Prevalence of CYP2C9 polymorphisms in the south of Europe

Sánchez-Diz, Paula; Estany‐Gestal, Ana; Aguirre, C; Blanco, Adoración; Carracedo, Ángel; Ibáñez, Luisa; Passiu, M.; Provezza, Lisa; Ramos-Ruíz, Ricardo; Ruiz, Borja; Salado-Valdivieso, Inés; Velasco, Eladio A.; Figueiras, Adolfo

doi:10.1038/tpj.2009.16

Cited by 26 publications

(18 citation statements)

References 27 publications

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“…In addition, the SP population studied here presented similar CYP2C9 allele frequencies to those previously reported in a recent publication of frequencies found in northern regions of South Europeans. 11 Furthermore, the frequency of CYP2C9*3 was lower (Po0.05) in MT (0.015) and MM (0.015) than in MA (0.06) and SP (0.08).…”

Section: Resultsmentioning

confidence: 90%

“…In addition, the present Spanish population from Extremadura appeared very representative, as it was found to be very similar in CYP2C9 allele frequencies to previously published data of White Europeans. 11,13,14 Clinical implications for patients carrying the low activity alleles CYP2C9*2 and CYP2C9*3 have been reported. Patients who are CYP2C9 'slow metabolizers', mostly *3/*3 carriers, and are under treatment with some narrow therapeutic index drugs (warfarin, acenocoumarol, glipizide, and phenytoin) may be at risk of severe drug toxicity.…”

Section: Discussionmentioning

confidence: 99%

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CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards

Dorado

et al. 2010

Pharmacogenomics J

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Earlier we had found that the CYP2C9*2 allelic frequency was lower in Mexican-Americans living in California than in Spaniards (SP). This was assumed to be related to the low CYP2C9*2 and *3 allele frequencies in Orientals. This study was therefore aimed at analyzing whether there were also differences in CYP2C9 allele frequencies between Mexican-Tepehuanos (MT) and Mexican-Mestizos (MM) living in northwestern Mexico and SP. The CYP2C9*2 frequency was expected to be lower in the indigenous MT than in the two other groups, and lower in MM than in SP as in our earlier study. CYP2C9 genotypes and allele frequencies of two populations of healthy volunteers, MT (n=99) and MM (n=102), were compared with a population of SP (n=327). The data were also compared with our previously published population of Mestizo-Mexican-Americans (MA). The CYP2C9 genotypes among the studied populations were in equilibrium. The frequencies of CYP2C9*2 were 0.01, 0.07, 0.08, and 0.16 for MT, MM, MA, and SP subjects, respectively. In agreement with our hypothesis, CYP2C9*2 was significantly lower in the Mexican populations than in the SP (P<0.05), and among Mexicans in the MT than in the MM and MA groups (P<0.05), which presented similar frequencies. Moreover, the frequency of CYP2C9*3 was found to be lower (P<0.05) in MM (0.015) and MT (0.015) than in MA (0.06) and SP (0.08). Finally, the CYP2C9*6 allele was present just in one MM subject, and CYP2C9*4 and *5 were not found in the studied populations. Therefore, these findings add further evidence about CYP2C9 genetic diversity within Hispanic populations with regard to their ancestry. Considering that CYP2C9*2 and CYP2C9*3 alleles have altered catalytic activities relative to CYP2C9*1, the present data suggest the need for pharmacogenetic studies to optimize drug dosages in different populations.

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards

Dorado

et al. 2010

Pharmacogenomics J

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“…Two dominant variants, CYP2C9*2 and CYP2C9*3, are common in Caucasians at frequencies of approximately 8%-14% and 4%-16%, respectively, while significantly lower frequencies of these variants were found in African and Asian populations [4,5] . A large-scale genetic polymorphism study revealed that approximately 40% of Europeans carry these two mutated alleles [6] . In contrast, the *2 variant is rarely found, and the *3 variant is present in only at 1%-4% of East Asian populations [7,8] , and our previous study demonstrated that only 0.28% and 5.6% of Chinese people carry the CYP2C9*2 or CYP2C9*3 allele, respectively [9] .…”

Section: Introductionmentioning

confidence: 99%

In vitro functional characterization of 37 CYP2C9 allelic isoforms found in Chinese Han population

