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Positive Selection in the Chromosome 16 VKORC1 Genomic Region Has Contributed to the Variability of Anticoagulant Response in Humans  [PDF]
Blandine Patillon, Pierre Luisi, Hélène Blanché, Etienne Patin, Howard M. Cann, Emmanuelle Génin, Audrey Sabbagh
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0053049
Abstract: VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8), and PRSS8) with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect.
VKORC1 Gene Analysis in an Iranian Warfarin Resistant Patient  [PDF]
P. Ghadam,F. Sadeghian,R. Sharifian,S. Sadrai
Journal of Biological Sciences , 2008,
Abstract: The vitamin K epoxide reductase subunit 1 (VKORC1) has been identified recently. It is a component of the enzyme vitamin K epoxide reductase that is the therapeutic target site of warfarin. In order to investigate the relationship between VKORC1 gene and warfarin dose response, we studied this gene in an Iranian warfarin resistant patient who receive more than 100 mg warfarin per day. The results showed that although warfarin concentration in his plasma was extremely higher than therapeutic level (22.8 mg L-1) but no mutation(s) found in the exons of VKORC1 gene. Other genes may be contributed in resistance to warfarin in this patient.
VKORC1 Common Variation and Bone Mineral Density in the Third National Health and Nutrition Examination Survey  [PDF]
Dana C. Crawford,Kristin Brown-Gentry,Mark J. Rieder
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015088
Abstract: Osteoporosis, defined by low bone mineral density (BMD), is common among postmenopausal women. The distribution of BMD varies across populations and is shaped by both environmental and genetic factors. Because the candidate gene vitamin K epoxide reductase complex subunit 1 (VKORC1) generates vitamin K quinone, a cofactor for the gamma-carboxylation of bone-related proteins such as osteocalcin, we hypothesized that VKORC1 genetic variants may be associated with BMD and osteoporosis in the general population. To test this hypothesis, we genotyped six VKORC1 SNPs in 7,159 individuals from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is a nationally representative sample linked to health and lifestyle variables including BMD, which was measured using dual energy x-ray absorptiometry (DEXA) on four regions of the proximal femur. In adjusted models stratified by race/ethnicity and sex, SNPs rs9923231 and rs9934438 were associated with increased BMD (p = 0.039 and 0.024, respectively) while rs8050894 was associated with decreased BMD (p = 0.016) among non-Hispanic black males (n = 619). VKORC1 rs2884737 was associated with decreased BMD among Mexican-American males (n = 795; p = 0.004). We then tested for associations between VKORC1 SNPs and osteoporosis, but the results did not mirror the associations observed between VKORC1 and BMD, possibly due to small numbers of cases. This is the first report of VKORC1 common genetic variation associated with BMD, and one of the few reports available that investigate the genetics of BMD and osteoporosis in diverse populations.
Association of Functional VKORC1 Promoter Polymorphism with Occurrence and Clinical Aspects of Ischemic Stroke in a Greek Population  [PDF]
Georgia Ragia,Stella Marousi,John Ellul,Vangelis G. Manolopoulos,Anna Tavridou
Disease Markers , 2013, DOI: 10.1155/2013/769574
Abstract: Genetic factors are considered to play an important role in determining the susceptibility to the occurrence, clinical course, and functional outcome of an acute ischemic stroke (IS). Undercarboxylation of specific vitamin K-dependent proteins, due to genetic polymorphisms of VKORC1, can affect both vascular calcification and thrombogenicity. We sought to determine the association of VKORC1 ?1639G > A polymorphism with IS incidence, age of onset, severity of disease, and functional outcome after an acute IS. VKORC1 ?1639G > A polymorphism was determined in 145 consecutive patients with first ever IS and 145 age- and sex-matched control subjects of Greek Caucasian origin using PCR-RFLP. Stroke severity and functional outcome were assessed on admission and at one month after stroke, respectively. Frequency of VKORC1 ?1639G > A genotypes did not differ between IS patients and controls ( , ). Moreover, carriage of the A allele was not associated with age of stroke onset, severity of disease (Scandinavian stroke scale score 32.2 versus 32.9, resp., ), or poor outcome at 1 month post-stroke (52.9 versus 64.4%, resp., ). In conclusion, VKORC1 ?1639G > A polymorphism is not a genetic determinant of IS occurrence, age of onset, severity, or functional outcome of disease in a Greek population. 