rs2740574 — CYP3A4 *1B -392A>G

The Most Abundant Drug-Metabolizing Enzyme — With a Controversial Variant

CYP3A4 is the workhorse of human drug metabolism, responsible for processing approximately 50% of all prescription medications. Located primarily in the liver and intestines, this cytochrome P450 enzyme¹¹ cytochrome P450 enzyme
A family of enzymes that catalyze oxidation reactions, crucial for metabolizing drugs, hormones, and toxins breaks down everything from statins to immunosuppressants to benzodiazepines. The rs2740574 variant, also known as CYP3A4*1B, sits in the gene's promoter region at position -392, where it may influence how much enzyme your cells produce.

But here's the puzzle: despite decades of research, scientists still debate whether this variant actually changes CYP3A4 activity in meaningful ways. The story of CYP3A4*1B is a cautionary tale about genetic complexity²² genetic complexity
Multiple factors including linkage disequilibrium, population structure, and gene-gene interactions can complicate interpretation in pharmacogenomics.

The Mechanism

rs2740574 is an A-to-G substitution 392 base pairs upstream of where CYP3A4's coding sequence begins. This promoter region contains binding sites for transcription factors — proteins that control how much enzyme gets made. The variant sits in the nifedipine-specific response element³³ nifedipine-specific response element
A DNA sequence that responds to the calcium channel blocker nifedipine by increasing CYP3A4 expression, potentially altering how transcription factors attach.

Early in vitro studies using luciferase reporter constructs⁴⁴ luciferase reporter constructs
Laboratory systems where a glowing protein reports gene activity suggested the G allele increased transcriptional activity. Some studies of human liver samples found CYP3A4*1B carriers had higher testosterone 6β-hydroxylation activity⁵⁵ testosterone 6β-hydroxylation activity
A standard laboratory test for measuring CYP3A4 function, using the steroid testosterone as a substrate and elevated nifedipine oxidase activity.

But the picture got murky when researchers looked at actual drug metabolism in living people. A phenotyping study using the dextromethorphan/methoxymorphinan ratio found no association between CYP3A4*1B and CYP3A4 activity⁶⁶ no association between CYP3A4*1B and CYP3A4 activity
In vivo measurements in healthy volunteers failed to replicate in vitro findings. Multiple studies reported inconsistent results.

The likely culprit? CYP3A4*1B exists in tight linkage disequilibrium⁷⁷ linkage disequilibrium
When two genetic variants are inherited together more often than chance would predict, complicating efforts to determine which variant causes an observed effect with CYP3A5*1, a variant in the neighboring CYP3A5 gene. In European populations, 67% of people with CYP3A4*1B also carry CYP3A5*1; in African populations, it's 100%. Since CYP3A5*1 definitively affects drug metabolism, it may be the true cause of effects attributed to CYP3A4*1B.

The Evidence

The most striking association involves prostate cancer in African American men. A meta-analysis of multiple case-control studies⁸⁸ meta-analysis of multiple case-control studies
Pooled analysis combining data from many independent studies to increase statistical power found GG homozygotes had roughly 10-fold higher risk of aggressive prostate cancer. But subsequent work revealed a critical flaw: after correction for population stratification⁹⁹ correction for population stratification
Statistical adjustment accounting for ancestral differences between cases and controls, the association disappeared. The apparent cancer link was an artifact of genetic ancestry differences, not a causal effect of the variant.

Similarly confounded are studies of drug metabolism. Some research found CYP3A4*1B carriers had higher clearance of docetaxel and cyclophosphamide¹⁰¹⁰ higher clearance of docetaxel and cyclophosphamide
Faster elimination of chemotherapy drugs from the body, while other studies found no effect or even opposite results. A breast cancer survival study¹¹¹¹ breast cancer survival study
85 patients treated with cyclophosphamide reported worse outcomes for CYP3A4*1B carriers (1.3-year median survival versus 2.7 years for wild-type), possibly due to impaired autoinduction reducing cyclophosphamide activation.

The most authoritative guidance comes from the 2023 CYP3A4 and CYP3A5 Genotyping Recommendations¹²¹² 2023 CYP3A4 and CYP3A5 Genotyping Recommendations
Joint consensus from AMP, CPIC, CAP, DPWG, and PharmGKB, a collaborative statement by six major pharmacogenomics organizations. Their verdict: CYP3A4*1B is "not included in the tier 1 or 2 recommendations" for routine clinical testing. Despite appearing on numerous haplotypes and showing association with the functional CYP3A5*1 allele, the independent effect of CYP3A4*1B remains unproven.

Practical Actions

If you carry one or two copies of CYP3A4*1B, what should you do? The honest answer is: probably nothing specific to this variant. Unlike CYP3A4*22 (a different variant with established reduced function) or CYP3A5*1/*3 (with clear clinical guidelines for tacrolimus dosing), CYP3A4*1B lacks actionable clinical recommendations.

