The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population

Fariba Emadian Razavi, Asghar Zarban, Fatemeh Hajipoor, Mohsen Naseri


The genetic factors are determinants in required dosage changes of warfarin among which are polymorphisms of CYP2C9 and VKORC1 genes. The present study aimed to determine the allele and genotype frequency of CYP2C9 and VKORC1 genes in Birjand population. This study was conducted on 120 individuals who referred to Imam Reza and Vali-Asr hospitals for PT/INR test. After extracting the genomic DNA, the considered sequences were amplified by PCR, and restriction fragment length polymorphism analysis was done by AvaII and KpnI enzymes to determine allele polymorphisms. Moreover, related sequences of VKORC1, after amplification, were sequenced for determining the genotype. Allelic and genotypic frequencies as well as Hardy-Weinberg equilibrium, observed heterozygosity, expected heterozygosity, and polymorphism information content were calculated by PowerMarker V 3.25 software. Amongst 120 individuals in this study with the mean age of 58.12 ± 12.7 years, 80.8%, 9.1%, and 10% exhibited the alleles of 1, 2, and 3 CYP2C9 gene, respectively. The genotype frequencies of 1/1, 1/2, 2/2, 3/1, 3/2, and 3/3 of this gene were found to be 64.1, 15.8, 0, 17.5, 2.5, and 0 %, respectively. In -1639 G>A region, VKORC1 had normal homozygote genotype (GG) and in 1173 C>T region, heterozygote (CT) with the frequency of 48.7% and 45.9% had the most prevalence. Compared with other populations, there is a considerable difference between the allele frequency of CYP2C9 and VKORC1 genetic variance. Since 35.8% of the selected populations carry an abnormal allele causing sensitivity to warfarin, the specialists at medical centers must be informed about the genotypes of patients before prescribing warfarin.


Warfarin; Coagulant; CYP2C9; VKORC1; Polymorphism

Full Text:



Nahar R, Deb R, Saxena R, Puri RD, Verma IC. Variability in CYP2C9 allele frequency: a pilot study of its predicted impact on warfarin response among healthy South and North Indians. Pharmacol Rep. 2013;65(1):187-194.

FDA news release: FDA approves updated warfarin (coumadin) prescribing information new genetic information may help providers improve initial dosing estimates of the anticoagulant for individual patients. Available from: /NewsEvents/%20Newsroom/PressAnnouncements/2007/ucm108967.htm.

Krajčíová Ľ, Petrovič R, Déžiová Ľ, Chandoga J, Turčáni P. Frequency of selected single nucleotide polymorphisms influencing the warfarin pharmacogenetics in Slovak population. Eur J Haematol. 2014;93(4):320-328.

Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med. 1993;95(3):315-328.

International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360(8):753-764.

Tamura T, Katsuda N, Hamajima N. A PCR method for VKORC1 G-1639A and CYP2C9 A1075C genotyping useful to warfarin therapy among Japanese.Springerplus. 2014;3:499: Doi: 10.1186/2193-1801-3-499.

Castelan-Martinez OD, Hoyo-Vadillo C, Sandoval-Garcia E, Sandoval-Ramirez L, Gonzalez-Ibarra M, Solano-Solano G, et al. Allele frequency distribution of CYP2C92 and CYP2C93 polymorphisms in six Mexican populations. Gene. 2013;523(2):167-172.

Rathore SS, Agarwal SK, Pande S, Singh SK, Mittal T, Mittal B. CYP4F2 1347 G > A & GGCX 12970 C > G polymorphisms: frequency in north Indians & their effect on dosing of acenocoumarol oral anticoagulant. Indian J Med Res. 2014;139(4):572-578.

Park SM, Lee JK, Chun SI, Lee HI, Kwon SU, Kang DW, et al. VKORC1 and CYP2C9 genotype variations in relation to warfarin dosing in Korean stroke patients. J Stroke. 2013;15(2):115-121.

Emadian Razavi F, Zarban A, Hajipoor F, Anani Sarab Gh, Naseri M. Allele and genotype frequencies of VKORC1 in Birjand population. Ir J Physiol Pharmacol. 2015;1(3):194-203.

Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin.Thromb Haemost. 2004;91(1):87-94.

Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011;90(4):625-629.

Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood. 2000;96(5):1816-1819.

Natarajan S, Ponde CK, Rajani RM, Jijina F, Gursahani R, Dhairyawan PP, et al. Effect of CYP2C9 and VKORC1 genetic variations on warfarin dose requirements in Indian patients. Pharmacol Rep. 2013;65(5):1375-1382.

Azarpira N, Namazi S, Hendijani F, Banan M, Darai M. Investigation of allele and genotype frequencies of CYP2C9, CYP2C19 and VKORC1 in Iran. Pharmacol Rep. 2010;62(4):740-746.

Kamal El-Din MA, Farhan MS, El Shiha RI, El-Kaffas RM, Mousa SM. Frequency of CYP2C9 and VKORC1 gene polymorphisms and their influence on warfarin dose in Egyptian pediatric patients. Paediatr Drugs. 2014;16(4):337-341.

Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res. 2007;120(1):1-10.

Cavallari LH, Perera MA. The future of warfarin pharmacogenetics in under-represented minority groups. Future Cardiol. 2012;8(4):563-576.

Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106(7):2329-2333.

Gaikwad T, Ghosh K, Shetty S. VKORC1 and CYP2C9 genotype distribution in Asian countries. Thromb Res. 2014;134(3):537-544.

