|Year : 2013 | Volume
| Issue : 1 | Page : 53-58
Genetic variation and haplotype structure of the gene Vitamin K epoxide reductase complex, subunit 1 in the Tamilian population
Dhakchinamoorthi Krishna Kumar, Deepak Gopal Shewade, Adithan Surendiran, Chandrasekaran Adithan
Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India
|Date of Web Publication||22-Feb-2013|
Dhakchinamoorthi Krishna Kumar
Department of Pharmacology, JIPMER, Pondicherry
Source of Support: ICMR Ref. No. 50/6/2010/, BMS. dated 03/11/2010,, Conflict of Interest: None
| Abstract|| |
Objective: To study the genetic variation and haplotype structure of Vitamin K epoxide reductase complex, subunit 1 (VKORC1) gene in the Tamilian population. Materials And Methods: The study was performed on 210 unrelated, healthy volunteers of the Tamilian population, of either sex between the age group of 18-60 years. Five ml of venous blood sample was collected using sodium ethylene diamine tetra acetic acid (EDTA) as anticoagulant. DNA was extracted using phenol-chloroform extraction method. Eight single nucleotide polymorphisms (SNPs) VKORC1 rs9923231 (G), rs7196161 (T), rs2884737 (T), rs17708472 (C), rs9934438 (C), rs8050894 (G), rs23596121 (C), and rs7294 (A) were studied using real-time quantitative Polymerase Chain Reaction (qPCR) method and they were included for constructing five-major haplotype blocks of VKORC1 gene. Results: The major alleles of VKORC1 rs9923231 (G), rs7196161 (T), rs2884737 (T), rs17708472 (C), rs9934438 (C), rs8050894 (G), and rs23596121 (C), were found to be at frequencies of 90.0%, 89.2%, 90.9%, 94.1%, 90.7%, 89.5% and 91.2%, respectively. The variant allele of VKORC1 rs7294 (A) was more frequent (83.6%) in the Tamilian population. The frequencies of haplotypes HAP1 (GTTCCGCA), HAP2 (ACGCTCTG), HAP3 (GTTTCGCG), HAP4 (GTTCCGCG) and HAP5 (GCTCCCCG) were found to be 80.0%, 7.4%, 4.7%, 1.5% and 1.1%, respectively. Conclusion: In the present study the allele- frequency distributions, genotype and haplotype frequencies of the VKORC1 gene was considered. The findings of this study provide the genetic information required for learning the association of VKORC1 genetic variation and oral anticoagulant dose variability among patients receiving oral anticoagulants in the Tamilian population.
Keywords: Genotype, haplotype, Vitamin K epoxide reductase complex subunit 1
|How to cite this article:|
Kumar DK, Shewade DG, Surendiran A, Adithan C. Genetic variation and haplotype structure of the gene Vitamin K epoxide reductase complex, subunit 1 in the Tamilian population. J Pharmacol Pharmacother 2013;4:53-8
|How to cite this URL:|
Kumar DK, Shewade DG, Surendiran A, Adithan C. Genetic variation and haplotype structure of the gene Vitamin K epoxide reductase complex, subunit 1 in the Tamilian population. J Pharmacol Pharmacother [serial online] 2013 [cited 2019 Jul 21];4:53-8. Available from: http://www.jpharmacol.com/text.asp?2013/4/1/53/107683
| Introduction|| |
Oral anticoagulants (OAs) such as warfarin, acenocoumarol and phenprocoumon are widely prescribed for patients to prevent thromboembolic events in various conditions.  These drugs have a narrow therapeutic index and need careful monitoring for initiation of therapy and maintenance. The actions of OAs are significantly dependent on the enzyme (vitamin k epoxide reductase) that is responsible for converting vitamin K epoxide to vitamin K hydroquinone which is the reduced form of vitamin K. This step is crucial in the mechanism of blood coagulation.
Vitamin K epoxide reductase complex, subunit 1 (VKORC1) is a significant molecule for cardiovascular diseases, since it is the target of oral anticoagulant drugs. The enzyme vitamin k epoxide reductase (VKOR), encoded by VKORC1, is specifically inhibited by coumarin oral anticoagulants and leads to diminished availability of reduced vitamin K, thereby inhibiting the clot formation. 