1. Introduction Ischemic stroke (IS), a multifactorial disease which shares many common risk factors with coronary artery disease, leads to a high mortality and disability rate [1]. However, distinct mechanisms may be critical in the development of acute ischemic coronary and cerebrovascular events. Both environmental and genetic factors are considered to play important role in determining the susceptibility to the occurrence, clinical course, and functional outcome of an acute IS. There is evidence that common variants in several genes, each exerting a modest effect, contribute to the risk of stroke [2]. Vitamin K-dependent proteins play a significant role in coagulation but also in bone metabolism and vascular calcification. Modification by -carboxylation is necessary for vitamin K-dependent proteins to become biologically active [3]. Vitamin K epoxide reductase complex subunit 1 (VKORC1) is involved in this process by mediating recycling of vitamin K 2,3 epoxide to vitamin K hydroquinone [4], a cofactor for the conversion of glutamate to -carboxyglutamic acid. VKORC1 is the target of coumarin derivatives, and several genetic variations of the VKORC1 gene influence response to anticoagulant therapy (for review, see [5]). Matrix Gla protein (MGP), a vitamin K-dependent
CYP2C9和VKORC1基因多态性对华法林抗凝强度的影响  [PDF]
薛乾,李伟,张宇峰,康波,肖健,陈万生,王志农
- , 2016, DOI: 10.16781/j.0258-879x.2016.05.0640
Abstract: 目的 探讨上海地区汉族人群中细胞色素氧化酶P450 2C9(CYP2C9)、维生素K环氧化物还原酶复合体1(VKORC1)基因多态性对华法林稳定剂量及华法林血浆浓度的影响。方法 纳入在体外循环下行瓣膜置换术且术后需服用华法林抗凝的患者226例,采用焦磷酸测序及UPLC/MS-MS法分别检测其CYP2C9和VKORC1基因型及其华法林血浆总浓度及游离浓度,分别以基因型、性别、年龄进行分组,比较不同组别患者华法林维持剂量和血浆浓度,并计算基因多态性及血药浓度、性别、年龄对华法林稳定剂量的贡献率。结果 CYP2C9(1061A/C)基因型中,AA型患者华法林维持量高于AC型(P<0.05);VKORC1(-1639G/A)基因型中,AG型患者华法林维持量高于AA型患者(P<0.01);VKORC1(1173C/T)基因型中, CT型患者华法林维持量高于TT型患者(P<0.01)。CYP2C9(1061A/C)不同基因型间其华法林血浆浓度差异无统计学意义,VKORC1(-1639G/A)不同基因型间及VKORC1(1173C/T)不同基因型间华法林血浆浓度差异有统计学意义(P<0.01)。男性患者所需华法林维持量高于女性患者(P<0.05),60岁以上患者所需华法林维持量低于60岁以下患者(P<0.05)。CYP2C9(1061A/C)、VKORC1(-1639G/A)、VKORC1(1173C/T)基因多态性及华法林血药浓度、年龄、性别分别解释了7.2%、29.1%、30.4%、6.7%、1.6%和1.4%的华法林个体剂量差异,多因素联合可解释47.2%的华法林个体剂量差异。结论 CYP2C9基因多态性与华法林抗凝药物剂量的个体间差异有关;VKORC1基因多态性与华法林抗凝药物剂量的个体间差异有关,且与其血药浓度密切相关。年龄和性别是影响华法林维持量的重要非基因因素。
Objective To evaluate the effect of gene polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on warfarin maintenance dose and plasma concentration in Chinese Han population in Shanghai. Methods A total of 226 patients who underwent oral warfarin anticoagulation therapy after valve replacement under cardiopulmonary bypass were enrolled in this study. The CYP2C9 1061A/C and VKORC1 -1639 G/A and 1173C/T genotypes were determined by pyrosequencing. The plasma level of warfarin was determined by the UPLC/MS-MS method. The patients were divided into different groups based on genotypes, sex and age. The average daily dose of warfarin and plasma concentration of warfarin were compared between different groups, and the contributions of genotype, plasma concentration, sex and age to warfarin daily dose were calculated. Results Maintenance dose of warfarin in patients with CYP2C9 1061A/C AA type was significantly higher than those with CYP2C9 1061A/C AC type (P<0.05). Maintenance dose of warfarin in patients with VKORC1 -1639G/A AG type was significantly higher than those with VKORC1 -1639G/A AA type (P<0.01). Maintenance dose of warfarin in patients with VKORC1 1173C/T CT type was significantly higher than those with VKORC1 1173C/T TT type (P<0.01). Significant differences of plasma warfarin concentration were also observed between VKORC1 -1639 G/A AA and AG as well as 1173C/T TT and CT genotypes (P<0.01), but not in those with CYP2C9 1061A/C genotypes. The average daily dose of warfarin was significantly higher in male patients than in females (P<0.05). The maintenance dose of warfarin was also significantly higher in patients under 60 years old than those aged above 60 years (P<0.05).
