16
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The Influence of Ethnicity on Warfarin Dosage Requirements in the Chilean Population

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Vitamin K antagonists are drugs that are widely prescribed around the world and their use has helped improve the prognosis of patients with thromboembolic disease. However, a high interindividual variability has been observed in dosage requirements to reach the desired anticoagulation range that could be due to environmental and genetic factors. Studies suggest that ethnicity influences coumarin response, supporting the observed differences in dose requirements across various populations. Studies using mitochondrial DNA (mtDNA) markers have suggested that the Chilean population has a predominantly Amerindian genetic pool.

          Objective

          To evaluate the influence of ethnicity, defined by the presence of Amerindian mtDNA haplogroups, on the variability in therapeutic response to warfarin in the Chilean population.

          Methods

          A total of 191 patients treated with warfarin were included in this study. Analysis of the mitochondrial genome for detecting the presence of Amerindian mtDNA haplogroups was performed using polymerase chain reaction and polymerase chain reaction restriction fragment length polymorphism techniques. The evaluation of warfarin requirements according to each haplogroup was performed by ANOVA with a 95% CI and assuming statistical significance at P < 0.05.

          Results

          Based on the presence of an mtDNA haplogroup, 91% of the Chilean population had an Amerindian background. There were no significant differences in warfarin dosage requirements among the different Amerindian haplogroups ( P = 0.083).

          Conclusions

          The presence of Amerindian mtDNA haplogroup does not influence warfarin dosage requirements in the Chilean population.

          Related collections

          Most cited references23

          • Record: found
          • Abstract: found
          • Article: not found

          The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen.

          Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Mitochondrial DNA mutations in disease and aging

            The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups.

              Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 -1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 -1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 -1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the -1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.
                Bookmark

                Author and article information

                Contributors
                Journal
                Curr Ther Res Clin Exp
                Curr Ther Res Clin Exp
                Current Therapeutic Research, Clinical and Experimental
                Elsevier
                0011-393X
                1879-0313
                08 January 2015
                December 2015
                08 January 2015
                : 77
                : 31-34
                Affiliations
                [1 ]The Clinical and Immunohematological Department, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
                [2 ]Molecular Diagnosis Laboratory, Faculty of Health Sciences, Universidad San Sebastián, Concepcion, Chile
                [3 ]Biomedical Laboratory Department, The National Hematology Reference Laboratory, Chile’s Public Health Institute, Santiago, Chile
                [4 ]Escuela de Tecnología Médica. Universidad Mayor, Santiago, Chile
                [5 ]Internal Medicine Department, Universidad de La Frontera, Temuco, Chile
                [6 ]Escuela de Ciencias de la Salud, Universidad Católica de Temuco, Temuco, Chile
                Author notes
                [* ]Address correspondence to: Iván Palomo, XX, The Clinical and Immunohematological Department, Universidad de Talca, Talca 3460000 Chile. ipalomo@ 123456utalca.cl
                Article
                S0011-393X(14)00031-9
                10.1016/j.curtheres.2014.12.002
                4329421
                8ecabd3c-1054-48e0-834c-05136c69cff5
                © 2015 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 29 December 2014
                Categories
                Article

                anticoagulant therapy,mitochondrial dna,pharmacogenomics,warfarin

                Comments

                Comment on this article