In recent years, studies had described genetic variation in the gene VKORC1 encoding the VKOR enzyme leading to altered function of the enzyme VKOR.  Hence common genetic variation in the gene leads to inter-individual variability in susceptibility to developing adverse drug reactions such as bleeding manifestations and other adverse reactions to OA.  The most widely studied single nucleotide polymorphism (SNP) of VKORC1 is -1639 G>A in the promoter region and has been described in a number of populations. ,, This polymorphism has been identified as the major allele in the Asian population.  The presence of this allele results in reduced dose requirement for oral anticoagulants. Other than VKORC1 5' flanking region polymorphisms, there are SNPs in the non-coding regions that produce significant variation in the oral anticoagulant dose requirement. ,,
Further, Reider et al.,  demonstrated a significant contribution of VKORC1 haplotypes to inter-individual variability in warfarin dose. The ten most common SNPs [at positions 381 (C>T), 861 (C>A), 2653 (G>C), 3673 (G>A), 5808 (T>G), 6009 (C>T), 6484 (C>T), 6853 (G>C), 7566 (C>T), and 9041 (G>A) of the VKORC1 reference sequence (GenBank accession number AY587020)] were used to construct the haplotypes. Among the haplotype groups, a low dose [Group A (H1-2.9 mg/day, H2- 3.0 mg/day)] and high dose [Group B (H7-6.30 mg/day, H8-4.8 mg/day, H9- 5.5 mg/day)] haplotypes were identified. These haplotype frequencies also vary among the different ethnic populations. Haplotype A is more frequent in Asians (89%); whereas Haplotype B is more frequent in Caucasians (58%). 
The Tamilian population is a south Indian sub-population that constitutes about 5.8% of the total population of India and resides in two states (Tamil Nadu, Pondicherry).  This population shares a common ancestry (Dravidians), but the present day population differs from one another in terms of language, culture and dietary habits with limited admixture. David Reich et al.,  found that the ancestral south Indians were distinct from the ancestral north Indians and east Indians.
In our previous studies we have reported that the variants in the genes encoding drug-metabolizing enzymes and drug transporters were significantly different in the Tamilian population as compared to other ethnic populations. ,, In the present study we aimed to establish the allele, genotype and haplotype frequencies of the VKORC1 gene in the Tamilian population which may provide us with the basic information needed for further pharmacogenetic studies of VKORC1 among the Tamilian population.
| Materials and Methods|| |
The study was conducted on 210 unrelated healthy volunteers from Tamil Nadu and Pondicherry. Both genders, aged between 18 and 60 years, were included in the study. Their nativity as Tamilian was assessed based on their family history of three generations from Tamil Nadu and Pondicherry and Tamil as their mother tongue. The study protocol was approved by the Institute Ethics Committee and the study was conducted according to the declaration of Helsinki. The study was explained to all the study participants and written informed consent was obtained.
Genotyping of Vitamin K epoxide reductase complex, subunit 1
Five milliliters of venous blood was collected using sodium ethylene diamine tetra acetic acid (EDTA) as anticoagulant. DNA was extracted by using standard phenol: chloroform method. Genotyping of VKORC1 was carried out by real-time thermo cycler (7300 Applied Biosystems; Life Technologies Corporation, Carlsbad, CA, USA) using TaqMan SNP genotyping assays [Table 1]. The Real-Time Polymerase Chain Reaction (RT- PCR) was carried out in duplicate in a 20-μL final volume that contained 10 μL of TaqMan universal PCR master mix (2x), 0.5 μL of 20x working stock of SNP genotyping assay and 4.5 μL of genomic DNA diluted in DNAase free water and 5 μL of MilliQ water (Millipore Corporate Headquarters, Billerica, MA, USA). The thermocycler conditions are given in [Table 1]. The allelic discrimination analysis was performed using 7300 SDS software Version 1.4.
