Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards

LLerena, Adrián; Dorado, Pedro; O'Kirwan, Fiona; Jepson, Ruth; Licinio, Júlio; Wong, Ma-Li

doi:10.1038/sj.tpj.6500278

Cited by 55 publications

(32 citation statements)

References 27 publications

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“…The minor *3 allele frequency has been described in the African population (1.8%) and the major allele in the Southern European (8.6%) population (Kurose et al, 2012). Both the CYP2C9*2 and *3 allele frequencies were similar to that reported by Llerena et al, (2004) in a Mexican-American population (9 and 5%, respectively).…”

Section: Resultssupporting

confidence: 64%

Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response

et al. 2013

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ABSTRACT. Oral anticoagulants of the coumarin type have an inconveniently narrow therapeutic window, making their use difficult. In Mexico, genetic variables that participate in the heterogeneity of the therapeutic response remain poorly investigated. With the focus on warfarin, extensive pharmacogenomic studies have been performed, including those on the CYP450 family and APOE. The objective of this study was to determine the contribution of CYP2C9, CYP2C19, and APOE polymorphisms to the variations in response to the doses of acenocoumarol, which is the main anticoagulant prescribed to the Mexican population. The polymerase chain reaction-restriction fragment length polymorphism method was applied to identify *2 and *3 of CYP2C9, *2 of CYP2C19, and APOE variants. The genetic distribution of every polymorphism tested showed high variability when compared with other populations worldwide. Our results showed statistical differences only in the CYP2C19 gene between the *1*1 and *1*2 groups, with effective acenocoumarol doses of 2.56 ± 1.34 mg/day vs 1.35 ± 0.84 mg/day (P = 0.005), respectively. Multiple regression analysis, including patient age and both the CYP2C9 and CYP2C19 genes, showed that these variables explained more than 20% of the dose variations. This is the first report in Mexico searching for the relationship between CYP450 and APOE polymorphisms and the dose requirements of acenocoumarol. Our results suggest that, in the Mexican population, CYP2C19 is more involved in acenocoumarol metabolism than CYP2C9 and APOE. Besides considering the age factor, pharmacogenetic testing for CYP2C19*2 before initiating acenocoumarol treatment could lead to a safer anticoagulation therapy in Mexican patients.

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Section: Resultssupporting

confidence: 64%

Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response

et al. 2013

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“…The observed frequency of two previously reported CYP2C9 structural variants, g.3608CϾT (CYP2C9*2) and g.42614AϾC (CYP2C9*3) were not significantly different between the Hispanics and non-Latino whites, nor were the determined frequencies different from those reported by LLerena et al (2004) for Hispanic Americans of Mexican descent. In contrast, there was a significant difference compared with the frequencies reported by Xie et al (2002).…”

Section: Discussionmentioning

confidence: 57%

Novel CYP2C9 Promoter Variants and Assessment of Their Impact on Gene Expression

et al. 2008

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There are a considerable number of reports identifying and characterizing genetic variants within the CYP2C9 coding region. Much less is known about polymorphic promoter sequences that also might contribute to interindividual differences in CYP2C9 expression. To address this problem, approximately 10,000 base pairs of CYP2C9 upstream information were resequenced using 24 DNA samples from the Coriell Polymorphism Discovery Resource. Thirty-one single-nucleotide polymorphisms (SNPs) were identified; nine SNPs were novel, whereas 22 were reported previously. Using both sequencing and multiplex single-base extension, individual SNP frequencies were determined in 193 DNA samples obtained from unrelated, selfreported Hispanic Americans of Mexican descent, and they were compared with similar data obtained from a non-Latino white cohort. Significant interethnic differences were observed in several SNP frequencies, some of which seemed unique to the Hispanic population. Analysis using PHASE 2.1 inferred nine common (Ͼ1%) variant haplotypes, two of which included the g.3608CϾT (R144C) CYP2C9*2 and two the g.42614AϾC (I359L) CYP2C9*3 SNPs. Haplotype variants were introduced into a CYP2C9/luciferase reporter plasmid using site-directed mutagenesis, and the impact of the variants on promoter activity assessed by transient expression in HepG2 cells. Both constitutive and pregnane X receptor-mediated inducible activities were measured. Haplotypes 1B, 3A, and 3B each exhibited a 65% decrease in constitutive promoter activity relative to the reference haplotype. Haplotypes 1D and 3B exhibited a 50% decrease and a 40% increase in induced promoter activity, respectively. These data suggest that genetic variation within CYP2C9 regulatory sequences is likely to contribute to differences in CYP2C9 phenotype both within and among different populations.

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“…Population diversity CYP2C9*2 and *3 allele frequencies were compared among the sampled populations and also among data previously published for 12 European populations scattered all over the continent from the United Kingdom, 17 Holland, 18 France, 16 Germany, 19 Hungary, 20 Italy, 21 Sweden, 22 Turkey, 12 Belgium, 13 Iran, 14 Spain 11 and the Europeans from the United States of America 23 (Table 4). No significant differences were observed among our five samples in any of the CYP2C9 variants.…”

Section: Validation Studymentioning

confidence: 99%

“…[11][12][13][14][15][16][17][18][19][20][21][22][23] Here we present a descriptive study of the prevalence of the most relevant CYP2C9 polymorphisms, CYP2C9*1 (wild type), CYP2C9*2 and CYP2C9*3, in population samples from both Spain (Basque Country, Catalonia, Central Spain and Galicia) and northern Italy (Verona) summing up a total of 1240 individuals. We also compared the allele frequencies on our population samples with those previously published for other European populations.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of CYP2C9 polymorphisms in the south of Europe

et al. 2009

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CYP2C9 is a major liver enzyme responsible of the metabolism of many clinically important drugs. The presence of CYP2C9 genetic polymorphisms has been associated with marked interindividual variability in its catalytic activity that could result in drug toxicity. Here we present frequencies of the most common CYP2C9 coding variants CYP2C9*2 (C430T) and CYP2C9*3 (A1075C) in representative samples of four regions from Spain (Basque Country, n ¼ 358; Catalonia, n ¼ 240; Central Spain, n ¼ 190 and Galicia, n ¼ 288) and one northern Italian region, (Verona, n ¼ 164), which range between 0.125 and 0.165 in the case of CYP2C9*2 and between 0.071 and 0.085 for CYP2C9*3. No significant differences between CYP2C9 allele frequencies were found comparing all the sampled populations. A more extensive comparative analysis using allele frequency data of populations widely spread over Europe was performed, showing significant differences in the CYP2C9*2 allele frequencies distribution between some of the regions, being quite homogeneous in the case of CYP2C9*3 variant. The results obtained show that above 40% of our samples carry a mutate allele, which can result in a poor metabolization of low therapeutic index drugs as oral anticoagulants (warfarin, acenocoumarol), oral antidiabetic drugs and some non-steroidal anti-inflammatory drugs. Our study constitutes both a large (n ¼ 1240) and robust allele frequency database on CYP2C9 polymorphisms, which represents one of the most numerous CYP2C9*2 and *3 database existing to date.

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Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards

Cited by 55 publications

References 27 publications

Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response

Genetic contribution of CYP2C9, CYP2C19, and APOE variants in acenocoumarol response

Novel CYP2C9 Promoter Variants and Assessment of Their Impact on Gene Expression

Prevalence of CYP2C9 polymorphisms in the south of Europe

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