Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements
Introduction The primary objective of this study was to determine whether variability in warfarin dose requirements is determined by common polymorphisms in genes whose products are involved in the pharmacodynamics and pharmacokinetics of warfarin, namely, the coagulation factors, vitamin K epoxide...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2006-04, Vol.79 (4), p.291-302 |
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| creator | Aquilante, Christina L. Langaee, Taimour Y. Lopez, Larry M. Yarandi, Hossein N. Tromberg, Jennifer S. Mohuczy, Dagmara Gaston, Katherine L. Waddell, Cassandra D. Chirico, Mark J. Johnson, Julie A. |
| description | Introduction
The primary objective of this study was to determine whether variability in warfarin dose requirements is determined by common polymorphisms in genes whose products are involved in the pharmacodynamics and pharmacokinetics of warfarin, namely, the coagulation factors, vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 (CYP) 2C9.
Methods
Patients (N = 350) receiving stable doses of warfarin at 3 consecutive visits were enrolled, and a deoxyribonucleic acid sample was collected. Samples were genotyped for polymorphisms in the factor II, factor VII, factor X, VKORC1, and CYP2C9 genes. A stepwise linear regression analysis was used to determine the independent effects of genetic and nongenetic factors on mean warfarin dose requirements.
Results
Variables associated with lower warfarin dose requirements were VKORC1 3673 AA genotype (P < .0001), VKORC1 3673 GA genotype (P < .0001), 1 variant CYP2C9 allele (P < .0001), 2 variant CYP2C9 alleles (P = .0004), increasing age (P = .0005), concomitant CYP2C9 inhibitors (P = .0005), and goal international normalized ratio (P = .01). Variables associated with higher warfarin dose requirements were weight (P < .0001), current smoker status (P = .0009), mean international normalized ratio (P = .001), concomitant CYP2C9 inducers (P = .006), factor X insertion/deletion genotype (P = .01), factor X insertion/insertion genotype (P = .04), factor VII deletion/deletion genotype (P = .04), and calculated vitamin K intake (P = .05). The linear regression model explained 51.4% of the variability in warfarin dose requirements.
Conclusion
Polymorphisms in warfarin drug target and metabolizing enzyme genes, in addition to nongenetic factors, were important determinants of warfarin dose requirements.
Clinical Pharmacology & Therapeutics (2006) 79, 291–302; doi: 10.1016/j.clpt.2005.11.011 |
| doi_str_mv | 10.1016/j.clpt.2005.11.011 |
| format | Article |
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The primary objective of this study was to determine whether variability in warfarin dose requirements is determined by common polymorphisms in genes whose products are involved in the pharmacodynamics and pharmacokinetics of warfarin, namely, the coagulation factors, vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 (CYP) 2C9.
Methods
Patients (N = 350) receiving stable doses of warfarin at 3 consecutive visits were enrolled, and a deoxyribonucleic acid sample was collected. Samples were genotyped for polymorphisms in the factor II, factor VII, factor X, VKORC1, and CYP2C9 genes. A stepwise linear regression analysis was used to determine the independent effects of genetic and nongenetic factors on mean warfarin dose requirements.
Results
Variables associated with lower warfarin dose requirements were VKORC1 3673 AA genotype (P < .0001), VKORC1 3673 GA genotype (P < .0001), 1 variant CYP2C9 allele (P < .0001), 2 variant CYP2C9 alleles (P = .0004), increasing age (P = .0005), concomitant CYP2C9 inhibitors (P = .0005), and goal international normalized ratio (P = .01). Variables associated with higher warfarin dose requirements were weight (P < .0001), current smoker status (P = .0009), mean international normalized ratio (P = .001), concomitant CYP2C9 inducers (P = .006), factor X insertion/deletion genotype (P = .01), factor X insertion/insertion genotype (P = .04), factor VII deletion/deletion genotype (P = .04), and calculated vitamin K intake (P = .05). The linear regression model explained 51.4% of the variability in warfarin dose requirements.
Conclusion
Polymorphisms in warfarin drug target and metabolizing enzyme genes, in addition to nongenetic factors, were important determinants of warfarin dose requirements.
