Copy number variation profiling in pharmacogenetics CYP-450 and GST genes in Colombian population

Ramírez, Brian; Niño-Orrego, María José; Cardenas, D.; Ariza, Kevin Enrique; Quintero, Karol; Bravo, Nora Constanza Contreras; Tamayo-Agudelo, Caroll; González, María Alejandra; Laissue, Paul; Mendoza, Dora Janeth Fonseca

doi:10.1186/s12920-019-0556-x

Cited by 11 publications

(4 citation statements)

References 49 publications

(62 reference statements)

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“…36 Studies have shown that CNVs play an important role in human disease 37,38 and drug-related genes by modifying drug metabolism and drug response. Ramírez et al 39 reported that 13 out of 14 pharmacogenes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, GSTM1, GSTP1, and GSTT1) have at least one type of CNVs (duplications and/or deletions), with no CNVs that were identified for CYP1A2. So far, most CNV association studies have been conducted in European ancestry populations.…”

Section: Copy Number Variants In Pharm Aco Gen Omicsmentioning

confidence: 99%

Multi‐Omics Studies in Historically Excluded Populations: The Road to Equity

Yang

Mishra

Perera

2023

Clin Pharma and Therapeutics

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Over the past few decades, genomewide association studies (GWASs) have identified the specific genetics variants contributing to many complex diseases by testing millions of genetic variations across the human genome against a variety of phenotypes. However, GWASs are limited in their ability to uncover mechanistic insight given that most significant associations are found in non‐coding region of the genome. Furthermore, the lack of diversity in studies has stymied the advance of precision medicine for many historically excluded populations. In this review, we summarize most popular multi‐omics approaches (genomics, transcriptomics, proteomics, and metabolomics) related to precision medicine and highlight if diverse populations have been included and how their findings have advance biological understanding of disease and drug response. New methods that incorporate local ancestry have been to improve the power of GWASs for admixed populations (such as African Americans and Latinx). Because most signals from GWAS are in the non‐coding region, other machine learning and omics approaches have been developed to identify the potential causative single‐nucleotide polymorphisms and genes that explain these phenotypes. These include polygenic risk scores, expression quantitative trait locus mapping, and transcriptome‐wide association studies. Analogous protein methods, such as proteins quantitative trait locus mapping, proteome‐wide association studies, and metabolomic approaches provide insight into the consequences of genetic variation on protein abundance. Whereas, integrated multi‐omics studies have improved our understanding of the mechanisms for genetic association, we still lack the datasets and cohorts for historically excluded populations to provide equity in precision medicine and pharmacogenomics.

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Section: Copy Number Variants In Pharm Aco Gen Omicsmentioning

confidence: 99%

Multi‐Omics Studies in Historically Excluded Populations: The Road to Equity

Yang

Mishra

Perera

2023

Clin Pharma and Therapeutics

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“…Indeed, it has been shown in a population of patients from Hong Kong that fewer than 20% of duplicated CYP2D6 alleles were duplications of functional alleles [44]. However, an increased copy number of functional CYP2D6 alleles increases the rate of metabolism of associated drugs [39], with some studies reporting as many as 13 copies of CYP2D6 in a single individual's genome [48]. Thus, an individual with more than two functional copies of CYP2D6 is considered to have ultra-rapid metabolism for CYP2D6 substrate drugs.…”

Section: Copy Number Variationmentioning

confidence: 99%

A Review of the Important Role of CYP2D6 in Pharmacogenomics

Taylor

Crosby²,

Yip

et al. 2020

Genes

131

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Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside.

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“…It is worth noting that our group has recently described a significant distribution (7.7%) of CYP2D6 duplications in a Colombian population, which may perturb the metabolism of drugs, including LTG. 51 LTG is extensively metabolised via UGT1A4, leading to the formation of LTG-N-2 and LTG-N-5 glucuronide which may affect LTG levels. 52,53 Patient SJS-17, who was affected by TEN, took LTG combined with valproic acid (VPA); the concomitant administration of these drugs has been associated with increased LTG serum concentration.…”

Section: Ph Gene Subset Analysismentioning

confidence: 99%