Establishment of a prediction algorithm for the Honghe minority group based on warfarin maintenance dose
Abstract
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. Anticoagulation and antiplatelet therapy in patients with prosthetic heart valves. J. Card. Surg. 35(12), 3521–3529 (2020).
- 2. 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. Warfarin dosage response related pharmacogenetics in Chinese population. PLOS ONE 10(1), e0116463 (2015).
- 4. 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. . Clinical model for predicting warfarin sensitivity. Sci. Rep. 9(1), 12856 (2019). • Describes the relevant variables of warfarin sensitivity and specificity.
- 6. . Warfarin dosing algorithms: a systematic review. Br. J. Clin. Pharmacol. 87(4), 1717–1729 (2021).
- 7. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med. 352(22), 2285–2293 (2005).
- 8. . 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. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin. Pharmacol. Ther. 80(1), 13–22 (2006).
- 10. . 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. . The future of warfarin pharmacogenetics in under-represented minority groups. Future Cardiol. 8(4), 563–576 (2012).
- 12. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLOS Genet. 5(3), e1000433 (2009).
- 13. 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. . Ethnic diversity and warfarin pharmacogenomics. Front. Pharmacol. 13, 866058 (2022).
- 15. Climatic factors determine the yield and quality of Honghe flue-cured tobacco. Sci. Rep. 10(1), 19868 (2020).
- 16. 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. 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. 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. A multi-factorial analysis of response to warfarin in a UK prospective cohort. Genome Med. 8(1), 2 (2016).
- 20. 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. . 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. . Statistics in medicine. Plast. Reconstr. Surg. 127(1), 437–444 (2011).
- 23. . 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. Genetic determinants of response to warfarin during initial anticoagulation. N. Engl. J. Med. 358(10), 999–1008 (2008).
- 25. Estimation of the warfarin dose with clinical and pharmacogenetic data. N. Engl. J. Med. 360(8), 753–764 (2009).
- 26. . 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. . 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. VKORC1 variants as significant predictors of warfarin dose in Emiratis. Pharmgenomics Pers. Med. 12, 47–57 (2019).
- 29. A global reference for human genetic variation. Nature 526(7571), 68–74 (2015).
- 30. Cytochrome P450 2C9 (CYP2C9) polymorphisms in Chinese Li population. Int. J. Clin. Exp. Med. 8(11), 21024–21033 (2015).
- 31. 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. . 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. . Pharmacogenetics of warfarin: challenges and opportunities. J. Hum. Genet. 58(6), 334–338 (2013).
- 34. . Cardiovascular pharmacogenomics: expectations and practical benefits. Clin. Pharmacol. Ther. 95(3), 281–293 (2014).
- 35. Predicting prolonged dose titration in patients starting warfarin. Pharmacoepidemiol. Drug Saf. 25(11), 1228–1235 (2016).
- 36. . Pharmacogenetics of warfarin dosing in patients of African and European ancestry. Pharmacogenomics 19(17), 1357–1371 (2018).