The genomic landscape of CYP2D6 variation in the Indian population

Abstract

Aim: The CYP2D6 gene is highly polymorphic, causing large interindividual variability in the metabolism of several clinically important drugs. Materials & methods: The authors investigated the diversity and distribution of CYP2D6 alleles in Indians using whole genome sequences (N = 1518). Functional consequences were assessed using pathogenicity scores and molecular dynamics simulations. Results: The analysis revealed population-specific CYP2D6 alleles (*86, *7, *111, *112, *113, *99) and remarkable differences in variant and phenotype frequencies with global populations. The authors observed that one in three Indians could benefit from a dose alteration for psychiatric drugs with accurate CYP2D6 phenotyping. Molecular dynamics simulations revealed large conformational fluctuations, confirming the predicted reduced function of *86 and *113 alleles. Conclusion: The findings emphasize the utility of comprehensive CYP2D6 profiling for aiding precision public health.

Keywords::

• CYP2D6
• cytochrome P450
• drug metabolism
• genomics
• Indian population
• molecular dynamics simulation
• personalized medicine
• pharmacogenomics
• pharmacology
• polymorphism

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/pgs-2023-0233

Author contributions

V Scaria and A Sivadas conceived the study. A Sivadas and S Sahana analyzed the IndiGenome dataset along with other population-scale genome datasets. S Rathore designed and performed the molecular dynamics simulation analysis. A Sivadas, S Rathore and S Sahana contributed to data interpretation and wrote the manuscript. V Scaria and S Sivasubbu contributed to the manuscript editing and approved the final version. All remaining authors contributed to the collection, sequencing and analysis of the IndiGen genome sequence data.

Financial disclosure

This work was supported by the Council of Scientific and Industrial Research, India. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Data sharing statement

Data from this study are available through one table, four figures, five supplementary tables and one supplementary figure in the manuscript.