Dai

Wang

et al. 2013

Acta Pharmacol Sin

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Aim: Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme that is responsible for the metabolism of approximately 15% of clinically important drugs. The aim of this study was to assess the catalytic characteristics of 37 CYP2C9 allelic isoforms found in Chinese Han population on the metabolism of tolbutamide in vitro. Methods: The wild-type and 36 CYP2C9 variants were expressed in sf21 insect cells using a baculovirus-mediated expression system. Then the insect microsomes were prepared for assessing the metabolic characteristics of each variant toward the CYP2C9-specific drug substrate tolbutamide. Results: Of 36 allelic variants tested, the intrinsic clearance values of 2 allelic isoforms (CYP2C9.36 and CYP2C9.51) were much higher than the wild-type CYP2C9.1 protein, 3 allelic isoforms (CYP2C9.11, CYP2C9.56 and N418T) exhibited similar intrinsic clearance values as the wild-type enzyme, whereas the other 31 variants showed significantly reduced intrinsic clearance values, ranging from 0.08% to 66.88%, for tolbutamide. Conclusion: Our study provides the most comprehensive data concerning the enzymatic activity of the CYP2C9 variants that are present in the Chinese Han population, and our data suggest that most of the carriers of these alleles might be paid more attention when using CYP2C9 mediated drugs clinically.

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“…7 However, 29.4% of patients had the CYP2C9*2 variant allele and 11.4% had the CYP2C9*3 variant allele, which are similar prevalences to those described for Spanish patients previously. 19,20 In previous studies, polymorphisms of both genes have been shown to be associated with adverse events and with a poor TTR in patients taking VKAs. 21 Thus, the presence of variant genotypes of CYP2C9 (*2 and *3) and VKORC1 (rs9923231 and rs9934438) is associated with increased risk of bleeding in warfarin users.…”

Section: Discussionmentioning

confidence: 98%

“…ROC curves comparisons were carried out by DeLong et al method. 12 Net reclassification improvement (NRI) and integrated discriminatory improvement (IDI) were performed according to the methods described by Pencina et al 13 Statistical analyses were performed using SPSS v. 19.0 (SPSS, Inc., Chicago, IL, USA) and MedCalc v. 16…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

Serna

Rivera‐Caravaca

Gónzález-Conejero

et al. 2018

Eur J Clin Investigation

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Background: Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS-BLED score. Material and methods: We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months. A baseline venous blood sample was obtained for DNA extraction. We gave an extra point to the HAS-BLED score if the patient was a simultaneous carrier of the VKORC1 and CYP2C9 polymorphisms related to bleeding, and we called this modified score "GEN|HAS-BLED." During a median follow-up of 7.6 years (IQR 5.6-8.0), all major bleeding events were recorded. Results: During follow-up, 106 (16.2%) patients experienced a major bleeding (2.81%/y; 42 intracranial haemorrhages and 44 gastrointestinal bleeding) and 24 (3.7%) died from major bleeding (0.48%/y). Cox regression analyses demonstrated a significant association between HAS-BLED or GEN|HAS-BLED and major bleeds, both as continuous or categorical scores. Comparison of receiver operating characteristic (ROC) curves shows that original HAS-BLED clinical score had better predictive ability than GEN|HAS-BLED (0.660, 95% CI 0.622-0.696 vs 0.645, 95% CI 0.607-0.682; P = .030). Discrimination and reclassification analyses showed that GEN|HAS-BLED did not improve sensitivity compared with the original score and even showed significant negative reclassification. Conclusion: Adding pharmacogenetic factors (ie polymorphisms of the VKORC1 and CYP2C9 genes) to the HAS-BLED score does not improve the prediction or discrimination performance for major bleeding. K E Y W O R D Satrial fibrillation, CYP2C9, haemorrhage, polymorphisms, VKORC1 Serna and Rivera-Caravaca equally contributed to this study. Rold an and Mar ın are joint senior authors.

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Prevalence of CYP2C9 polymorphisms in the south of Europe

Cited by 26 publications

References 27 publications

CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards

CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards

In vitro functional characterization of 37 CYP2C9 allelic isoforms found in Chinese Han population

Pharmacogenetics of vitamin K antagonists and bleeding risk prediction in atrial fibrillation

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