Pharmacogenomic profiling of CYP2D6 polymorphisms and their impact on drug metabolism

In the Peruvian Amazon, where indigenous communities have limited access to therapeutic drug monitoring, understanding how genetic variation affects drug metabolism could prevent both treatment failures and toxicity. This research profiled CYP2D6 allele and diplotype frequencies in 218 unrelated adults from three indigenous Amazonian communities near Iquitos, Peru, and correlated genotype with predicted metabolizer phenotype. Genotyping was performed using the Agena MassARRAY iPLEX platform covering 24 CYP2D6 variant positions. The most common diplotype was *1/*1 (extensive metabolizer, 34.2%), followed by *1/*4 (intermediate, 18.7%) and *1/*2 (extensive, 14.3%). Poor metabolizer genotypes (*4/*4, *5/*5) accounted for 10.1% of the cohort, while ultra-rapid metabolizers (*2xN carriers) comprised 7.5%. The predicted phenotype distribution was: 48.5% extensive, 35.6% intermediate, 10.1% poor, and 5.8% ultra-rapid. These frequencies differ markedly from European and East Asian reference populations and have direct implications for dosing codeine, tamoxifen, and beta-blockers in Amazonian populations. The data highlight the need for population-specific pharmacogenomic guidance in under-represented indigenous groups.

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CYP2D6 Phenotype SpectrumClose ×

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Freq (%): *1/*1 vs *1/*4 vs *1/*2 vs *4/*4 vs *2/*41Close ×

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Introduction

In the regional context of the Peruvian Amazon, where healthcare infrastructure is sparse and drug supply chains unreliable, getting the dose right on the first try isn't just a matter of optimization - it can mean the difference between a cure and a crisis [1]. CYP2D6, one of the most polymorphic drug-metabolizing enzymes in the human cytochrome P450 superfamily, processes roughly 25% of all clinically used medications, including opioids, antidepressants, antipsychotics, beta-blockers, and tamoxifen [2]. Over 130 CYP2D6 allelic variants have been identified, ranging from null alleles (*3, *4, *5) that produce no functional enzyme to gene duplications (*1xN, *2xN) that produce excess enzyme [3]. The resulting metabolizer phenotype - poor (PM), intermediate (IM), extensive (EM), or ultra-rapid (UM) - dramatically affects drug plasma levels and clinical outcomes.

A PM receiving standard codeine doses gets no pain relief (codeine requires CYP2D6 conversion to morphine), while a UM may experience respiratory depression from the same dose [4]. Indigenous Amazonian populations are among the least studied groups in pharmacogenomics, despite their distinct population history and genetic structure [5]. This research characterized CYP2D6 allele frequencies and predicted metabolizer phenotypes in three communities near Iquitos, Peru, at the Centro de Investigación Amazónica from March to November 2023.

Material And Methods

Material A total of 218 unrelated adults (≥18 years, self-identified indigenous Amazonian ancestry) were recruited from three communities along the Napo and Marañón river systems near Iquitos, Loreto, Peru. Buccal swab samples were collected after written informed consent in Spanish and the local indigenous language. DNA was extracted using the Oragene-DNA kit (DNA Genotek). Ethics approval: Centro de Investigación Amazónica Research Ethics NAAS Rating: 4.82 IJBS 2025; 7(5): 195-197 Yolanda Mamani Department of Genetics, Centro de Investigación Amazónica, Iquitos, Peru Milagros Ccama Department of Genetics, Centro de Investigación Amazónica, Iquitos, Peru Yolanda Mamani Department of Genetics, Centro de Investigación Amazónica, Iquitos, Peru https://www.biologyjournal.net

Results

Table 1: CYP2D6 diplotype frequencies and predicted metabolizer phenotype in 218 Amazonian indigenous adults Diplotype n Freq (%) Activity score Phenotype *1/*1 75 34.4 2.0 EM *1/*4 41 18.8 1.0 IM *1/*2 31 14.2 2.0 EM *4/*4 18 8.3 0 PM *2/*41 21 9.6 1.25 IM *2xN/*1 16 7.3 ≥3.0 UM Other 16 7.3 Variable Mixed The *4 null allele had a frequency of 19.3%, higher than East Asian populations (~1%) but lower than Northern Europeans (~22%) (Table 1). Gene duplication frequency (7.5%) was intermediate between European (~3%) and East African (~29%) populations. Committee (Protocol CIA-REC-2022-011, December 2022), with additional community-level consent obtained through local health councils.

Diplotype	n	Freq (%)	Activity score	Phenotype
*1/*1	75	34.4	2.0	EM
*1/*4	41	18.8	1.0	IM
*1/*2	31	14.2	2.0	EM
*4/*4	18	8.3	0	PM
*2/*41	21	9.6	1.25	IM
*2xN/*1	16	7.3	≥3.0	UM
Other	16	7.3	Variable	Mixed

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CYP2D6 diplotype frequencies and predicted metabolizer

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Methods

CYP2D6 genotyping covered 24 variant positions including *2, *3, *4, *5 (gene deletion), *6, *10, *17, *29, *35, *41, and gene duplication (*xN) using the Agena Bioscience MassARRAY iPLEX ADME panel at the Centro de Investigación Amazónica molecular genetics laboratory. Allele calling followed the PharmVar consensus nomenclature. Diplotypes were assigned using Stargazer v1.0.8. Predicted metabolizer phenotype was determined by activity score: PM (score 0), IM (0.25-1.0), EM (1.25-2.25), UM (≥2.5) following CPIC guidelines [6].

Allele frequencies were compared with published data for European (CEU), East Asian (CHB+JPT), and Latin American mestizo populations using Fisher's exact test. Hardy-Weinberg equilibrium was tested per locus. Fig 1: CYP2D6 diplotype frequency distribution in 218 Amazonian indigenous adults classified by metabolizer phenotype Fig 2: Heatmap of predicted relative metabolic ratios for five CYP2D6 substrate drugs across four metabolizer phenotypes https://www.biologyjournal.net and of predicted and measured metabolic phenotypes across world populations. Expert Opinion on Drug Metabolism and Toxicology. 2014;10(11):1569-1583. 9.

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Heatmap of predicted relative metabolic ratios for five CYP2D6 substrate drugs across four metabolizer phenotypes

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CYP2D6 diplotype frequency distribution in 218 Amazonian indigenous adults classified by metabolizer phenotype

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Discussion

The 10.1% PM prevalence in this Amazonian cohort is clinically significant: roughly 1 in 10 individuals would fail to convert codeine to morphine, rendering it ineffective for pain management - a common use in remote Amazonian clinics [7, 8]. Conversely, the 7.5% UM frequency means that standard codeine doses could produce dangerous morphine levels in a similar fraction of the population. The allele frequency profile doesn't match any single reference population in existing pharmacogenomic databases, which underscores the problem of applying European- or Asian-derived dosing guidelines to under- represented indigenous groups [9, 10]. Population-specific genotyping panels or at minimum, awareness-based prescribing guidelines, are needed for these communities.

Conclusion

CYP2D6 polymorphism frequencies in Amazonian indigenous Peruvians differ substantially from reference populations used in pharmacogenomic guidelines. The high PM (10.1%) and UM (7.5%) frequencies have direct implications for codeine, tamoxifen, and beta-blocker prescribing in these communities. These data argue for incorporating population-specific pharmacogenomic data into treatment protocols for under-represented indigenous populations [11, 12, 13].

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