Statistical analysis was performed using the GraphPad InStat 3 software (GraphPad Software Inc., San Diego, CA, USA). Hardy-Weinberg equilibrium was tested by Chi-square test to compare the observed genotype frequencies with the expected genotype frequencies calculated from the observed allele frequencies. Chi-square test was used for comparisons of different ethnic groups. P < 0.05 was considered statistically significant. Pair-wise linkage disequilibrium (LD) pattern and haplotype frequencies were estimated using HAPLOVIEW 4.1.  Haplotypes were estimated by accelerated expectation-maximization (EM) algorithm in HAPLOVIEW. The confidence interval range for LD was set between 0.7 and 0.98. D' values from 0.7-1.0 indicate strong LD between pair of SNPs. Whereas D' value <0.7 indicates moderate LD and D' value of <0.2 indicates no LD.
| Results|| |
A total of 204 [95 men, 109 women; age (±SD) 35.8 ± 7.9 years] samples of healthy volunteers were included for the analysis; six samples were lost during processing of DNA. The frequency distributions of VKORC1 genotypes [Table 2] were found to be in Hardy-Weinberg equilibrium [4 × 3 contingency table; rs9923231- χ² = 0.53, P = 0.46, rs7196161- χ² = 0.07, P = 0.79, rs2884737- χ² = 0.07, P = 0.78, rs17708472- χ² = 0.14, P = 0.70, rs9934438- χ² = 0.04, P0 = 0.85, rs8050894- χ² = 0.04, P = 0.0.84, rs2359612- χ² = 0.13, P = 0.72, rs7294, χ² = 0.06, P = 0.79)].
|Table 2: Genotype and allele frequencies of VKORC1 in the Tamilian population|
Click here to view
The allele frequency of VKORC1 in Tamilians was compared with other ethnic populations [Table 3]. The most studied SNPs (rs9923231, rs9934438, rs2359612 and rs7294) were compared with other ethnic populations. The results reveal that the frequency distribution of Han Chinese, Caucasians and African Americans were significantly different from the Tamilian population (P < 0.001). The frequency distributions of rs9923231 and rs9934438 among North Indians were not significantly different from the Tamilian population which is in south India (P > 0.05). The haplotype structure and pair-wise LD pattern of the eight VKORC1 SNPs were identified [Figure 1] and their frequencies in the Tamilian population were established [Table 4] by accelerated expectation-maximization (EM) algorithm. A strong LD pattern (D'>0.8) was observed between all the SNPs except between rs7294 and other SNPs, where only a moderate LD (D' <0.8) was observed. But the LD between rs17708472 and rs7294 was found to be strong (D'>0.8).
|Figure 1: Linkage disequilibrium pattern of VKORC1 genetic variants in the Tamilian population. The single nucleotide polymorphisms (SNPs) in Chromosome 16 were positioned according to the order and orientation. Each of the variant is given with its specific chromosomal position and the rsID. LD pattern of the rs9923231, rs7196161, rs2884737, rs1770847, rs9934438, rs8050894, rs23596121and rs7294 in the Tamilian population. Red and pink colors represent a very strong LD pattern (D'>0.8) and white color represents moderate to low LD (D' <0.8 to > 0.5)|
Click here to view
|Table 3: Distribution of widely studied VKORC1 allele frequencies among different ethnic groups|
Click here to view
| Discussion|| |
The present study investigated the baseline allele and genotype frequencies, LD pattern, Hardy- Weinberg equilibrium and haplotype structures of OA dose-altering VKORC1 genetic variants rs9923231, rs7196161, rs2884737, rs9934438, rs8050894, rs2359612 and rs7294 on Chromosome 16 in the Tamilian population. Other than the VKORC1 genetic variation, the two common genetic variants (CYP2C9*2 and CYP2C9*3) in the cytochrome p450 2C9 (CYP2C9) gene were known to significantly reduce the oral anticoagulant dose. 
The frequencies of these polymorphisms are significantly different in other ethnic populations. In our previous study we have established the frequencies of CYP2C9 variants in the Tamilian population.  The previous studies have reported that Asians, African Americans, Caucasians and Japanese with variant alleles for CYP2C9*2, CYP2C9*3 and VKORC1 rs9923231 G>A are sensitive to OA and they require low maintenance dose. , Those carrying the homozygous wild type allele required a higher or intermediate OA dose. They take a long time to achieve the stable dose with international normalized ratio (INR) values within the therapeutic range (2.0 to 3.0/3.5). 