Clinical Pharmacology & Therapeutics (2006) 79, 291–302; doi: 10.1016/j.clpt.2005.11.011</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1016/j.clpt.2005.11.011</identifier><identifier>PMID: 16580898</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>New York, NY: Nature Publishing</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Anticoagulants - administration & dosage ; Anticoagulants - metabolism ; Anticoagulants - therapeutic use ; Aryl Hydrocarbon Hydroxylases - genetics ; Biological and medical sciences ; Blood Coagulation Factors - genetics ; Cytochrome P-450 CYP2C9 ; DNA Primers ; Factor VII - genetics ; Factor X - genetics ; Female ; Genotype ; Humans ; International Normalized Ratio ; Male ; Medical sciences ; Middle Aged ; Mixed Function Oxygenases - genetics ; Pharmacology. Drug treatments ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Prothrombin - genetics ; Vitamin K Epoxide Reductases ; Warfarin - administration & dosage ; Warfarin - metabolism ; Warfarin - therapeutic use</subject><ispartof>Clinical pharmacology and therapeutics, 2006-04, Vol.79 (4), p.291-302</ispartof><rights>2006 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3679-bc5f962992e2ab3cab397720261d036df44c0ceb9beb2b61fd9dcff597e6c9993</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1016%2Fj.clpt.2005.11.011$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1016%2Fj.clpt.2005.11.011$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17703211$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16580898$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aquilante, Christina L.</creatorcontrib><creatorcontrib>Langaee, Taimour Y.</creatorcontrib><creatorcontrib>Lopez, Larry M.</creatorcontrib><creatorcontrib>Yarandi, Hossein N.</creatorcontrib><creatorcontrib>Tromberg, Jennifer S.</creatorcontrib><creatorcontrib>Mohuczy, Dagmara</creatorcontrib><creatorcontrib>Gaston, Katherine L.</creatorcontrib><creatorcontrib>Waddell, Cassandra D.</creatorcontrib><creatorcontrib>Chirico, Mark J.</creatorcontrib><creatorcontrib>Johnson, Julie A.</creatorcontrib><title>Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>Introduction
The primary objective of this study was to determine whether variability in warfarin dose requirements is determined by common polymorphisms in genes whose products are involved in the pharmacodynamics and pharmacokinetics of warfarin, namely, the coagulation factors, vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 (CYP) 2C9.
Methods
Patients (N = 350) receiving stable doses of warfarin at 3 consecutive visits were enrolled, and a deoxyribonucleic acid sample was collected. Samples were genotyped for polymorphisms in the factor II, factor VII, factor X, VKORC1, and CYP2C9 genes. A stepwise linear regression analysis was used to determine the independent effects of genetic and nongenetic factors on mean warfarin dose requirements.
Results
Variables associated with lower warfarin dose requirements were VKORC1 3673 AA genotype (P < .0001), VKORC1 3673 GA genotype (P < .0001), 1 variant CYP2C9 allele (P < .0001), 2 variant CYP2C9 alleles (P = .0004), increasing age (P = .0005), concomitant CYP2C9 inhibitors (P = .0005), and goal international normalized ratio (P = .01). Variables associated with higher warfarin dose requirements were weight (P < .0001), current smoker status (P = .0009), mean international normalized ratio (P = .001), concomitant CYP2C9 inducers (P = .006), factor X insertion/deletion genotype (P = .01), factor X insertion/insertion genotype (P = .04), factor VII deletion/deletion genotype (P = .04), and calculated vitamin K intake (P = .05). The linear regression model explained 51.4% of the variability in warfarin dose requirements.
Conclusion
Polymorphisms in warfarin drug target and metabolizing enzyme genes, in addition to nongenetic factors, were important determinants of warfarin dose requirements.
Clinical Pharmacology & Therapeutics (2006) 79, 291–302; doi: 10.1016/j.clpt.2005.11.011</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Anticoagulants - administration & dosage</subject><subject>Anticoagulants - metabolism</subject><subject>Anticoagulants - therapeutic use</subject><subject>Aryl Hydrocarbon Hydroxylases - genetics</subject><subject>Biological and medical sciences</subject><subject>Blood Coagulation Factors - genetics</subject><subject>Cytochrome P-450 CYP2C9</subject><subject>DNA Primers</subject><subject>Factor VII - genetics</subject><subject>Factor X - genetics</subject><subject>Female</subject><subject>Genotype</subject><subject>Humans</subject><subject>International Normalized Ratio</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Mixed Function Oxygenases - genetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Polymerase Chain Reaction</subject><subject>Polymorphism, Genetic</subject><subject>Prothrombin - genetics</subject><subject>Vitamin K Epoxide Reductases</subject><subject>Warfarin - administration & dosage</subject><subject>Warfarin - metabolism</subject><subject>Warfarin - therapeutic use</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkctu1DAUQC0EokPhB1ggb2DVBD8mTrxBQhGPipGYxbC2HOe69ciJUzuhnT_p59bDjNQtC8uyde65i4PQe0pKSqj4vC-Nn-aSEVKVlJaE0hdoRSvOClHx6iVaEUJkIRkXF-hNSvv8XMumeY0uqKga0shmhR6vR-sXGA3gYLEJ-mbxenZhxFabOcQr_NfNenAj_oVhCg-uBxyhX8ysE2R-mDw84LR0y-hmTK-wHntsDnMwtzEMgLfrimDWSnwDI-Ap-MMQ4nTr0pBwXnKvo9Ux2_uQjuK7xUUYYJzTW_TKap_g3fm-RH--f9u1P4vN7x_X7ddNYbioZdGZykrBpGTAdMdNPrKuGWGC9oSL3q7XhhjoZAcd6wS1veyNtZWsQRgpJb9En07eKYa7BdKsBpcMeK9HCEtSom4YrUiTQXYCTQwpRbBqim7Q8aAoUcceaq-OPdSxh6JU5R556MPZvnQD9M8j5wAZ-HgGdDLa26hH49IzV9eEs3-iLyfu3nk4_Mdq1W537Wa7y1-CM8mfAF-7qo0</recordid><startdate>200604</startdate><enddate>200604</enddate><creator>Aquilante, Christina L.