CYP2C9 Variations and Their Pharmacogenetic Implications Among Diverse South Asian Populations

Nizamuddin, Sheikh; S, Dubey; Singh, Sakshi; Sharma, Saurav; Machha, Pratheusa; Thangaraj, Kumarasamy

doi:10.2147/pgpm.s272015

Cited by 8 publications

(13 citation statements)

References 22 publications

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“…SNPs with significant allele frequency variation with EAS and high fixation index identified in this study include three intronic SNPs ( rs2359612 , rs8050894 , rs9934438 ) and one in 3′UTR ( rs7294 ) of VKORC1 gene. Missense SNP rs1057910 ( CYP2C9 ) along with the observed VKORC1 variants have been associated with varied warfarin dosage in both South-Indian and North-Indian populations ( Nizamuddin et al, 2021 ; Arun Kumar et al, 2015 ; Krishna Kumar et al, 2014 ; Giri et al, 2014 ; Shalia et al, 2012 ). Similarly, intronic SNP ( rs6785049 ) present in NR1I2 has significant allele frequency variation in AFR.…”

Section: Discussionmentioning

confidence: 99%

Genetic diversity of ‘Very Important Pharmacogenes’ in two South-Asian populations

Bharti

Banerjee

Achalere

et al. 2021

PeerJ

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Objectives Reliable identification of population-specific variants is important for building the single nucleotide polymorphism (SNP) profile. In this study, genomic variation using allele frequency differences of pharmacologically important genes for Gujarati Indians in Houston (GIH) and Indian Telugu in the U.K. (ITU) from the 1000 Genomes Project vis-à-vis global population data was studied to understand its role in drug response. Methods Joint genotyping approach was used to derive variants of GIH and ITU independently. SNPs of both these populations with significant allele frequency variation (minor allele frequency ≥ 0.05) with super-populations from the 1000 Genomes Project and gnomAD based on Chi-square distribution with p-value of ≤ 0.05 and Bonferroni’s multiple adjustment tests were identified. Population stratification and fixation index analysis was carried out to understand genetic differentiation. Functional annotation of variants was carried out using SnpEff, VEP and CADD score. Results Population stratification of VIP genes revealed four clusters viz., single cluster of GIH and ITU, one cluster each of East Asian, European, African populations and Admixed American was found to be admixed. A total of 13 SNPs belonging to ten pharmacogenes were identified to have significant allele frequency variation in both GIH and ITU populations as compared to one or more super-populations. These SNPs belong to VKORC1 (rs17708472, rs2359612, rs8050894) involved in Vitamin K cycle, cytochrome P450 isoforms CYP2C9 (rs1057910), CYP2B6 (rs3211371), CYP2A2 (rs4646425) and CYP2A4 (rs4646440); ATP-binding cassette (ABC) transporter ABCB1 (rs12720067), DPYD1 (rs12119882, rs56160474) involved in pyrimidine metabolism, methyltransferase COMT (rs9332377) and transcriptional factor NR1I2 (rs6785049). SNPs rs1544410 (VDR), rs2725264 (ABCG2), rs5215 and rs5219 (KCNJ11) share high fixation index (≥ 0.5) with either EAS/AFR populations. Missense variants rs1057910 (CYP2C9), rs1801028 (DRD2) and rs1138272 (GSTP1), rs116855232 (NUDT15); intronic variants rs1131341 (NQO1) and rs115349832 (DPYD) are identified to be ‘deleterious’. Conclusions Analysis of SNPs pertaining to pharmacogenes in GIH and ITU populations using population structure, fixation index and allele frequency variation provides a premise for understanding the role of genetic diversity in drug response in Asian Indians.

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Section: Discussionmentioning

confidence: 99%

Genetic diversity of ‘Very Important Pharmacogenes’ in two South-Asian populations

Bharti

Banerjee

Achalere

et al. 2021

PeerJ

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“…c.1075A>C on its own causes severely decreased function, and thus CYP2C9*3 is classified by CPIC as a "no function" allele. CYP2C9*68 has an additional SNV interfering with splicing predicted to be deleterious/probably damaging 94 . It remains unknown, though, whether p.D379A on CYP2C9*18 also impacts function.…”

Section: Cyp2c9 Allele Genotype and Phenotype Frequencies Across Populationsmentioning

confidence: 99%

“…Alleles fulfilling the submission requirements receive an evidence level of “Mod” or “Lim” depending on the degree of uncertainty. Figure details two examples of alleles submitted by Nizamudin et al 94 . The authors used data of 210 subjects and BEAGLE to infer haplotypes.…”