That said, CYP3A4 itself is critically important. This enzyme metabolizes statins¹³¹³ statins
Cholesterol-lowering drugs including atorvastatin, simvastatin, and lovastatin, immunosuppressants (tacrolimus, cyclosporine), benzodiazepines¹⁴¹⁴ benzodiazepines
Anti-anxiety medications like alprazolam, midazolam, and triazolam, calcium channel blockers (amlodipine, diltiazem, nifedipine), many antidepressants (citalopram, escitalopram, sertraline), and chemotherapy agents. Drug-drug interactions involving CYP3A4 are among the most common and clinically significant.

If you're on multiple medications, especially combinations including a CYP3A4 substrate plus a strong inhibitor (like taking simvastatin with clarithromycin or grapefruit juice), discuss potential interactions with your pharmacist or physician. Inhibitors can increase drug levels 3- to 8-fold¹⁵¹⁵ Inhibitors can increase drug levels 3- to 8-fold
Particularly dangerous with narrow therapeutic index drugs, raising toxicity risk.

Interactions

The elephant in the room is CYP3A5*1 (rs776746). This variant in the neighboring CYP3A5 gene is strongly linked with CYP3A4*1B, especially in African populations. CYP3A5 expressors (those with at least one CYP3A5*1 allele) produce substantially more total CYP3A enzyme and require higher tacrolimus doses¹⁶¹⁶ higher tacrolimus doses
CPIC guidelines recommend 1.5-2x higher starting doses for CYP3A5 expressors after organ transplantation. Any observed effect of CYP3A4*1B might actually reflect CYP3A5*1 activity.

Within CYP3A4 itself, the *22 allele (rs35599367) is far more consequential than *1B. CYP3A4*22 carriers have 20-30% reduced enzyme activity¹⁷¹⁷ 20-30% reduced enzyme activity
Documented consistently across multiple in vitro and in vivo studies and face higher risk of tacrolimus-induced nephrotoxicity. If you're undergoing pharmacogenomic testing for drug metabolism, CYP3A4*22 and CYP3A5*1/*3 are the variants with established clinical utility.

The broader CYP3A family also includes CYP3A7 (primarily expressed in fetal liver) and CYP3A43 (minor role in adults). Gene-gene interactions, compensatory expression¹⁸¹⁸ compensatory expression
When one enzyme is reduced, cells may upregulate related enzymes, and individual variation in intestinal versus hepatic CYP3A4 activity all contribute to the challenge of predicting drug metabolism from genetics alone.

Ancestry Considerations

The rs2740574 G allele shows one of the starkest frequency differences between populations: essentially absent in East Asians (0%), rare in Europeans (~4%), and common in African populations (50-80% depending on the specific population studied). This population-specific distribution¹⁹¹⁹ population-specific distribution
Likely reflects evolutionary selection pressures or genetic drift in different ancestral environments.

For African and African American individuals, the high frequency of CYP3A4*1B means most people carry at least one copy. In the Malian population study²⁰²⁰ Malian population study
Sample of 200 individuals from Mali, CYP3A4*1B appeared in the majority of participants. This prevalence, combined with 100% linkage with CYP3A5*1 in African populations, makes it nearly impossible to separate their effects.

The prostate cancer associations that initially made headlines were likely confounded by population structure — genetic ancestry differences between cases and controls that had nothing to do with the variant's function. This is a common pitfall in genetic association studies²¹²¹ common pitfall in genetic association studies
Inadequate adjustment for ancestry can produce spurious associations when studying admixed populations.

Gene-Gene Interaction Proposals

Based on the research, here are documented gene-gene interactions worth noting for compound action consideration:

CYP3A4*1B + CYP3A5*1 (rs776746): When a person carries both CYP3A4*1B and CYP3A5*1 (the CYP3A5 expresser allele), the combined effect on total CYP3A enzyme activity is driven primarily by CYP3A5*1. This combination is nearly universal in African populations (100% linkage disequilibrium). The combined recommendation would be: follow CPIC guidelines for CYP3A5*1 regarding tacrolimus dosing; the CYP3A4*1B status does not add independent information. Monitor for drug-drug interactions involving CYP3A substrates, as total CYP3A capacity is elevated.

CYP3A4*1B + CYP3A4*22 (rs35599367): CYP3A4*22 is a decreased-function variant. If someone carries both *1B (uncertain effect) and *22 (established decreased function), the *22 allele dominates the phenotype. Combined recommendation: follow clinical guidance for CYP3A4*22 — expect reduced CYP3A4 activity, higher tacrolimus levels, increased risk of toxicity with narrow therapeutic index CYP3A4 substrates. The *1B allele does not modify this.