Non-genetic factors and polymorphisms in genes CYP2C9 and VKORC1: predictive algorithms for TTR in Brazilian patients on warfarin

  • Marcus Fernando S. Praxedes
  • Maria Auxiliadora P. MartinsEmail author
  • Aline O. M. Mourão
  • Karina B. Gomes
  • Edna A. Reis
  • Renan P. Souza
  • Emílio Itamar F. Campos
  • Daniel D. Ribeiro
  • Manoel Otávio C. Rocha



This study was designed to evaluate the association of non-genetic factors and polymorphisms CYP2C9*2 (rs1799853), CYP2C9*3 (rs1075910), and VKORC1-G1639A (rs9923231) with time in therapeutic range (TTR), and to build a regression model to predict the quality of oral anticoagulation control in a sample of Brazilian patients.


This is a retrospective cohort study developed at an anticoagulation clinic of a university hospital. Overall, 312 patients were included. The quality of oral anticoagulation control was evaluated by TTR. TTR was dichotomized for analysis, using two cutoff points for classification as inadequate (TTR ≤ 60.0%) and optimal (TTR ≥ 75.0%) control.


The average age was 60.4 ± 13.5 years, with a predominance of women (187; 59.9%). The -G1639A polymorphism of the VKORC1 gene, when evaluated, based on the recessive inheritance pattern [AA × (GA + GG)], patients with AA genotype exhibited a higher TTR (68.2% versus 62.8%, p = 0.017). TTR ≤ 60.0% was associated with number of drugs in chronic use, assistance for warfarin administration, reports of not taking warfarin, absenteeism, sex (female), and target INR (International Normalized Ratio; 2.00–3.00). TTR ≥ 75.0% was associated with sex (male), target INR (2.00–3.00), assistance for warfarin administration, reports of not taking warfarin, and absenteeism. The two algorithms proposed showed adequate ability to predict TTR presenting good sensitivity and specificity.


Our findings provided useful information for risk stratification depending on TTR level and for future investigations on the quality of oral anticoagulation control in Brazilian anticoagulation clinics.


Algorithms Warfarin Cytochrome P-450 CYP2C9 VKORC1 protein Quality of health care 


Authors’ contribution

MFSP analyzed the database, interpreted the results obtained, and drafted the manuscript following the suggested recommendations from other authors. MOCR and MAPM contributed significantly to the conception and design of the study, reviewed the study proposal, and participated in drafting the manuscript and in each subsequent revision. AOMM designed the study, organized data collection, analyzed the data, interpreted the results, and revised the manuscript. KBGG and EIFC contributed to the process of genotyping and revised the manuscript critically. EAR provided statistical support and revised the manuscript. RPS provided statistical support, analyzed the data, organized data collection, interpreted the results, and revised the manuscript. DDR critically reviewed the manuscript.

Funding information

This study was supported by the National Council for Scientific and Technological Development (CNPq), the Coordination for the Improvement of Higher Level Education Personnel (CAPES) and the State of Minas Gerais Research Foundation (FAPEMIG), Brazil, and the Pró-reitoria Pesquisa of the Universidade Federal Minas Gerais, Brazil. KBG, RPS, and MOCR are fellows of CNPq.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Marcus Fernando S. Praxedes
    • 1
    • 2
  • Maria Auxiliadora P. Martins
    • 1
    • 3
    • 4
    Email author
  • Aline O. M. Mourão
    • 3
  • Karina B. Gomes
    • 1
  • Edna A. Reis
    • 1
  • Renan P. Souza
    • 5
  • Emílio Itamar F. Campos
    • 3
  • Daniel D. Ribeiro
    • 4
  • Manoel Otávio C. Rocha
    • 3
    • 4
  1. 1.Faculdade de FarmáciaUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Centro de Ciências da SaúdeUniversidade Federal do Recôncavo da BahiaSanto Antônio de JesusBrazil
  3. 3.Faculdade de MedicinaUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  4. 4.Hospital das ClínicasUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  5. 5.Instituto de Ciências BiológicasUniversidade Federal de Minas GeraisBelo HorizonteBrazil

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