Mechanistic insights into the CYP2C19 genetic variants prevalent in the Indian population

• Published in: Gene Vol. 784; p. 145592
• Main Authors: Naushad, Shaik Mohammad, Vattam, Kiran Kumar, Devi, Yadamreddy Kanaka Durga, Hussain, Tajamul, Alrokayan, Salman, Kutala, Vijay Kumar
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.06.2021
• Subjects: Adult; Aged; alleles; Computer Simulation; CYP2C19; Cytochrome P-450 CYP2C19 - genetics; European Continental Ancestry Group - genetics; exons; Female; gain-of-function mutation; GATA transcription factors; Gene Frequency; Genetic Variation; genotype; genotyping; Genotyping Techniques - methods; Global Screening Array; Healthy Volunteers; Humans; In silico analysis; India; loss-of-function mutation; Male; Metagenomics; Middle Aged; probability; therapeutics; transcription (genetics); Transcriptional factor binding; Young Adult; India; MEF2; NMA; ESS; In silico analysis; CYP2C19; GATA1; PCA; GSA; ESE; EVI1; Transcriptional factor binding; RM; Global Screening Array; PM
• DOI: 10.1016/j.gene.2021.145592
• ISSN: 0378-1119; 1879-0038

•Established the distribution of CYP2C19 variants in Indians using Infinium global screening array.•Five CYP2C19 variants were identified in Indians (*2, *3, *6,*8 and *17)•The *2 and *17 variants are prevalent while *3, *6 and *8 are rare.•The *2, *3 and *7 have lesser probability of exon skipping, while *17 has more probability.•In the presence of *17 variant, GATA1, MEF2 and EVI1 transcription factors binding is enhanced.•This increased binding contributes to DNA curvature in the presence of *17 variant.•The *5,*6, *8, *9 and *10 variants with higher evolutionary preservation are probably damaging.•Region-specific data of Indians clustered together except for Assamese. CYP2C19 metabolizes the antiplatelet and antiepileptic drugs. Any alteration in CYP2C19 activity might influence the therapeutic efficacy. The objective of this study was to identify CYP2C19 variants prevalent in Indians and perform their in silico characterization. Infinium global screening array (GSA) was used for CYP2C19 genotyping in 2000 healthy Indians. In addition, we performed in silico characterization of the identified variants. Out of the 11 variants covered (*2, *3, *4,*5,*6, *7,*8, *9,*10,*11, and *17), five were identified in Indians (*2, *3, *6,*8 and *17). The *2 and *17 were the most prevalent alleles (minor allele frequencies, MAF: 32.0% and 13.95%). The *3, *6 and *8 were rare (MAFs: 0.425%, 0.025% and 0.05%). The *2 variant is shown to affect the splicing at the fifth exon–intron boundary. The *3 variant is a non-sense variant that is predicted to be deleterious. On the otherhand, the *17 variant showed more binding affinity for GATA binding protein 1 (GATA1), myocyte enhancer factor 2 (MEF2) and ectotropic viral integration site 1 (EVI1). The *6 and *8 variants predicted to be deleterious. The *2, *3 and *7 variants showed lesser probability of exon skipping, while *17 showed more probability. The genotype distribution of Indian subjects is comparable with that of South Asians (SAS) (1000 genome project, phase 3). The *2, *3 and *17 variants are the key pharmacogenetic determinants in Indians. The *2 and *3 are loss-of-function variants. The *17 is a gain-of-function variant with increased binding of transcriptional factors.