CYP2A6 rs28399434: Nicotine Metabolism & Function
The rs28399434 single nucleotide polymorphism is a regulatory variant located in the promoter region of the human CYP2A6 gene. It is widely recognized as the defining marker of the CYP2A6*9 star allele, which impairs transcription and reduces enzyme activity. Individuals carrying this variant typically metabolize nicotine and certain therapeutic compounds at a slower rate than non-carriers.
What each genotype means
Normal enzyme activity
This genotype represents the most common form of the CYP2A6 gene, often referred to as the *1 allele. Individuals with this profile typically exhibit standard rates of nicotine metabolism. Please consult with a healthcare provider or pharmacist if you have questions regarding how your metabolism might influence medication response or smoking cessation strategies.
This is the most common genotype, found in the vast majority of individuals across all global populations.
Reduced enzyme activity
This genotype includes one copy of the *9 variant, which is associated with decreased transcriptional activity of the CYP2A6 enzyme. Research suggests this may lead to a slower rate of nicotine metabolism compared to those without the variant. Because this can influence how your body processes certain substances, please discuss your genetic profile with a clinician or pharmacist.
Carried by approximately 1 in 8 to 1 in 10 people of European ancestry, and is more frequently observed in East Asian populations.
Likely decreased enzyme activity
This genotype consists of two copies of the *9 variant, which is linked to reduced transcriptional activity of the CYP2A6 enzyme. This may result in a slower rate of nicotine metabolism, potentially affecting smoking behaviors or the processing of specific medications. Please consult with a healthcare professional or pharmacist to understand the clinical implications for your specific health needs.
This genotype is relatively rare, occurring in a small percentage of the population, with higher prevalence observed in East Asian cohorts compared to European populations.
Molecular Profile and Genetic Context
The single nucleotide polymorphism rs28399434 is located on chromosome 19 within the promoter region of the CYP2A6 gene, traditionally annotated as -48T>G relative to the translational start site. Because it disrupts the gene's TATA-box promoter element, it directly interferes with transcription factor binding, which lowers baseline messenger RNA expression. This regulatory disruption forms the defining haplotype for the pharmacogenetic allele known as CYP2A6*9. Unlike missense mutations that modify the folded enzyme structure, rs28399434 diminishes the absolute abundance of normally structured CYP2A6 enzyme produced by hepatic tissue. The CYP2A6 locus resides within an intricate cluster of homologous genes and pseudogenes, including CYP2A7, making accurate molecular genotyping reliant on specialized sequencing or assay design to avoid false-positive calls.
Biological Role of CYP2A6 in Metabolism
The CYP2A6 gene encodes cytochrome P450 2A6, a heme-containing hepatic enzyme primarily responsible for the phase I oxidation of xenobiotics. CYP2A6 executes approximately 80 to 90 percent of the initial metabolic clearance of nicotine, converting it into cotinine, and subsequently transforming cotinine into trans-3'-hydroxycotinine. In addition to nicotine clearance, CYP2A6 contributes to the oxidation of clinical therapeutics such as the antiretroviral agent efavirenz, the anticoagulant coumarin, and certain oral anticancer prodrugs like tegafur. When transcriptional efficiency is lowered by the rs28399434 variant allele, circulating substrates remain active in the bloodstream for a longer biological half-life, which shifts the pharmacokinetics of both environmental compounds and prescribed drugs.
Clinical and Research Evidence
Multiple pharmacogenomic investigations demonstrate that the rs28399434 variant is statistically associated with a reduced rate of nicotine metabolism in vivo, often quantified by a lower salivary or plasma nicotine metabolite ratio. In clinical cohorts of smokers, individuals carrying the decreased-function allele often consume fewer cigarettes per day, smoke with lower puff volume, and experience different success rates when utilizing nicotine replacement therapies. Pharmacological studies have also observed elevated plasma levels of secondary substrates such as efavirenz in individuals who carry reduced-function CYP2A6 genotypes, particularly when the primary metabolizing enzyme CYP2B6 is also impaired. Despite these reproducible pharmacokinetic associations, overall clinical evidence for direct dosing modification is considered limited by bodies like CPIC, as personalized clinical guidelines for CYP2A6 remain under development.
