Tacrolimus metabolism (CYP3A5 gene)

The CYP3A5 enzyme breaks down the transplant drug tacrolimus. Whether your body makes this enzyme sets how much drug you need, and many people of European descent make little or none of it.

What CYP3A5 does, and why most Europeans do not use it

CYP3A5 is one of the liver and gut enzymes that metabolise a wide range of drugs. This variant, *3, introduces a splice change that prevents functional enzyme from being made, and it is so common in some populations that having no working CYP3A5 is the norm rather than the exception.

People with at least one functional copy are called expressers and clear CYP3A5 substrates faster. People with two *3 copies are non-expressers and rely on the related enzyme CYP3A4 instead.

Where it actually matters: tacrolimus

Tacrolimus is the immunosuppressant most transplant recipients take to prevent organ rejection, and it has a narrow therapeutic window: too little risks rejection, too much risks kidney damage. CYP3A5 expressers clear it substantially faster and need noticeably higher doses to reach the same blood level.

CPIC rates this evidence level A and recommends a higher starting dose for expressers, with the usual therapeutic drug monitoring on top. This is one of the clearer genotype-to-dose relationships in transplant medicine, and it is also the narrow situation in which this result means anything.

The ancestry pattern is unusually strong

In 1000 Genomes reference data, about 87% of European-ancestry individuals carry two non-functional copies and are non-expressers. In African-ancestry samples that figure falls to around 9%, so the large majority are expressers, with East Asian and South Asian samples in between at roughly half.

That difference has practical consequences: tacrolimus dosing guidance developed in mostly European-ancestry populations systematically underdoses expressers, which is one of the clearer examples of why pharmacogenetics has to account for ancestry.

What this variant does not tell you

Outside tacrolimus, the evidence thins quickly. CYP3A5 contributes to the metabolism of many drugs, but CYP3A4 usually dominates, and no guideline recommends adjusting other medicines on the basis of CYP3A5 genotype alone.

Other CYP3A5 non-functional alleles exist, including *6 and *7 which are more common in African-ancestry populations, and they are not read here. That matters most in exactly the group where expresser status is most common.

What each rs776746 genotype means

rs776746 has three possible genotypes: TT, CT and CC.

Fast tacrolimus metabolism (rs776746 TT). You make the CYP3A5 enzyme (the normal type), which breaks down the transplant drug tacrolimus. People who make it clear the drug quickly, so they usually need a higher dose. This only matters if you ever take tacrolimus.

Intermediate tacrolimus metabolism (rs776746 CT). You carry one working copy and one non-working copy of CYP3A5. You still make some of the enzyme that clears the transplant drug tacrolimus, so you'd fall in an intermediate dosing range. Relevant only in a transplant setting.

Slow tacrolimus metabolism (rs776746 CC). You carry the non-working version of CYP3A5, so you make little or none of the enzyme, which is common in people of European descent. You clear the transplant drug tacrolimus slowly, so standard dosing usually fits. This only comes into play if you ever need tacrolimus.

Evidence & sources

Across global populations, about 80% of people carry two copies of this variant, and about 4% carry none.

CPIC provides dosing guidance for tacrolimus based on this gene.

This variant appears in 9 published genetic studies: PubMed 30801552 · PubMed 31959995 · PubMed 33755393 · PubMed 35977080 · PubMed 36357675 · PubMed 36635386 · PubMed 37277652 · PubMed 37524825 · PubMed 39644095.

Common questions

Does this affect my everyday medicines? For almost everyone, no. The established clinical use is tacrolimus dosing after transplant, where expressers need higher doses. For other drugs CYP3A4 generally dominates, and no guideline acts on CYP3A5 genotype alone.

Why do so many Europeans have no working CYP3A5? The non-functional *3 allele reached very high frequency outside Africa, so about 87% of European-ancestry people carry two copies. Which version is ancestral matters less than the practical consequence: dosing guidance built in one population can be wrong in another.

Related

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