Genotype frequencies of VKORC1 and CYP2C9 in Native and Mestizo populations from Mexico, potential impact for coumarin dosing

Villegas-Torres, Beatriz; Sanchez-Giron, Francisco; Jaramillo-Villafuerte, Karla; Soberón, Xavier; González-Covarrubias, Vanessa

doi:10.1016/j.gene.2014.12.068

Cited by 15 publications

(7 citation statements)

References 23 publications

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“…We identified five variants with lower allele frequency in Natives vs. Mestizos, CEU or MXL on, CYP2C19 *2 rs4244285, NAT2 rs1799930 , CYP2D6 rs28371725, SLCO1B1 rs41419015, and ABCB1 rs2032582. In addition to the already discussed VKORC1–CYP2C9 *2/*3 interplay, our results on CYP2C9 validate previous reports showing that Mestizos are 3× and 4× more likely to show impaired CYP2C9 metabolism than Natives due to CYP2C9 *2 and *3 (Villegas-Torres et al, 2015). CYP2C9 is the second most expressed CYP in liver after CYP3A4, and impacts 15% of all drugs including losartan, NSAIDs, phenytoin, and hypoglycemic agents, (Sconce et al, 2005;Van Booven et al, 2010).…”

Section: Discussionsupporting

confidence: 90%

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Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico

et al. 2019

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The identification and characterization of pharmacogenetic variants in Latin American populations is still an ongoing endeavor. Here, we investigated SNVs on genes listed by the Pharmacogenomics Knowledge Base in 1284 Mestizos and 94 Natives from Mexico. Five institutional cohorts with NGS data were retrieved from different research projects at INMEGEN, sequencing files were filtered for 55 pharmacogenes present in all cohorts to identify novel and known variation. Bioinformatic tools VEP, PROVEAN, and FATHMM were used to assess, in silico, the functional impact of this variation. Next, we focused on 17 genes with actionable variants that have been clinically implemented. Allele frequencies were compared with major continental groups and differences discussed in the scope of a pharmacogenomic impact. We observed a wide genetic variability for known and novel SNVs, the largest variation was on UGT1A > ACE > COMT > ABCB1 and the lowest on APOE and NAT2. Although with allele frequencies around 1%, novel variation was observed in 16 of 17 PGKB genes. In Natives we identified 59 variants and 58 in Mestizos. Several genes did not show novel variation, on CYP2B6, CYP2D6, and CYP3A4 in Natives; and APOE, UGT1A, and VKORC1 in Mestizos. Similarities in allele frequency, comparing major continental groups for VIP pharmacogenes, hint towards a comparable PGx for drugs metabolized by UGT1A1, DPYD, ABCB1, CBR3, COMT, and TPMT; in contrast to variants on CYP3A5 and CYP2B6 for which significant MAF differences were identified. Our observations offer some discernment into the extent of pharmacogenetic variation registered up-to-date in Mexicans and contribute to quantitatively dissect actionable pharmacogenetic variants in Natives and Mestizos.

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Section: Discussionsupporting

confidence: 90%

“…Genotypes of PGKB variants in Table 2 were in complete concordance with previous genotyping experiments by RTPCR ex. CYP2C9/VKORC1 (Villegas-Torres et al, 2015), DMET microarray (Gonzalez-Covarrubias et al, 2016) and by NGS (Gonzalez-Covarrubias et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico

et al. 2019

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“…Maybe because CYP4F2 (rs2108622) has a lower impact (Danese et al, 2012 ), and R-acenocumarol is metabolized by several CYPs other than CYP2C9 . Moreover, reported variants that impair CYP2C9 activity are present in low frequency in Mexican Mestizos (Villegas-Torres et al, 2015 ). Instead, we observed dose association with variants on SULT1A1 and CYP2DP8 .…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol

et al. 2017

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Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2. Using a Bayesian approach, we identified variants influencing acenocumarol dosing on, VKORC1 (2), SULT1A1 (1), and CYP2D8P (1) explaining 40–55% of dose variability. A collection of pharmacogenetic variation on 110 genes related to the PK/PD of coumarins is also presented. Our results offer an initial insight into the use of a targeted NGS approach in the pharmacogenomics of coumarins in Mexican Mestizos.

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“…For example, CY-P3A5*3, affecting tacrolimus disposition, is 2 times more frequent in Asian populations compared to Europeans, and variant CYP2D6*10, impacting at least 25% of all prescription drugs, is more common among individuals from Malaysia and China compared to other continental groups. Caucasian populations require a 30% lower dose of warfarin compared to Africans due to CYP2C9 and VKORC1 polymorphisms [28][29][30] . These variants account for 35% dose variations in Europeans, ~ 30% in Mexicans 31 , and 10% in African-Americans; .…”

Section: Ethnic Differences In Pgxmentioning

confidence: 99%

“…PGx research in Latin America has identified either similar frequencies on actionable markers among populations or striking differences. In this regard, variants on CYP3A5, VKORC1 rs9923231, CYP2C9, and SLCO1B1 show significant population differentiation (Fst) in admixed populations within Latin America compared to Europeans, Asians, or Africans 29,30,32 . Nevertheless, PGx differences are often 10-to 40-fold within individuals in any population, while differences between two ethnic groups are rarely > 2-or 3-fold 33 .…”

Section: Ethnic Differences In Pgxmentioning

confidence: 99%

Pharmacogenomics: Current Actionable Variants

González-Covarrubias

Lozano

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et al. 2021

RIC

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Pharmacogenomics (PGx), one of the several tools of precision medicine, has been slowly implemented in the clinic during the past decades. This process generally starts with direct and indirect genotype-phenotype associations of gene variants and drug efficacy, or adverse drug reactions, followed by replication and validation studies. Institutional efforts led by the PGx Research Network, The PGx Knowledge Base, and The Clinical Pharmacogenetics Implementation Consortium, mine all available data for further validation or research in additional populations. This data mining gives rise to a detailed classification of over 200 druggene pairs which, with enough documentation, may become part of a publishable guideline to aid clinicians in drug selection and dosing using genetics. The US Food and Drug Administration utilizes these guidelines to issue warnings and recommendations for specific drugs and their cautioning serves clinicians and pharmacists worldwide. Here, we aim to discuss the steps of this process and list existing actionable drug-gene pairs. Moreover, we describe the current status of PGx knowledge in populations from Mexico for actionable variants on the 19 genes listed by present PGx guidelines affecting 47 drugs. Our review collects current allele frequency information for these actionable variants, lists gaps of PGx information for relevant markers, and highlights the importance of continuing PGx research in Native and Mestizo populations. (REV INVEST CLIN. [AHEAD OF PRINT]

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Genotype frequencies of VKORC1 and CYP2C9 in Native and Mestizo populations from Mexico, potential impact for coumarin dosing

Cited by 15 publications

References 23 publications

Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico

Variation in Actionable Pharmacogenetic Markers in Natives and Mestizos From Mexico

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol

Pharmacogenomics: Current Actionable Variants

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