It has been reported that patients with varying degrees of warfarin resistance carry mutations at least in one copy of the VKORC1 gene.  More recent findings reveal that VKORC1 genetic variation has a greater impact than CYP2C9 genetic variation on warfarin dose variance.  Haplotype analyses have shown that most of the non-coding SNPs are in strong linkage disequilibrium. Based on haplotypes, individuals may be divided into two groups, haplotypes A (H1 and H2) and B (H7, H8 and H9), which are associated with lower and higher warfarin dose requirements, respectively. The haplotype frequencies were found to have a significant influence on the OA dose requirement in Asian populations. 
A previous study has established the haplotype frequency (296 (C>T), 776 (C>A), 3673 (G>A), 5723 (T>G), 1173 (C>T) and 698 (G>A) in Malaysian Indians and found that the TCGTCA (H7) is more frequent in Indians as compared to the Chinese and Malays. The H7 haplotype group has been associated with higher dose requirement,  and our study on the Tamilian population is in line with this observation. Hence, OA dose requirement in Tamilian subjects may be higher in comparison with the Chinese and Japanese. According to another study conducted in Malaysia, the mean dose of warfarin was 3.7 mg, and the mean daily dose of warfarin was significantly higher in Indians than the Chinese and Malay patients, 4.9 mg/day versus 3.5 and 3.3 mg/day, respectively.  Consequently, it is clear that other than inter-individual difference, studying the inter-ethnic variation is also important in the required OA dose variation throughout the world.
Other than the CYP2C9 and VKORC1 genes, studies have reported that variation in the CYP4F2, GGCX and EPHX1 genes significantly influences the OA dose requirement. ,, But the association of these genetic variations is negligible when compared to the CYP2C9 and VKORC1. Hence, it is important to establish the baseline data on genetic variations of the functionally important VKORC1 gene, to initiate genetic studies for a particular population/cohort before conducting pharmacogenetic studies on OAs.
In association with the previous study reports the United States food and drug administration (US FDA) updated the OAs' label with including the new table with the range of expected therapeutic warfarin doses based on CYP2C9 and VKORC1 genotypes. Based on the pharmacogenetic information many studies have proposed OA dose-predicting algorithms for calculating the maintenance dose and initial dose of OAs using multivariate statistical techniques. ,,,, But the proposed algorithms appear to be specific for each population group, very likely due to differences in allele, genotype and haplotype frequencies.
In India very few studies have reported the association of genetic variation and OA dose requirement. , In the present study we have established the haplotype frequency in the Tamilian population, information that, to the best of our knowledge has not been reported before.
In conclusion, we report allele and genotype frequencies of eight important SNPs in the VKORC1 gene, their linkage disequilibrium pattern and haplotype structure in the Tamilian population. The reported data may provide the baseline information for studying the association of haplotypes with warfarin and acenocoumarol dose requirement in Tamilian patients.
| Acknowledgments|| |
This research project was funded by the Indian Council of Medical Research (ICMR), New Delhi, India (ICMR Ref. No. 50/6/2010/BMS, dated 03/11/2010). Ms. S. Kalaivani, and Mrs. N. Revathy, Technical Assistants, are gratefully acknowledged.
