We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Establishment of a prediction algorithm for the Honghe minority group based on warfarin maintenance dose

    Mengjiao Qian‡

    Department of Cardiothoracic Surgery, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ‡Authors contributed equally to this work

    Search for more papers by this author

    ,
    Huan Zhao

    Department of Neurology, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Yunli Lou‡

    Department of Medical Records & Statistics, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ‡Authors contributed equally to this work

    Search for more papers by this author

    ,
    Jing Wang

    Department of Cardiothoracic Surgery, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Sibo Wang

    Department of Cardiothoracic Surgery, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Zhongyin Wang

    Department of Cardiothoracic Surgery, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Haibo Ou

    Department of Cardiothoracic Surgery, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Jun Li

    Department of Cardiothoracic Surgery, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Fajian Yang

    Clinical Pharmacy Laboratory, Department of Pharmacy, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Lingying Bai

    Clinical Pharmacy Laboratory, Department of Pharmacy, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Hong Lv

    Clinical Pharmacy Laboratory, Department of Pharmacy, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Xuguan Peng

    Department of Cardiothoracic Surgery, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    ,
    Xiao Chen

    Department of Cardiothoracic Surgery, The Yunnan South Central Hospital (The First People's Hospital of Honghe Prefecture), Mengzi, Yunnan, 661100, PR China

    &
    Xiubing Yang‡

    *Author for correspondence:

    E-mail Address: 75608846@qq.com

    Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Bejing, 100029, PR China

    ‡Authors contributed equally to this work

    Search for more papers by this author

    Published Online:https://doi.org/10.2217/pgs-2022-0038

    Background:CYP2C9 and VKORC1 are important factors in warfarin metabolism. The authors explored the effects of these genetic polymorphisms and clinical factors on a warfarin maintenance dose and then established the prediction algorithm for Honghe minorities in China. Materials & methods: Quantitative fluorescence PCR determined the mutation frequency of CYP2C9 and VKORC1-1639 G>A alleles. The authors collected the relevant clinical factors, including age, gender, body surface area (BSA), international normalized ratio value, daily warfarin dose, comorbidity and concomitant prescriptions. Results: The mean values of BSA and international normalized ratio in Honghe minorities were lower than in Han Chinese (p = 0.00). The genotype of CYP2C9*1/*1 and VKORC1-1639 AA was the main allele, the mutationfrequency of VKORC1-1639 AA and the number of male of Honghe minorities were lower than that of Han Chinese (p = 0.013 and p = 0.04). The significances of the effect on actual warfarin dose value were gender, VKORC1 AA mutant, CYP2C9*1/*1, age, hypertension and BSA sequentially. Conclusion: By multiple linear regression analysis with genetic and clinical factors, the authors determined a prediction algorithm for adjusting individual dosing of warfarin in this population. Clinical trial registration number: ChiCTR2100051778.