Novel mutations in the VKORC1 gene of wild rats and mice – a response to 50 years of selection pressure by warfarin?
Simone Rost, Hans-Joachim Pelz, Sandra Menzel, Alan D MacNicoll, Vanina León, Ki-Joon Song, Thomas J?kel, Johannes Oldenburg, Clemens R Müller
BMC Genetics , 2009, DOI: 10.1186/1471-2156-10-4
Abstract: In the present study, we have sequenced the VKORC1 genes of more than 250 rats and mice trapped in anticoagulant-exposed areas from four continents, and identified 18 novel and five published missense mutations, as well as eight neutral sequence variants, in a total of 178 animals. Mutagenesis in VKORC1 cDNA constructs and their recombinant expression revealed that these mutations reduced VKOR activities as compared to the wild-type protein. However, the in vitro enzyme assay used was not suited to convincingly demonstrate the warfarin resistance of all mutant proteinsOur results corroborate the VKORC1 gene as the main target for spontaneous mutations conferring warfarin resistance. The mechanism(s) of how mutations in the VKORC1 gene mediate insensitivity to coumarins in vivo has still to be elucidated.Coumarin derivatives, e.g. warfarin, act as vitamin K-antagonists and are in world-wide use as anticoagulants for therapy and prophylaxis of thrombotic diseases in humans, and as rodenticides for pest control. The physiological target of coumarins is the endoplasmic enzyme vitamin K-epoxide reductase (VKOR) [1,2]. A key component of the VKOR was recently identified and named VKORC1 [3,4]. Mutations in VKORC1 have been shown to cause two different hereditary phenotypes: warfarin-resistance (OMIM #122700) and defective blood coagulation owing to vitamin K-dependent coagulation factor deficiency type 2 (VKCFD2; OMIM #607473) [3]. The vitamin K-cycle provides vitamin K-hydroquinone, the essential cofactor for the γ-glutamyl carboxylase catalysing the post-translational modification of the vitamin K-dependent proteins [5]. These proteins are involved in blood coagulation (factor II, VII, IX, X, Protein S, C and Z), cell cycle regulation (growth-arrest specific protein 6) and bone metabolism (osteocalcin and matrix gla-protein) [6,7]. Coumarins inhibit blood coagulation by suppressing VKOR activity and consequently γ-carboxylation of vitamin K-dependent proteins.Warfarin i
Warfarin Dosing in a Patient with CYP2C9*3*3 and VKORC1-1639 AA Genotypes  [PDF]
Mark Johnson,Craig Richard,Renee Bogdan,Robert Kidd
Case Reports in Genetics , 2014, DOI: 10.1155/2014/413743
Abstract: Genetic factors most correlated with warfarin dose requirements are variations in the genes encoding the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR). Patients receiving warfarin who possess one or more genetic variations in CYP2C9 and VKORC1 are at increased risk of adverse drug events and require significant dose reductions to achieve a therapeutic international normalized ratio (INR). A 74-year-old white female with atrial fibrillation was initiated on a warfarin dose of 2 mg PO daily, which resulted in multiple elevated INR measurements and three clinically significant hemorrhagic events and four vitamin K antidote treatments over a period of less than two weeks. Genetic analysis later revealed that she had the homozygous variant genotypes of CYP2C9*3*3 and VKORC1-1639 AA. Warfarin dosing was subsequently restarted and stabilized at 0.5?mg PO daily with therapeutic INRs. This is the first case report of a white female with these genotypes stabilized on warfarin, and it highlights the value of pharmacogenetic testing prior to the initiation of warfarin therapy to maximize efficacy and minimize the risk of adverse drug events. 1. Introduction Warfarin is the most widely used anticoagulant in the world and has been consistently shown to be effective at preventing emboli in patients with prosthetic heart valves or atrial fibrillation [1]. Achieving a safe and effective warfarin maintenance dose can take weeks or months after the initiation of therapy due to its narrow therapeutic range and wide interindividual dose variation [2]. Unexpected sensitivity to warfarin commonly results in prolonged bleeding caused by excessive anticoagulation and warfarin is the number one cause of hospitalization due to an adverse drug event in the USA [3]. Clinical factors including age, height, weight, gender, race, diet, smoking, comorbidities, prosthetic heart valve, and other medications contribute to the dose variability of warfarin, but genetic factors have been shown to be the largest contributor to the dose variability of warfarin [2, 3]. The two genetic factors that are most correlated with warfarin dose requirements are variations in the genes encoding the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKOR) [1]. CYP2C9 is the primary enzyme responsible for inactivating warfarin. The CYP2C9*3 variant allele has been shown to cause an 80% decrease in enzymatic activity of CYP2C9 and therefore contributes to the dose variance of warfarin [4]. The pharmacological target for warfarin is inhibition of the VKOR
