Frequency of Common CYP2C9 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

Abstract

Polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9) gene result in interindividual variability in warfarin dose requirement. There is a need for characterization of genotype frequency distribution in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common CYP2C9 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted, and genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of the results. Data were analyzed using SPSS version 20. Genotype frequency distribution of CYP2C9*2 and CYP2C9*3 was found to be different from other populations. Of these 2 polymorphisms, CYP2C9*2 did not demonstrate significant effect on warfarin dose requirement, whereas CYP2C9*3 did show significant effect ( P value = .012). It is concluded that there is a need to study genotype frequency distribution and their effect on warfarin dose variability among different populations due to diversity in outcome.

VKORC1 and CYP2C9*3 Polymorphisms and Their Impacts to Acenocoumarol Dosage in Vietnamese Heart Valve Replacement Patients

“…Other studies on the North and the South Indian patients with mechanical heart valve showed that the patients carried the combination of variant alleles of CYP2C9*2, *3 and VKORC1-1639 and -1173 received lower dose of acenocoumarol treatment to reach INR from 2.5 to 3.0 [11,14]. Similar conclusions were proposed by Hungarian [12], Lebanese [13], Romanian [15], Pakistani [20]. A difference in our study to previous studies was that CYP2C9 polymorphism was not related to acenocoumarol dose in Vietnamese patients.…”

Variations in the frequencies of polymorphisms in the CYP2C9 gene in six major ethnicities of Pakistan

“…To our knowledge, this is the first study to report frequencies of CYP2C9 gene polymorphisms in various ethnicities of the Pakistani population. Although there have been a few studies from Pakistan in which frequency of CYP2C9*2 and CYP2C9*3 were reported [29][30][31] , all of these studies involved patients with different diseases and, therefore, unable to capture the actual frequency of these polymorphisms in a general Pakistani population. The frequencies of CYP2C9*2 and CYP2C9*3 reported in these publications are 5.1% for CYP2C9*2, 15.4% for CYP2C9*3 in breast cancer patients 29 , 4.45% for CYP2C9*2, 22.8% for CYP2C9*3 in cardiovascular patients taking warfarin 31 and 12.1% for CYP2C9*2, 14.1% for CYP2C9*3 in heart valve replacement patients taking warfarin 30 .…”

“…Although there have been a few studies from Pakistan in which frequency of CYP2C9*2 and CYP2C9*3 were reported 29 – 31 , all of these studies involved patients with different diseases and, therefore, unable to capture the actual frequency of these polymorphisms in a general Pakistani population. The frequencies of CYP2C9*2 and CYP2C9*3 reported in these publications are 5.1% for CYP2C9*2 , 15.4% for CYP2C9*3 in breast cancer patients 29 , 4.45% for CYP2C9*2 , 22.8% for CYP2C9*3 in cardiovascular patients taking warfarin 31 and 12.1% for CYP2C9*2 , 14.1% for CYP2C9*3 in heart valve replacement patients taking warfarin 30 . These frequencies vary significantly from one study to another and are also different from the ones we have reported for the healthy Pakistani population in this study.…”

Frequency of Common VKORC1 Polymorphisms and Their Impact on Warfarin Dose Requirement in Pakistani Population

“…For CYP2C9*3, patients with homozygous variant genotype (*3/*3) warfarin dose was significantly lower than homozygous wild type (*1/*1), but the dose requirement of heterozygous variant genotypes was not significantly different. 13 That is why the overall variability caused by all 4 SNPs to the warfarin dose is small (3.8%). There is a wide range of dose variability explained by these genotypes, reported in other international studies.…”

“…4,[8][9][10][11][12] We have already studied CYP2C9 polymorphisms and their effect on warfarin dose in Pakistani population. 13 That study data were used to assess the overall influence of both CYP2C9 and VKORC1 polymorphisms on warfarin dose requirement in present study. To expedite the use of VKORC1 genotyping along with CYP2C9 genotypes routinely in anticoagulation practice, it is imperative to determine the allelic frequency in different populations.…”