| References|| |
|1.||Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8-21S. |
|2.||Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004;427:541-4. |
|3.||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;106:135-40. |
|4.||Gan GG, Phipps ME, Lee MM, Lu LS, Subramaniam RY, Bee PC, et al. Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations. Ann Hematol 2011;90:635-41. |
|5.||Tham LS, Goh BC, Nafziger A, Guo JY, Wang LZ, Soong R, et al. A warfarin-dosing model in Asians that uses single: Nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9. Clin Pharmacol Ther 2006;80:346-55. |
|6.||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;106:2329-33. |
|7.||Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MT, et al. Warfarin pharmacogenetics: A single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood 2010;115:3827-34. |
|8.||Wadelius M, Chen LY, Eriksson N, Bumpstead S, Ghori J, Wadelius C, et al. Polymorphisms in the VKORC1 gene are strongly associated with warfarin dosage requirements in patients receiving anticoagulation. J Med Genet 2006;43:740-4. |
|9.||Kosaki K, Yamaghishi C, Sato R, Semejima H, Fuijita H, Tamura K, et al. 1173C>T polymorphism in VKORC1 modulates the required warfarin dose. Pediatr Cardiol 2006;27:685-8. |
|10.||Zhang W, Zhang WJ, Zhu J, Kong FC, Li YY, Wang HY, et al. Genetic polymorphisms are associated with variations in warfarin maintenance dose in Han Chinese patients with venous thromboembolism. Pharmacogenomics 2012;13:309-21. |
|11.||Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005;352:2285-93. |
|12.||Geisen C, Watzka M, Sittinger K, Steffens M, Daugela L, Seifried E, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost 2005;94:773-9. |
|13.||Provisional population totals paper 1 of 2011. Available from: http://www.censusindia.gov.in/2011-prov-results/. [Last accessed on 2012 Nov]. |
|14.||Reich D, Thangaraj K, Patterson N, Price AL, Singh L. Reconstructing Indian population history. Nature 2009;24:489-94. |
|15.||Jose R, Chandrasekaran A, Sam SS, Gerard N, Chanolean S, Abraham BK, et al. CYP2C9 and CYP2C19 genetic polymorphisms: Frequencies in the south Indian population. Fundam Clin Pharmacol 2005;19:101-5. |
|16.||Krishnakumar D, Gurusamy U, Dhandapani K, Surendiran A, Baghel R, Kukreti R, et al. Genetic polymorphisms of drug-metabolizing phase I enzymes CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Fundam Clin Pharmacol 2012;26:295-306. |
|17.||Umamaheswaran G, Krishna Kumar D, Kayathiri D, Rajan S, Shewade DG, Dkhar SA, et al. Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population. Mol Biol Rep 2012;39:6343-51. |
|18.||Barrett JC, Fry B, Maller J, Daly MJ. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21:263-5. |
|19.||Wang TL, Li HL, Tjong WY, Chen QS, Wu GS, Zhu HT, et al. Genetic factors contribute to patient-specific warfarin dose for Han Chinese. Clin Chim Acta 2008;396:76-9. |
|20.||Liu Y, Zhong SL, Yang M, Tan HH, Fei HW, Chen JY, et al. Distribution of variant alleles association with warfarin pharmacokinetics and pharmacodynamics in the Han population of China. Beijing Da Xue Xue Bao 2011;43:798-803. |
|21.||Cavallari LH, Momary KM, Patel SR, Shapiro NL, Nutescu E, Viana MA. Pharmacogenomics of warfarin dose requirements in Hispanics. Blood Cells Mol Dis 2011;46:147-50. |
|22.||Kimura R, Miyashita K, Kokubo Y, Akaiwa Y, Otsubo R, Nagatsuka K, et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res 2007;120:181-6. |
|23.||Yoshizawa M, Hayashi H, Tashiro Y, Sakawa S, Moriwaki H, Akimoto T, et al. Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients. Thromb Res 2009;124:161-6. |
|24.||Shahin MH, Khalifa SI, Gong Y, Hammad LN, Sallam MT, El Shafey M, et al. Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients. Pharmacogenet Genomics 201;21:130-5. |
|25.||Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther 2008;83:312-21. |
|26.||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;62:740-6. |