Population Distribution and Frequency Patterns
The frequency of rs28399434 exhibits significant global variation across diverse biogeographical ancestries. The minor G allele is relatively common in East Asian populations, presenting allele frequencies between 15% and 23%. In individuals of European ancestry, the minor allele frequency typically ranges between 6% and 11%. Lower but measurable frequencies are detected in African ancestry populations (approximately 5% to 8%), while distinct frequencies have been identified in specific Indigenous North American and Alaska Native groups. Because the prevalence of other non-functional CYP2A6 alleles (such as the CYP2A6*4 whole-gene deletion) also varies widely across these groups, the cumulative metabolic profile of an individual depends on their combined multi-variant genotype.
Interpreting Results and Clinical Perspective
Knowledge of an rs28399434 genotype provides probabilistic insight into drug clearance rates rather than a standalone medical diagnosis. While carrying a decreased-function allele correlates with slower substrate breakdown, genetic variation accounts for only a fraction of total metabolic variability; factors like age, renal clearance, sex, liver function, and co-prescribed enzyme inhibitors play vital roles. Readers should never independently alter the dosage of any prescription medication, such as antiretroviral drugs or smoking cessation aids, based on genetic data. Any therapeutic decisions or interpretation of pharmacogenomic testing must be evaluated in collaboration with a licensed healthcare provider, medical geneticist, or clinical pharmacologist.
How common is this variant?
The minor G allele has an approximate frequency of 0.06 in populations of European ancestry and reaches higher frequencies of around 0.15 to 0.23 in East Asian populations.
Frequently asked questions
What does having the rs28399434 variant mean for nicotine use?
Carrying the variant reduces CYP2A6 enzyme levels, which causes nicotine to break down more slowly in the body. Research shows that slow metabolizers often smoke fewer cigarettes each day and take in lower levels of smoke toxins. However, smoking remains hazardous to cardiovascular and pulmonary health regardless of metabolic genotype.
Does rs28399434 affect how prescription medications work?
Yes, CYP2A6 participates in clearing medications such as the HIV drug efavirenz, the anticoagulant coumarin, and certain chemotherapy agents. Individuals with lower enzyme activity may accumulate higher drug concentrations, especially if alternate pathways are also reduced. Patients should discuss potential pharmacogenomic implications directly with their doctor or pharmacist.
Is the CYP2A6*9 allele the same as rs28399434?
In pharmacogenetic nomenclature, rs28399434 is the defining single nucleotide polymorphism that establishes the CYP2A6*9 haplotype. It denotes a nucleotide substitution in the promoter region (-48T>G) that impairs normal gene transcription. Other star alleles in CYP2A6 are caused by different point mutations or large-scale structural deletions.
Can I use my genotype to adjust my smoking cessation treatment?
While studies suggest that normal and slow metabolizers respond differently to nicotine replacement therapy versus non-nicotine medications, genetic test results are not a substitute for clinical guidance. You should not modify medical dosages or stop cessation treatments without first consulting a healthcare provider.
Sources & further reading
Educational information only, last refreshed 9/6/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Functional splice-site variant defining CYP2A6*20 associated with significantly reduced enzyme activity and slower nicotine and coumarin clearance.
Defining functional variant for the CYP2A6*2 allele (L160H) causing defective nicotine C-oxidation and slower metabolic nicotine clearance.
Defines the non-functional CYP2A6*2 allele (p.Leu160His) conferring absent nicotine C-oxidation activity and slow nicotine metabolism.
Associated with the CYP2A6 locus and variation in rate of nicotine metabolism and cigarette consumption.
Functional polymorphism defining the CYP2A6*9 reduced-function promoter variant causing slower nicotine and cotinine metabolism.
Defining coding polymorphism for CYP2A6*8 (p.Arg365Gln), resulting in significantly decreased catalytic activity towards substrate medications including tegafur.