    Tweetable abstract

    The combination of CYP2C9*1/*1 and VKORC1-1639 AA was principal genetic determinants of warfarin maintenance doses in Honghe minorities, China. Accordingly, a prediction algorithm was constructed as a reference for adjusting individual dosing of warfarin in this population.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Aikins J, Koomson A, Ladele M et al. Anticoagulation and antiplatelet therapy in patients with prosthetic heart valves. J. Card. Surg. 35(12), 3521–3529 (2020).
    • 2. Xia X, Huang N, Li B et al. To establish a model for the prediction of initial standard and maintenance doses of warfarin for the Han Chinese population based on gene polymorphism: a multicenter study. Eur. J. Clin. Pharmacol. 78(1), 43–51 (2022).
    • 3. Li S, Zou Y, Wang X et al. Warfarin dosage response related pharmacogenetics in Chinese population. PLOS ONE 10(1), e0116463 (2015).
    • 4. Zeng WT, Zheng QS, Huang M et al. Genetic polymorphisms of VKORC1, CYP2C9, CYP4F2 in Bai, Tibetan Chinese. Pharmazie 67(1), 69–73 (2012). • The first report of the effects of interethnic allele mutants on warfarin metabolism among Chinese minorities.
    • 5. Ma Z, Cheng G, Wang P, Khalighi B, Khalighi K. Clinical model for predicting warfarin sensitivity. Sci. Rep. 9(1), 12856 (2019). • Describes the relevant variables of warfarin sensitivity and specificity.
    • 6. Asiimwe IG, Zhang EJ, Osanlou R, Jorgensen AL, Pirmohamed M. Warfarin dosing algorithms: a systematic review. Br. J. Clin. Pharmacol. 87(4), 1717–1729 (2021).
    • 7. Rieder MJ, Reiner AP, Gage BF et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. 352(22), 2285–2293 (2005).
    • 8. Joffe HV, Xu R, Johnson FB, Longtine J, Kucher N, Goldhaber SZ. Warfarin dosing and cytochrome P450 2C9 polymorphisms. Thromb. Haemost. 91(6), 1123–1128 (2004). • The earlier case report of CYP2C9 variation associated with warfarin dosing.
    • 9. Schalekamp T, Brassé BP, Roijers JF et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin. Pharmacol. Ther. 80(1), 13–22 (2006).
    • 10. Cîmpan PL, Chira RI, Mocan M, Anton FP, Farcaş AD. Oral anticoagulant therapy – when art meets science. J. Clin. Med. 8(10), 10 –21 (2019). •• A comprehensive review of the effects of CYP2C9 and VKORC1 alleles on warfarin metabolism and pharmacogenetics.
    • 11. Cavallari LH, Perera MA. The future of warfarin pharmacogenetics in under-represented minority groups. Future Cardiol. 8(4), 563–576 (2012).
    • 12. Takeuchi F, McGinnis R, Bourgeois S et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLOS Genet. 5(3), e1000433 (2009).
    • 13. Takahashi H, Wilkinson GR, Nutescu EA et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African–Americans. Pharmacogenet. Genomics 16(2), 101–110 (2006).
    • 14. Asiimwe IG, Pirmohamed M. Ethnic diversity and warfarin pharmacogenomics. Front. Pharmacol. 13, 866058 (2022).
    • 15. Tang Z, Chen L, Chen Z et al. Climatic factors determine the yield and quality of Honghe flue-cured tobacco. Sci. Rep. 10(1), 19868 (2020).
    • 16. Hu L, Gu T, Fan X et al. Genetic polymorphisms of 24 Y-STR loci in Hani ethnic minority from Yunnan Province, southwest China. Int. J. Legal Med. 131(5), 1235–1237 (2017).
    • 17. Ohno M, Yamamoto A, Ono A et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur. J. Clin. Pharmacol. 65(11), 1097–1103 (2009). •• A key report describing how a warfarin dosing algorithm is constructed according to clinical factors and genetic phenotype requirements.
    • 18. de Oliveira Magalhães Mourão A, Braga Gomes K, Afonso Reis E et al. Algorithm for predicting low maintenance doses of warfarin using age and polymorphisms in genes CYP2C9 and VKORC1 in Brazilian subjects. Pharmacogenomics J. 20(1), 104–113 (2020).
    • 19. Bourgeois S, Jorgensen A, Zhang EJ et al. A multi-factorial analysis of response to warfarin in a UK prospective cohort. Genome Med. 8(1), 2 (2016).
    • 20. Santos PC, Marcatto LR, Duarte NE et al. Development of a pharmacogenetic-based warfarin dosing algorithm and its performance in Brazilian patients: highlighting the importance of population-specific calibration. Pharmacogenomics 16(8), 865–876 (2015).
    • 21. Steyerberg EW, Eijkemans MJ, Harrell FE Jr, Habbema JD. Prognostic modeling with logistic regression analysis: in search of a sensible strategy in small data sets. Med. Decis. Making 21(1), 45–56 (2001).
    • 22. Januszyk M, Gurtner GC. Statistics in medicine. Plast. Reconstr. Surg. 127(1), 437–444 (2011).
    • 23. Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. Ann. Intern. Med. 162(1), 55–63 (2015).
    • 24. Schwarz UI, Ritchie MD, Bradford Y et al. Genetic determinants of response to warfarin during initial anticoagulation. N. Engl. J. Med. 358(10), 999–1008 (2008).
    • 25. Klein TE, Altman RB, Eriksson N et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 360(8), 753–764 (2009).
    • 26. Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch. Biochem. Biophys. 333(2), 447–458 (1996).
    • 27. Chaidaroglou A, Kanellopoulou T, Panopoulos G, Stavridis G, Degiannis D. Extremely low therapeutic doses of acenocoumarol in a patient with CYP2C9*3/*3 and VKORC1-1639A/A genotype. Pharmacogenomics 20(5), 311–317 (2019).
    • 28. Al-Mahayri ZN, Al Jaibeji HS, Saab Y et al. VKORC1 variants as significant predictors of warfarin dose in Emiratis. Pharmgenomics Pers. Med. 12, 47–57 (2019).
    • 29. Auton A, Brooks LD, Durbin RM et al. A global reference for human genetic variation. Nature 526(7571), 68–74 (2015).
    • 30. Ding Y, Yang D, Zhou L et al. Cytochrome P450 2C9 (CYP2C9) polymorphisms in Chinese Li population. Int. J. Clin. Exp. Med. 8(11), 21024–21033 (2015).
    • 31. Biswas M, Bendkhale SR, Deshpande SP et al. Association between genetic polymorphisms of CYP2C9 and VKORC1 and safety and efficacy of warfarin: results of a 5 years audit. Indian Heart J. 70(Suppl. 3), S13–S19 (2018). • A comprehensive review of CYP2C9, VKORC1 genetic polymorphisms and mutant frequency in the Asian population.
    • 32. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(Suppl. 2), S44–S88 (2012).
    • 33. Lee MT, Klein TE. Pharmacogenetics of warfarin: challenges and opportunities. J. Hum. Genet. 58(6), 334–338 (2013).
    • 34. Turner RM, Pirmohamed M. Cardiovascular pharmacogenomics: expectations and practical benefits. Clin. Pharmacol. Ther. 95(3), 281–293 (2014).
    • 35. Finkelman BS, French B, Bershaw L et al. Predicting prolonged dose titration in patients starting warfarin. Pharmacoepidemiol. Drug Saf. 25(11), 1228–1235 (2016).
    • 36. Shendre A, Dillon C, Limdi NA. Pharmacogenetics of warfarin dosing in patients of African and European ancestry. Pharmacogenomics 19(17), 1357–1371 (2018).