<i>VKORC1</i>
            Haplotypes in Five East-Asian Populations and Indians

Lee, Ming Ta Michael; Chen, Chien-Hsiun; Chuang, Hui-Ping; Lu, Limin; Chou, Ching‐Heng; Chen, Ying-Ting; Liu, Chih-Yang; Wen, Ming‐Shien; Lu, Jang‐Jih; Chang, Chih-Hung; Wu, Jer‐Yuarn; Chen, Yuan-Tsong

doi:10.2217/pgs.09.80

Cited by 15 publications

(17 citation statements)

References 19 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study by Gan et al showed that among the Asian populations, Indians require higher warfarin doses compared with the Chinese and Malay patients, and these variations could mainly be due to different allele frequencies and polymorphisms in CYP2C9 and VKORC1 [9]. These results were further supported by findings of others who demonstrated that the VKORC1 haplotype in Indians was significantly different from other Asian populations [10,11]. It is thus imperative to ascertain differences in genotype frequencies in smaller populations within countries such as India to aid in the understanding and prediction of population level differences in drug metabolism and action.…”

Section: Introductionmentioning

confidence: 69%

Genetic Epidemiology of Pharmacogenetic Variations in CYP2C9 , CYP4F2 and VKORC1 Genes Associated with Warfarin Dosage in the Indian Population

et al. 2014

View full text Add to dashboard Cite

Based on genotypic distribution, the majority of the Indian subpopulation might require higher doses for stable anticoagulation, whereas careful assessment is required for Tibeto-Burmans who are expected to have intermediate dose requirement. This is the largest global genetic epidemiological study examining variants associated with warfarin that could potentially be valuable to clinicians in optimizing dosage strategies.

show abstract

Section: Introductionmentioning

confidence: 69%

Genetic Epidemiology of Pharmacogenetic Variations in CYP2C9 , CYP4F2 and VKORC1 Genes Associated with Warfarin Dosage in the Indian Population

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Consequently, the combined G/A and A/A genotype frequencies ranged from 19.7% (African–American) to 77.5% (Asian). However, the Asian g.-1639G>A frequency significantly deviated from Hardy–Weinberg equilibrium (p < 0.0001), presumably as a result of subpopulation heterogeneity [23,24], as our Asian cohort was comprised of different ethnicities.…”

Section: Resultsmentioning

confidence: 91%

Combined CYP2C9 , VKORC1 and CYP4F2 Frequencies among Racial and Ethnic Groups

et al. 2010

View full text Add to dashboard Cite

Aims-CYP4F2*3 (p.V433M) has been associated with higher warfarin dose requirements; however, its frequency, like other CYP2C9 and VKORC1 variants, has not been systematically assessed in major racial/ethnic populations. Thus, we determined the individual and combined frequencies of important CYP2C9, VKORC1 and CYP4F2 variants in several racial/ethnic groups. Results-The combined frequencies of variant CYP2C9 alleles were 0.133, 0.078, 0.212, 0.178 and 0.212 among African-American, Asian, Caucasian, Hispanic and AJ individuals, respectively. CYP4F2*3 frequencies were prevalent (0.233-0.342) among Asian, Caucasian, Hispanic and AJ individuals, while significantly less frequent among African-Americans (0.117; p < 0.0001). In addition, CYP4F2*3 was in linkage disequilibrium with rs2189784, an allele recently associated with time-to-therapeutic international normalized ratio, among all studied populations. Importantly, 87-95% of Asian, Caucasian, Hispanic and AJ individuals had a variant CYP2C9, VKORC1 and/or CYP4F2*3 allele, compared with only 53% of African-Americans (p < 0.0001). Materials & methods-HealthyConclusions-Compared with other racial/ethnic populations studied, only approximately one in 80 African-Americans were CYP4F2*3 homozygous, indicating that this population would benefit less from dosing algorithms that include this variant. In addition, the unique allele frequency profiles identified among the different populations partly explain why genotype-guided warfarin dosing algorithms perform less well for African-Americans and suggest that other unidentified genetic and/ or nongenetic factors that influence warfarin dosage may exist in this population.

show abstract

“…This included 1306 subjects from the IWPC cohort (138 with genotype information only); 317 subjects from 6 different Asian countries with genotype information only 41 ; 316 subjects from 5 countries in South America, Africa, and the Middle East with genotype information only who were recruited as part of the PharmacoGenetics for Every Nation Initiative 42 ; and 6812 participants (2108 non-Hispanic blacks, 2631 nonHispanic whites, and 2073 Mexican Americans) ascertained as part of the Third National Health and Nutrition Examination Survey (NHANES), a population-based, racially representative cross-sectional study in the United States 43 (http://www.cdc.gov/nchs/nhanes.htm).…”

Section: Worldwide Haplotype Surveymentioning

confidence: 99%

Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Limdi

Wadelius

Cavallari

et al. 2010

Blood

Self Cite

331

294

View full text Add to dashboard Cite

Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 ؊1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 ؊1639G>A among Asians (n ‫؍‬ 1103), blacks (n ‫؍‬ 670), and whites (n ‫؍‬ 3113).Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multivariable linear regression. VKORC1 ؊1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction.VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the ؊1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups. (Blood. 2010;115(18):3827-3834) IntroductionWarfarin, the most commonly prescribed anticoagulant, exhibits large interpatient variability in dose requirements. Patient-specific factors (eg, age, body size, race, concurrent diseases, and medications) explain some of the variability in warfarin dose, but genetic factors influencing warfarin response explain a significantly higher proportion of the variability in dose. 1 Candidate-gene association studies 2-22 have identified 2 genes responsible for the main proportion of the genetic effect: CYP2C9, which codes for the enzyme cytochrome P450 2C9 that metabolizes S-warfarin, 23,24 and VKORC1, which codes for warfarin's target, vitamin K epoxide reductase. 25,26 The influence of CYP2C9 and VKORC1 has also been confirmed by genome-wide association studies among whites. 27,28 These studies suggest that identification of common variants in other genes exhibiting influence of magnitude similar to that of CYP2C9 and VKORC1 is unlikely in whites. The most influential CYP2C9 polymorphisms are nonsynonymous coding variants resulting in reduced enzyme activity and decreased metabolic capacity. [29][30][31] In contrast, common VKORC1 variants associated with warfarin dose are noncoding polymorphisms, the effects of which are thought to be mediated through differential expression of the VKOR protein. 32 These polymorphisms are within a region of strong linkage disequilibrium (LD) among patients of European ancestry; thus, they may all point to the same common causal polymorphism. 10,14 However, neither the causative VKORC1 polymorphism nor the molecula...

show abstract

VKORC1 Haplotypes in Five East-Asian Populations and Indians

Cited by 15 publications

References 19 publications

Genetic Epidemiology of Pharmacogenetic Variations in CYP2C9 , CYP4F2 and VKORC1 Genes Associated with Warfarin Dosage in the Indian Population

Genetic Epidemiology of Pharmacogenetic Variations in CYP2C9 , CYP4F2 and VKORC1 Genes Associated with Warfarin Dosage in the Indian Population

Combined CYP2C9 , VKORC1 and CYP4F2 Frequencies among Racial and Ethnic Groups

Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Contact Info

Product

Resources

About