RT Journal Article
SR Electronic
T1 Genetic polymorphism of Cytochrome-P450-2C9 (CYP2C9) in Indian populations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 113993
DO 10.1101/113993
A1 Sheikh Nizamuddin
A1 Shivendra Dubey
A1 Sakshi Singh
A1 Saurav Sharma
A1 Anshuman Mishra
A1 K Harish
A1 Harsh Joshi
A1 K. Thangaraj
YR 2017
UL http://biorxiv.org/content/early/2017/03/05/113993.abstract
AB Cytochrome-P450-2C9 (CYP2C9) metabolizes wide range of drugs and highly express in human liver. Various mutations of CYP2C9 (R144C, I359L etc.), associated with drug-response, are highly diverse. We aimed to investigate the genetic diversity of CYP2C9 in Indian-subcontinent, using 1278 subjects from 36 populations. High frequency of CYP2C9*3 (0-0.179) was observed, comparative to other populations, including Europeans. Subjects having CYP2C9*3/*3 requires lower dose of warfarin, comparative to CYP2C9*1/*3 or CYP2C9*1/*1. Since, Indians are practicing marriage among their caste system, we predicted and observed high frequency (0-0.05) of CYP2C9*3/*3. Out of 21 populations, living outside of Indian subcontinent, only Toscani and Southern Han-Chinese have 0.009 and 0.01 CYP2C9*3/*3, respectively, lower than Indians,. We found a non-synonymous mutation (L362V), observed only in Indian-subcontinent, and have 0-0.056 allelic, 0-0.037 L/V and 00.037 V/V genotype frequency. We observed unfavorable interatomic interactions between hydroxylation sites of warfarin and reactive oxyferryl heme in mutant, comparative to wild-type CYP2C9, in molecular dynamic simulations; and predict lower kinetic activity.