CYP2A6 rs28399444: Nicotine Metabolism and Variant Impact
The rs28399444 polymorphism is a well-studied genetic variant located within the human CYP2A6 gene. It is widely cataloged in pharmacogenomic research as a reduced-function variant that leads to slower clearance of nicotine and its primary metabolite, cotinine. Carrying one or more alternative alleles at this locus can influence an individual's metabolic rate and smoking cessation pharmacology.
What each genotype means
Normal enzyme activity
This genotype represents the most common form of the gene, typically associated with standard nicotine metabolism rates. Individuals with this profile generally process nicotine at expected speeds, though individual metabolic rates can still vary based on other genetic and environmental factors. Please discuss any concerns regarding medication response or smoking cessation strategies with your clinician or pharmacist.
This is the most common genotype observed across most global populations.
Reduced enzyme activity
This genotype includes one copy of the variant associated with reduced CYP2A6 function, which may lead to slower metabolism of nicotine and certain other substances. Research suggests that individuals with reduced-function variants may experience different outcomes with nicotine-related behaviors or medications compared to those with two fully functional copies. Please consult with your healthcare provider or pharmacist to understand how this may influence your specific health context or treatment plans.
Carried by a significant portion of the population, with frequencies varying by ancestry, often appearing in approximately 10-25% of individuals depending on the specific ethnic group.
Slow enzyme activity
This genotype indicates the presence of two copies of the variant, which is linked to significantly reduced CYP2A6 enzyme activity and slower metabolism of nicotine. Because this enzyme is critical for processing nicotine, individuals with this profile may metabolize it less efficiently than the general population. It is recommended that you discuss the implications of this genotype with your clinician or pharmacist, especially if you are considering smoking cessation therapies or taking medications metabolized by this enzyme.
This genotype is less common than the others, occurring in a smaller percentage of the population across most studied ancestries.
Genomic Context and the CYP2A6 Gene
The single nucleotide polymorphism rs28399444 resides within the cytochrome P450 family 2 subfamily A member 6 (CYP2A6) gene, positioned on the long arm of chromosome 19. The CYP2A6 gene encodes a crucial phase I hepatic enzyme responsible for the metabolic oxidation of various clinically relevant pharmaceutical compounds, endogenous molecules, and environmental toxins. Most notably, CYP2A6 is the principal enzyme in the human liver tasked with metabolizing nicotine into cotinine, and subsequently cotinine into trans-3'-hydroxycotinine. The rs28399444 variant alters regulatory or functional expression of the gene, traditionally linked to specific star-allele designations such as CYP2A6*9 (and discussed in structural contexts regarding CYP2A6*20), which impair normal hepatic enzyme activity.
Pharmacogenomic Evidence and Metabolic Impact
Research documented across pharmacogenomic databases such as PharmGKB highlights that variations at rs28399444 cause a decrease in CYP2A6 expression and subsequent catalytic efficiency. Because the CYP2A6 enzyme handles upwards of 80% of systemic nicotine clearance, individuals harboring the variant allele show reduced clearance rates of nicotine and cotinine in pharmacokinetic studies. Clinical investigations have noted that intermediate or slow metabolizers experience longer circulating half-lives of nicotine, which can directly modulate smoking behavior, daily cigarette consumption, and the bioavailability of certain xenobiotics. However, clinical implementation panels such as CPIC note that while the biochemical effect on nicotine kinetics is robust, the overall strength of actionable therapeutic evidence for tailoring primary drug dosing guidelines remains limited.
Ancestral Diversity and Allele Frequencies
The distribution of rs28399444 varies substantially across global populations, reflecting the complex evolutionary landscape of the CYP2A6 locus. According to population genetics studies and global databases, the minor allele frequency is modest in individuals of European ancestry, hovering around 6% to 11%. In contrast, the variant is significantly more prevalent in East Asian cohorts, reaching frequencies of approximately 15% to 23%. Indigenous populations, including certain Alaska Native and American Indian tribes, display distinct patterns of CYP2A6 variation that alter average community metabolism metrics. These varying baseline frequencies demonstrate that individual metabolic rates cannot be inferred solely from ancestral background without direct genetic typing.
Clinical Utility and Lifestyle Considerations
Understanding your rs28399444 genotype can provide educational context regarding how quickly your liver processes nicotine and specific secondary substrates, including the antiretroviral drug efavirenz or the cancer therapy letrozole. However, this genetic information is not a diagnostic test for nicotine addiction, nor should it ever be used to modify medical treatments independently. Pharmacokinetic interactions involve multiple genes, environmental influences, kidney function, and diet. Anyone using nicotine replacement therapies, smoking cessation aids, or medications metabolized by CYP2A6 should review any genetic insights directly with a physician or clinical pharmacist before considering dosing alterations.
How common is this variant?
The minor allele occurs at an estimated frequency of approximately 0.06 (6%) in European populations and reaches approximately 0.15 (15%) to 0.23 (23%) in East Asian populations.
Frequently asked questions
What does the CYP2A6 rs28399444 variant do?
The rs28399444 variant reduces the activity of the CYP2A6 enzyme in the liver. Because this enzyme is primarily responsible for breaking down nicotine, having the variant leads to slower clearance of nicotine and cotinine from the bloodstream.
Does this variant guarantee I will find it harder to quit smoking?
No, having this variant does not determine whether you can quit smoking. While slower nicotine metabolism alters the rate at which nicotine levels fall, cessation success is influenced by psychological, behavioral, and broader physiological factors.
Can I use this result to change my prescription medications?
No, you should never alter, start, or discontinue any medication based on personal genetic results alone. If you have questions about how your liver metabolizes specific drugs, consult your doctor or a pharmacist for comprehensive clinical guidance.
How common is the rs28399444 variant worldwide?
The variant's frequency varies by geographic ancestry, occurring in about 6% of European alleles and upwards of 15% to 20% in East Asian populations. It is also found at varying rates in certain Indigenous and African cohorts.
Sources & further reading
Educational information only, last refreshed 9/7/2026. 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.
Functional variant in CYP2A6 defining the *9 allele with decreased transcriptional activity and reduced rate of nicotine metabolism.
Associated with the CYP2A6 locus and variation in rate of nicotine metabolism and cigarette consumption.
Defining coding polymorphism for CYP2A6*8 (p.Arg365Gln), resulting in significantly decreased catalytic activity towards substrate medications including tegafur.