rs13107325 — SLC39A8 A391T

The ZIP8 Transporter — A Pleiotropic Gene Linking Metal Metabolism to Gut Health

SLC39A8¹¹ SLC39A8
Also known as ZIP8 (Ziv-Irt-like Protein 8) encodes a membrane transporter that moves divalent metal ions — particularly manganese, zinc, and iron — from outside the cell into the cytoplasm.

The protein acts as a transporter for multiple metal ions including Zn²⁺, Cd²⁺, Fe²⁺, Mn²⁺, Hg²⁺, and Co²⁺ . The A391T variant (rs13107325) is one of the most pleiotropic genetic variants identified by genome-wide association studies, meaning it influences multiple, seemingly unrelated traits across different body systems.

The Mechanism

The A391T substitution replaces alanine with threonine at position 391²² replaces alanine with threonine at position 391
A more polar amino acid in the protein structure.

While the intrinsic transport properties remain similar to wild-type ZIP8, cellular uptake of zinc, cadmium, and iron is significantly reduced due to decreased ZIP8 plasma membrane expression . The variant protein simply doesn't reach the cell surface as efficiently, limiting the amount of metal ions that can be transported into cells.

This has particularly important consequences in the intestinal epithelium.

Intestinal epithelial SLC39A8 controls intestinal manganese absorption and epithelial integrity . When ZIP8 function is impaired, manganese becomes less available to intestinal cells³³ manganese becomes less available to intestinal cells
Mn is essential for glycosyltransferase enzymes, which build the protective glycocalyx layer and mucus that form the gut barrier.

The Evidence

The strongest association is with Crohn's disease⁴⁴ Crohn's disease
A form of inflammatory bowel disease.

In an exome-wide study of 10,523 IBD cases and 5,726 controls, the A391T variant was significantly associated with Crohn's disease (combined meta-analysis p=5.55×10⁻¹³, OR=1.31) . The T allele (threonine) is the risk variant.

More strikingly, the Crohn's disease risk allele was associated with altered colonic microbiome composition in both healthy controls (p=0.009) and Crohn's disease cases (p=0.0009), with microbes depleted in healthy carriers strongly overlapping with those reduced in CD patients (p=9.24×10⁻¹⁶) and overweight individuals (p=6.73×10⁻¹⁶) . This suggests the variant affects the gut ecosystem even before disease develops.

Mouse studies confirm the mechanism.

A393T knockin mice (corresponding to human A391T) showed markedly reduced manganese levels in whole blood, liver, and colon, with levels of zinc and iron unchanged , demonstrating specificity for manganese.

Electron microscopy revealed the glycocalyx in mutant mice was sparse and significantly shorter than in wild-type mice

— direct evidence of impaired barrier function.

The variant has remarkably broad effects.

GWAS showed the A391T polymorphism is associated with reduced arterial blood pressure, increased body mass index, increased HDL-cholesterol, and schizophrenia .

It has also been linked to adolescent idiopathic scoliosis, with the minor allele associated with greater spinal curvature, decreased height, increased BMI, and lower plasma manganese .

Practical Implications

If you carry one or two copies of the T allele, your intestinal cells absorb less manganese and zinc from food. This can weaken the gut barrier over time, potentially increasing susceptibility to intestinal inflammation and altering which bacteria thrive in your colon. The microbiome shifts resemble those seen in Crohn's disease and obesity, even in otherwise healthy people.

The reduced manganese transport affects enzymes throughout the body that require manganese as a cofactor, particularly those involved in building protective glycoproteins. This may explain the association with scoliosis (bone and cartilage development), lower blood pressure (vascular function), and neuropsychiatric effects (brain requires manganese for neurotransmitter metabolism).

Dietary intake of manganese becomes more important when you have this variant.

Higher dietary manganese intake was associated with lower BMI, higher HDL cholesterol, lower triglycerides, and reduced body fat percentage — effects that oppose the risks conferred by the genetic variant .

Interactions

The effects of this variant are most pronounced when combined with low dietary manganese intake or with other genetic variants affecting gut barrier function, metal metabolism, or inflammatory pathways. The microbiome alterations may interact with dietary factors that influence bacterial composition, such as fiber intake and fermented foods. No specific multi-SNP compound effects have been formally documented yet, but the microbiome-mediated effects suggest that variants in other IBD risk genes may compound the impact.