Tabatabi M, Monfaredan A, Bargahi N. CYP2C9 gene allelic variation and the required dose of warfarin in patients with a history of thrombosis in North West of Iran. Med J Tabriz Univ Med Sci. 2012;2(34):75-80 (In Persian).

Shalia KK, Doshi SM, Parikh S, Pawar PP, Divekar SS, Varma SP, et al. Prevalence of VKORC1 and CYP2C9 gene polymorphisms in Indian population and its effect on warfarin response. J Assoc Physicians India. 2012;60:34-38.

Kimura R, Miyashita K, Kokubo Y, Akaiwa Y, Otsubo R, Nagatsuka K, et al. Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res. 2007;120(2):181-186.

Zhao F, Loke C, Rankin SC, Guo JY, Lee HS, Wu TS, et al. Novel CYP2C9 genetic variants in asian subjects and their influence on maintenance warfarin dose. Clin Pharmacol Ther 2004;76(3):210-219.

Zand N, Tajik N, Moghaddam AS, Milanian I. Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Iranian population. Clin Exp Pharmacol Physiol. 2007;34(1-2):102-105.

Vorob'eva NM, Panchenko EP, Dobrovol'skii AB, Titaeva EV, Khasanova ZB, Konovalova NV, et al. Polymorphisms of genes CYP2C9 and VKORC1 in patients with venous thromboembolic complications in Moscow population: effects on stability of anticoagulant therapy and frequency of hemorrhage. Ter Arkh. 2011;83(6):59-65.

Yoon YR, Shon JH, Kim MK, Lim YC, Lee HR, Park JY, et al. Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br J Clin Pharmacol. 2001;51(3):277-280.

Nakai K, Habano W, Nakai K, Fukushima N, Suwabe A, Moriya S, et al. Ethnic differences in CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) genotypes in Japanese and Israeli populations. Life Sci. 2005;78(1):107-111.

Gu Q, Kong Y, Schneede J, Xiao YB, Chen L, Zhong QJ, et al. VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China. Eur J Clin Pharmacol. 2010 Dec;66(12):1217-1227.

Yang JQ, Morin S, Verstuyft C, Fan LA, Zhang Y, Xu CD, et al. Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations. Fundam Clin Pharmacol. 2003;17(3):373-376.

Vargens DD, Damasceno A, Petzl-Erler M-L, Suarez-Kurtz G. Letter to the Editor: Combined CYP2C9, VKORC1 and CYP4F2 frequencies among Amerindians, Mozambicans and Brazilians. Pharmacogenomics. 2011;12(6):769-772.

Burian M, Grosch S, Tegeder I, Geisslinger G. Validation of a new fluorogenic real-time PCR assay for detection of CYP2C9 allelic variants and CYP2C9 allelic distribution in a German population. Br J Clin Pharmacol. 2002;54(5):518-521.

Aynacioglu AS, Brockmoller J, Bauer S, Sachse C, Guzelbey P, Ongen Z, et al. Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol. 1999;48(3):409-415.

Lam MP, Cheung BM. The pharmacogenetics of the response to warfarin in Chinese. Br J Clin Pharmacol. 2012;73(3):340-347.

Baniasadi S, Beizaee S, Kazemi B, Behzadnia N, Shafaghi B, Bandehpour M, et al. Novel VKORC1 mutations associated with warfarin sensitivity. Cardiovasc Ther. 2011;29(4):e1-5.

Salehifar E, Farhadi F, Janbabai Gh, Ahangar N. Frequency of VKORC1 gene polymorphisms and its association with warfarin dose requirement in patients from mazandaran province. J Mazand Univ Med Sci. 2012;22(94):44-52.

Tabatabi M, Monfaredan A, Bargahi N, Oskouyi S. Evaluate the frequency polymorphism 1639 G> A gene VKORC1 in patients with cardiovascular disorders in North West of Iran. Arak Med Univ J. 2013;15(4):40-6 (In Persian).

Hadjipanagi D, Chrysanthou S, Voskarides K, Deltas C. Genetic polymorphisms in warfarin and tacrolimus-related genes VKORC1, CYP2C9 and CYP3A5 in the Greek-Cypriot population. BMC Res Notes. 2014;7:123-126.

Lund K, Gaffney D, Spooner R, Etherington AM, Tansey P, Tait RC. Polymorphisms in VKORC1 have more impact than CYP2C9 polymorphisms on early warfarin International Normalized Ratio control and bleeding rates. Br J Haematol. 2012;158(2):256-261.

Steimer W, Zöpf K, von Amelunxen S, Pfeiffer H, Bachofer J, Popp J, et al. Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers. Clin Chem. 2004;50(9):1623-1633.

Scibona P, Redal MA, Garfi LG, Arbelbide J, Argibay PF, Belloso WH. Prevalence of CYP2C9 and VKORC1 alleles in the Argentine population and implications for prescribing dosages of anticoagulants. Genet Mol Res. 2012;11(1):70-76.

Owen RP, Gong L, Sagreiya H, Klein TE, Altman RB. VKORC1 pharmacogenomics summary. Pharmacogenet Genomics. 2010;20(10):642-644.

Bodin L, Verstuyft C, Tregouet DA, Robert A, Dubert L, Funck-Brentano C, et al. Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood. 2005;106(1):135-140.


  • There are currently no refbacks.