rs10403955 — CYP2B6

Intronic CYP2B6 haplotype-tagging variant associated with altered plasma concentrations of efavirenz, S-methadone, and other CYP2B6-metabolized drugs

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CYP2B6 Intronic Haplotype Tag — A Pharmacokinetic Signal in One of the Body's Most Variable Drug-Metabolizing Genes

The CYP2B6 enzyme accounts for only 1–4% of total hepatic cytochrome P450 content yet handles metabolism of several high-stakes medications: the HIV antiretroviral efavirenz, the addiction-treatment drug methadone, the antidepressant and smoking-cessation aid bupropion, the cancer drug cyclophosphamide, and the anesthetic and antidepressant ketamine. CYP2B6 is the most polymorphic human CYP enzyme11 CYP2B6 is the most polymorphic human CYP enzyme
more than 100 defined alleles make CYP2B6 activity highly variable between individuals, producing up to 100-fold inter-individual differences in plasma drug concentrations at standard doses.

rs10403955 is an intronic variant (c.172-468T>G) located deep in intron 1 of CYP2B6 on chromosome 19. It does not alter the enzyme's amino acid sequence but marks a haplotype block in the gene's regulatory and intronic architecture that tags reduced CYP2B6 metabolic activity at the population level.

The Mechanism

Unlike the well-characterized missense variant rs3745274 (516G>T, p.Q172H), rs10403955 sits 468 base pairs upstream of exon 2 within an intronic region. Its G allele acts as a tagging SNP22 tagging SNP
a variant in strong linkage disequilibrium with one or more functional variants in the same haplotype block, allowing it to predict activity even without itself being causal. The T allele belongs to haplotype blocks associated with higher CYP2B6 expression and enzyme activity; the G allele marks haplotypes where expression or splicing is impaired.

Wang et al. (2011)33 Wang et al. (2011)
CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer identified a trinucleotide haplotype block (rs8100458–rs10500282–rs10403955) in intron 1 of CYP2B6 where the T allele of rs10403955 was significantly associated with higher S-methadone clearance and lower plasma concentrations (P < 0.0017). Conversely, carriers of the G allele have lower clearance — resulting in higher drug accumulation at standard doses.

The Evidence

In a prospective study of 366 Taiwanese patients receiving methadone maintenance therapy, Wang et al. demonstrated44 Wang et al. demonstrated
CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer that the rs10403955 T/G haplotype block explained a meaningful fraction of inter-individual variability in S-methadone plasma concentration-to-dose ratios. The S-enantiomer is the pharmacologically active form responsible for mu-opioid receptor binding and opioid maintenance effects, and also the form that prolongs cardiac QT intervals, making its accumulation clinically significant.

For efavirenz, Carr et al. (2010)55 Carr et al. (2010)
Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort included rs10403955 as one of three CYP2B6 tagging SNPs representing 11 associated variants. Among 219 HIV-infected Chilean patients, a composite genetic model containing these tagging SNPs predicted efavirenz concentrations exceeding the CNS-toxicity threshold of 4 μg/mL with an odds ratio of 48.1 (95% CI 13.5–207.7; P < 0.001). The model had 97% specificity and 92% negative predictive value, demonstrating that CYP2B6 haplotype tagging — including this locus — can meaningfully stratify toxicity risk before treatment.

The G allele frequency varies by ancestry: approximately 25% in Europeans, 37% in Africans, 21% in East Asians, 39% in South Asians, and 35% in Latino populations, reflecting the same broad ancestry stratification seen in the primary CYP2B6 functional variant rs3745274.

Practical Implications

The haplotype context of rs10403955 makes it clinically informative for anyone prescribed a CYP2B6-metabolized drug. Homozygous GG carriers represent approximately 9% of the global population and are most likely to experience reduced enzymatic clearance, leading to higher plasma concentrations of efavirenz (with CNS toxicity risk), methadone (with QT-prolongation and accumulation risk), and other CYP2B6 substrates. Heterozygous GT carriers (~42% of the population) show intermediate accumulation.

Importantly, rs10403955 should be interpreted alongside primary functional variants in CYP2B6 (especially rs3745274 and rs28399499) for the most accurate metabolizer phenotype assignment. CPIC guidelines define CYP2B6 metabolizer phenotypes primarily through the star-allele system: poor metabolizers should receive efavirenz dose reductions to 400 mg or 200 mg daily instead of the standard 600 mg.

Interactions

rs10403955 lies within a haplotype block with rs8100458 and rs10500282, forming an intronic triad that modulates CYP2B6 expression as a unit. The primary functional variants in CYP2B6 — rs3745274 (516G>T, defining CYP2B6*6/*9) and rs28399499 (983T>C, defining CYP2B6*16/*18) — are the classical anchors of the CYP2B6 star-allele system, and rs10403955 captures independent haplotype information not fully explained by those coding variants alone. CYP2B6 activity is also strongly inducible by rifampin and by efavirenz itself, meaning that drug-drug interactions can partially overcome or exaggerate the genetic effect depending on co-medications.

Drug Interactions

efavirenz increased_toxicity literature
methadone dose_adjustment literature
bupropion reduced_efficacy literature
cyclophosphamide dose_adjustment literature
ketamine dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal Metabolizer Normal

Standard CYP2B6 haplotype — typical drug clearance

You carry two copies of the reference T allele at this intronic CYP2B6 position. This haplotype is associated with typical CYP2B6 enzyme activity and standard clearance rates for drugs metabolized by this enzyme, including efavirenz, methadone, bupropion, and ketamine. Approximately 49% of people globally share this genotype (57% of Europeans, 63% of East Asians). Standard dosing protocols for CYP2B6-metabolized drugs are designed for individuals with this metabolic profile.

GT Intermediate Metabolizer Intermediate

One G allele — modestly reduced CYP2B6 haplotype activity

The GT genotype marks one copy of a haplotype block (with rs8100458 and rs10500282) that was associated with lower S-methadone clearance in the Wang et al. 2011 study. As a tagging variant, the G allele reflects reduced CYP2B6 expression or efficiency within this region. For efavirenz, intermediate metabolizers typically experience 1.5–2 fold higher plasma concentrations compared to normal metabolizers, increasing the probability of CNS side effects such as vivid dreams, dizziness, and mood changes. For methadone, clearance is reduced by 20–40%, slowing accumulation but not eliminating it.

GG Poor Metabolizer Poor

Two G alleles — substantially reduced CYP2B6 haplotype activity

Homozygous GG carriers show the lowest CYP2B6 activity of the three genotypes at this locus. The intronic haplotype block tagged by the G allele impairs CYP2B6 expression or splicing, and with two copies of this haplotype the cumulative effect on drug clearance is substantial. For efavirenz, plasma concentrations can be 2–4 fold above average, dramatically increasing the risk of neuropsychiatric toxicity (dizziness, insomnia, depression, suicidal ideation) and treatment discontinuation. For methadone, reduced clearance leads to prolonged QT intervals and accumulation of the cardioactive S-enantiomer, raising risk of life-threatening arrhythmias. For bupropion, conversion to the pharmacologically active metabolite hydroxybupropion is reduced, potentially diminishing antidepressant and smoking cessation efficacy.