FUT2 creates — so non-secretors do not express A, B, or H antigens in their mucus regardless of their ABO blood type. This means ABO-mediated disease associations on mucosal surfaces (such as susceptibility to H. pylori) can be modified by FUT2 status.

The variant rs602662 (S258G) and rs492602 are in strong linkage disequilibrium with rs601338 and show similar associations with B12 levels and disease risk. In East Asian populations, a different FUT2 variant (rs1047781, A385T) is the primary determinant of secretor status, since the W143X variant is nearly absent in that population (allele frequency <0.2%).