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CYP2C9 Variations and Their Pharmacogenetic Implications Among Diverse South Asian Populations

Authors Nizamuddin S, Dubey S, Singh S, Sharma S, Machha P, Thangaraj K

Received 20 July 2020

Accepted for publication 1 December 2020

Published 27 January 2021 Volume 2021:14 Pages 135—147


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Martin Bluth

Sheikh Nizamuddin,1,2 Shivendra Dubey,1 Sakshi Singh,1 Saurav Sharma1 , Pratheusa Machha,1,3 Kumarasamy Thangaraj1,3,4

1CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India; 2German Cancer Consortium (DKTK) c/o Zentrale Klinische Forschung (ZKF), University Medical Center, Freiburg, Germany; 3AcSIR (Academy of Scientific and Innovative Research), CSIR-Centre for Cellular and Molecular Biology, Hyderabad 500007, India; 4DBT-Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India

†Mr Sharma passed away on June 11, 2019.

Correspondence: Kumarasamy Thangaraj
CSIR-Centre for Cellular and Molecular Biology, Hyderabad, Telangana 500007, India
Fax +91-40-27160311

Introduction: Allelic frequency distribution of drug metabolizing enzyme genes among populations is important to identify risk groups for adverse drug reaction and to select representative populations for clinical trials. Although India emerged as an important hub for clinical trials, information about the pharmacogenetic diversity for this region is still lacking. Here, we investigated genetic diversity of cytochrome-P450-2C9 (CYP2C9) gene which metabolizes wide range of drugs and is highly expressed in the human liver.
Methods: In total, 1278 individuals from 36 diverse Indian populations, 210 individuals from in-house data-repository and 489 other South Asian samples from the 1000 Genomes Project were selected. Variants observed in CYP2C9 gene were subjected to various statistical analyses.
Results: High frequency of CYP2C9*3 (∼ 13%) and CYP2C9*3/*3 (∼ 1%) was observed among South Asians, compared to 21 populations living outside the Indian subcontinent. The allelic/genotypic frequency does not correlate with geographical location or linguistic affiliation, except populations speaking Tibeto-Burmans language, who have lower frequency of CYP2C9*3 and CYP2C9*3/*3. Since, South Asians practice strict endogamy, presence of unique mutation and high frequency of homozygous genotypes not surprising. CYP2C9*3 has been associated with therapeutic response.The effect of CYP2C9*3/*3 is more pronounced compared to heterozygous and wild type homozygous genotypes as evident in many in vitro studies. As South Asians have high frequency, it would be interesting to explore potential of CYP2C9*3 as a marker for personalized therapy. Our study revealed several rare functional variants, which form eight novel and rare haplotypes of CYP2C9 (CYP2C9*63–*70). Of which, CYP2C9*64, *65, *66, *68, *69 and *70 haplotypes are South Asian-specific.
Conclusion: Overall, we find high genetic heterogeneity within South Asians and identified South Asian-specific putative functional CYP2C9 haplotypes. High frequency of CYP2C9*3 and CYP2C9*3/*3 was observed in South Asian populations. Taken together, current study greatly enriches the knowledge of naturally occurring CYP2C9 variants and its diversity in South Asia, which are relevant to further CYP2C9-related functional research and for personalized medicine.

Keywords: pharmacogenetics, CYP2C9, South Asians, genetic diversity

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