Section: Curation Effortsmentioning

confidence: 99%

“…The second example provided in Figure received an evidence level of “Lim.” As illustrated, seven SNVs were computationally inferred to represent the CYP2C9*3.002 suballele, while a novel variant, c.1297C>T (p.R433W, rs776908257), was predicted to be located on the opposite chromosome forming the novel CYP2C9*67 haplotype. Due to the uncertainty of the phase of two nonsynonymous variants in this subject, the impact of the p.R433W amino acid change on enzyme activity remains to be established experimentally ( in silico analyses predict p.R433W being deleterious or probably damaging 94 ). Based on BEAGLE and in silico predictions, a CYP2C9*3/*67 genotype may lead to PM status while a CYP2C9*1/*3 genotype (with p.R433W being on the *3 allele) would translate into IM status.…”

Section: Curation Effortsmentioning

confidence: 99%

“…Alleles fulfilling the submission requirements receive an evidence level of "Mod" or "Lim" depending on the degree of uncertainty. Figure 4c details two examples of alleles submitted by Nizamudin et al 94 The authors used data of 210 subjects and BEAGLE to infer haplotypes. The first example represents a subject who was heterozygous for two variants, which were phased in trans suggesting that c.431G>A (p.R144H) is the sole SNV on the novel haplotype designated as CYP2C9*63.…”

Section: Reviewmentioning

confidence: 99%

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PharmVar GeneFocus: CYP2C9

Sangkuhl

Claudio‐Campos

Cavallari

et al. 2021

Clin Pharma and Therapeutics

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The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene. Genetic variation within the CYP2C9 gene locus impacts the metabolism or bioactivation of many clinically important drugs including NSAIDs, phenytoin, antidiabetic agents and angiotensin receptor blocker. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC). Table 2 Novel allele(s) and confirmed suballele(s) Core Allele Designation Novel alleles/suballeles

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Leflunomide‐induced liver injury: Differences in characteristics and outcomes in Indian and US registries

Devarbhavi

Ghabril

Barnhart

et al. 2022

Liver International

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Background Leflunomide, a disease‐modifying anti‐rheumatic drug, has been associated with elevations of serum aminotransferases. Herein, we describe the clinical, laboratory features and outcomes of 17 patients with leflunomide/teriflunomide hepatotoxicity from two large drug‐induced liver injury (DILI) registries. Methods Consecutive, adjudicated cases of leflunomide (n = 16)‐or teriflunomide (n = 1)‐related DILI from a single centre in Bangalore, India and the multicentre US Drug‐Induced Liver Injury Network (DILIN) were reviewed. Results Nine (0.8%) of the 1070 Indian patients and 8 (0.5%) of the 1400 DILIN patients fulfilled the criteria for DILI because of leflunomide‐ or teriflunomide. 89% of the Indian cases were women and all were associated with severe cutaneous adverse reaction (SCAR) and a median drug latency of 49 days, whereas 37.5% of the DILIN cases were female, none exhibited SCAR and the median drug latency was 166 days. Hepatocellular injury (70%) was more common in women than men (92% vs. 20%) and was associated with younger mean age (41 vs. 59 years), higher peak INR (2.3 vs. 1.2) and higher mortality (58% vs. 0%). Mortality was observed in six patients from India (2 of the three with myocarditis) and one received liver transplantation from the USA. Conclusion Leflunomide‐induced liver injury is predominantly hepatocellular. Leflunomide hepatotoxicity is more likely accompanied by SCAR, a short latency and a higher mortality in the Indian cohort, with a predominance of females, compared to US DILIN patients. The differences in skin involvement, immunoallergic features and outcomes among subjects from India vs. the USA suggest that genetic or environmental factors are important in the pathogenesis of liver injury.

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CYP2C9 Variations and Their Pharmacogenetic Implications Among Diverse South Asian Populations

Cited by 8 publications

References 22 publications

Genetic diversity of ‘Very Important Pharmacogenes’ in two South-Asian populations

Genetic diversity of ‘Very Important Pharmacogenes’ in two South-Asian populations

PharmVar GeneFocus: CYP2C9

Leflunomide‐induced liver injury: Differences in characteristics and outcomes in Indian and US registries

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