|27.||Rathore SS, Agarwal SK, Pande S, Mittal T, Mittal B. Frequencies of VKORC1 -1639 G>A, CYP2C9*2 and CYP2C9*3 genetic variants in the Northern Indian population. Biosci Trends 2010;4: 333-7. |
|28.||Suriapranata IM, Tjong WY, Wang T, Utama A, Raharjo SB, Yuniadi Y, et al. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians. BMC Med Genet 2011; 12: 80. |
|29.||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;1:70-6. |
|30.||Carlquist JF, Horne BD, Muhlestein JB, Lappé DL, Whiting BM, Kolek MJ, et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: A prospective study. J Thromb Thrombolysis 2006;22:191-7. |
|31.||Spreafico M, Lodigiani C, van Leeuwen Y, Pizzotti D, Rota LL, Rosendaal F, et al. Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy. Pharmacogenomics 2008;9:1237-50. |
|32.||Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004;427:537-41. |
|33.||Aquilante CL, Langaee TY, Lopez LM, Yarandi HN, Tromberg JS, Mohuczy D, et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther 2006;79:291-302. |
|34.||Lal S, Sandanaraj E, Jada SR, Kong MC, Lee LH, Goh BC, et al. Influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients. Br J Clin Pharmacol 2008;65:260-4. |
|35.||McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE. CYP4F2 Is a Vitamin K1 Oxidase: An Explanation for Altered Warfarin Dose in Carriers of the V433M Variant. Mol Pharmacol 2009;75:1337-46. |
|36.||Chan SL, Thalamuthu A, Goh BC, Chia KS, Chuah B, Wong A, et al. Exon sequencing and association analysis of EPHX1 genetic variants with maintenance warfarin dose in a multiethnic Asian population. Pharmacogenet Genomics 2011;21:35-41. |
|37.||Pavani A, Naushad SM, Rupasree Y, Kumar TR, Malempati AR, Pinjala RK, et al. Optimization of warfarin dose by population-specific pharmacogenomic algorithm. Pharmacogenomics J 2012;12:306-11. |
|38.||Gage BF, Lesko LJ. Pharmacogenetics of warfarin: Regulatory, scientific, and clinical issues. J Thromb Thrombolysis 2008;25:45-51. |
|39.||Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009;360:753-64. |
|40.||Schelleman H, Chen J, Chen Z, Christie J, Newcomb CW, Brensinger CM, et al. Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans. Clin Pharmacol Ther 2008;84:332-9. |
|41.||Rathore SS, Agarwal SK, Pande S, Singh SK, Mittal T, Mittal B. Therapeutic dosing of acenocoumarol: Proposal of a population specific pharmacogenetic dosing algorithm and its validation in north Indians. PLoS One 2012;7:e37844. |
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Value of VKORC1 (-1639G>A) rs9923231 genotyping in predicting warfarin dose: a replication study in South Indian population
| ||S. Harikrishnan,Linda Koshy,Ram Subramanian,G. Sanjay,C.P. Vineeth,A. Jayakumaran Nair,G.M. Nair,P.R. Sudhakaran |
| ||Indian Heart Journal. 2018; |
|[Pubmed] | [DOI]|
||Frequency of Common VKORC1 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population
| ||Aisha Qayyum,Muzammil Hasan Najmi,Qaisar Mansoor,Muhammad Irfan,Abdul Khaliq Naveed,Andleeb Hanif,Ali Raza Kazmi,Muhammad Ismail |
| ||Clinical and Applied Thrombosis/Hemostasis. 2018; 24(2): 323 |
|[Pubmed] | [DOI]|
||An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population
| ||Dhakchinamoorthi Krishna Kumar,Deepak Gopal Shewade,Marie-Anne Loriot,Philippe Beaune,B. V. Sai Chandran,Jayaraman Balachander,Chandrasekaran Adithan |
| ||European Journal of Clinical Pharmacology. 2015; 71(2): 173 |
|[Pubmed] | [DOI]|
||Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population
| ||Dhakchinamoorthi Krishna Kumar,Deepak Gopal Shewade,Marie-Anne Loriot,Philippe Beaune,Jayaraman Balachander,B. V. Sai Chandran,Chandrasekaran Adithan |
| ||European Journal of Clinical Pharmacology. 2014; 70(1): 47-56 |
|[Pubmed] | [DOI]|
||VKORC1 and CYP2C9 genotype distribution in Asian countries
| ||Tejasvita Gaikwad,Kanjaksha Ghosh,Shrimati Shetty |
| ||Thrombosis Research. 2014; |
|[Pubmed] | [DOI]|
||Effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirement in South Indian population
| ||Madhan, S., Kumar, D.K., Kumar, D.T., Balachander, B., Adithan, C. |
| ||Indian Journal of Physiology and Pharmacology. 2013; 57(3): 308-317 |