The c.-1639g>A polymorphism of the VKORC1 gene and his influence on the therapeutic response during oral anticoagulants use  [PDF]
Kova? Mirjana,Raki?evi? Ljiljana,Masla? Aleksandar,Radojkovi? Dragica
Vojnosanitetski Pregled , 2009, DOI: 10.2298/vsp0908617k
Abstract: Background/Aim. A single nucleotide polymorphism c.- 1639G>A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral anticoagulants (OA). The aim of the study was to determine the incidence and the effect of c.-1639G>A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA. Methods. Our study included 200 consecutive patients requiring low (n = 43), medium (n = 127) and high (n = 30) acenocoumarol dose. Results. Out of 43 low dose patients, 40 (93 %) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p < 0.0001). In 33 patients (16.5%) the overdose occurred during the initiation of anticoagulant therapy and in 11 patients (5.5%) it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p < 0.000001). Conclusion. VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5 % of our patients - carriers of AA genotype, before anticoagulation therapy initiation.
Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism
Alexander Semmler, Susanna Moskau, Holger Lutz, Peter Meyer, Michael Linnebank
BMC Research Notes , 2011, DOI: 10.1186/1756-0500-4-439
Abstract: Haplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262 G than expected from normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele.Given that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage.The monomeric enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR, EC 607093, OMIM 236250) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF). 5-MTHF is a methyl group donor for the remethylation of homocysteine to methionine. The T-allele of the MTHFR polymorphism c.677C>T (A222V, rs1801133) is associated with reduced MTHFR activity and, thus with an increased total plasma homocysteine level [1]. The frequency of the T-allele of MTHFR c.677C>T differs between ethnic groups and ranges from 6-10% in African countries [2,3] to more than 17% in Caucasians in North America [1,4,5] and more than 50% in Mexican populations [3]. In the literature, the presence of the T-allele has been associated with cardiovascular and cerebrovascular diseases, venous thrombosis, neural tube defects and various cancers [6]. It was hypothesized that this might be due to increased plasma homocysteine levels in carriers of the MTHFR c.677T allele [7]. In addition, the allele's function for DNA synthesi
Genetic and Demographic Outcomes in a Population of Patients with Headache and Facial Pain  [PDF]
Jonathan Eskenazi, Miriam Nuno, Steven Graff-Radford, Oana M. Dumitrascu
Journal of Behavioral and Brain Science (JBBS) , 2018, DOI: 10.4236/jbbs.2018.86022
Abstract: Background: Pharmacogenetics information about cytochrome p450 (CYP450) polymorphism in patients with headaches is limitedly reported. Similarly, the genetic factors linking various headache types and vascular disorders are poorly described. We aimed to characterize the genetic profile of a cohort of headache and facial pain subjects. Methods: Medical records of consecutive headache subjects that underwent PersonaGeneTM testing were reviewed. PersonaGeneTM panel assessed CYP450, apolipoprotein E (ApoE), methylene tetrahydrofolate reductase (MTHFR), Factor II, Factor V Leiden and Vitamin K epoxide reductase complex subunit 1 (VKORC1). Demographic information, headache diagnosis and genetic profiling were analyzed and compared with data obtained from the general population. Results: Out of 130 headache patients, 91.3% were Caucasian and 70.8% had migraine. Compared to the general Caucasian population, our Caucasian headache patients were significantly different for CYP3A4/A5 and CYP2D6 (p < 0.001) and comparable regarding CYP2C9 and CYPC19. Whereas MTHFR genotype was similar, ApoE and Factor V Leiden were different in headache patients (p = 0.001). Less headache patients showed intermediate sensitivity to warfarin (p = 0.009) based on VQORC1 genotyping. No differences were noticed between migraine and other headache type diagnoses for all the genetic tests. Conclusion: Distinctive profiles for CYP450, ApoE, Factor V Leiden and VQORC1 were observed in our Caucasian headache cohort. These results may impact headache subjects’ pharmacological treatment options and vascular risk ascertainment.
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