</creator><creator>Langaee, Taimour Y.</creator><creator>Lopez, Larry M.</creator><creator>Yarandi, Hossein N.</creator><creator>Tromberg, Jennifer S.</creator><creator>Mohuczy, Dagmara</creator><creator>Gaston, Katherine L.</creator><creator>Waddell, Cassandra D.</creator><creator>Chirico, Mark J.</creator><creator>Johnson, Julie A.</creator><general>Nature Publishing</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200604</creationdate><title>Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements</title><author>Aquilante, Christina L. ; Langaee, Taimour Y. ; Lopez, Larry M. ; Yarandi, Hossein N. ; Tromberg, Jennifer S. ; Mohuczy, Dagmara ; Gaston, Katherine L. ; Waddell, Cassandra D. ; Chirico, Mark J. ; Johnson, Julie A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3679-bc5f962992e2ab3cab397720261d036df44c0ceb9beb2b61fd9dcff597e6c9993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Anticoagulants - administration & dosage</topic><topic>Anticoagulants - metabolism</topic><topic>Anticoagulants - therapeutic use</topic><topic>Aryl Hydrocarbon Hydroxylases - genetics</topic><topic>Biological and medical sciences</topic><topic>Blood Coagulation Factors - genetics</topic><topic>Cytochrome P-450 CYP2C9</topic><topic>DNA Primers</topic><topic>Factor VII - genetics</topic><topic>Factor X - genetics</topic><topic>Female</topic><topic>Genotype</topic><topic>Humans</topic><topic>International Normalized Ratio</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Mixed Function Oxygenases - genetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Polymerase Chain Reaction</topic><topic>Polymorphism, Genetic</topic><topic>Prothrombin - genetics</topic><topic>Vitamin K Epoxide Reductases</topic><topic>Warfarin - administration & dosage</topic><topic>Warfarin - metabolism</topic><topic>Warfarin - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aquilante, Christina L.</creatorcontrib><creatorcontrib>Langaee, Taimour Y.</creatorcontrib><creatorcontrib>Lopez, Larry M.</creatorcontrib><creatorcontrib>Yarandi, Hossein N.</creatorcontrib><creatorcontrib>Tromberg, Jennifer S.</creatorcontrib><creatorcontrib>Mohuczy, Dagmara</creatorcontrib><creatorcontrib>Gaston, Katherine L.</creatorcontrib><creatorcontrib>Waddell, Cassandra D.</creatorcontrib><creatorcontrib>Chirico, Mark J.</creatorcontrib><creatorcontrib>Johnson, Julie A.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Aquilante, Christina L.</au><au>Langaee, Taimour Y.</au><au>Lopez, Larry M.</au><au>Yarandi, Hossein N.</au><au>Tromberg, Jennifer S.</au><au>Mohuczy, Dagmara</au><au>Gaston, Katherine L.</au><au>Waddell, Cassandra D.</au><au>Chirico, Mark J.</au><au>Johnson, Julie A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2006-04</date><risdate>2006</risdate><volume>79</volume><issue>4</issue><spage>291</spage><epage>302</epage><pages>291-302</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>Introduction
The primary objective of this study was to determine whether variability in warfarin dose requirements is determined by common polymorphisms in genes whose products are involved in the pharmacodynamics and pharmacokinetics of warfarin, namely, the coagulation factors, vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 (CYP) 2C9.
Methods
Patients (N = 350) receiving stable doses of warfarin at 3 consecutive visits were enrolled, and a deoxyribonucleic acid sample was collected. Samples were genotyped for polymorphisms in the factor II, factor VII, factor X, VKORC1, and CYP2C9 genes. A stepwise linear regression analysis was used to determine the independent effects of genetic and nongenetic factors on mean warfarin dose requirements.
Results
Variables associated with lower warfarin dose requirements were VKORC1 3673 AA genotype (P < .0001), VKORC1 3673 GA genotype (P < .0001), 1 variant CYP2C9 allele (P < .0001), 2 variant CYP2C9 alleles (P = .0004), increasing age (P = .0005), concomitant CYP2C9 inhibitors (P = .0005), and goal international normalized ratio (P = .01). Variables associated with higher warfarin dose requirements were weight (P < .0001), current smoker status (P = .0009), mean international normalized ratio (P = .001), concomitant CYP2C9 inducers (P = .006), factor X insertion/deletion genotype (P = .01), factor X insertion/insertion genotype (P = .04), factor VII deletion/deletion genotype (P = .04), and calculated vitamin K intake (P = .05). The linear regression model explained 51.4% of the variability in warfarin dose requirements.
Conclusion
Polymorphisms in warfarin drug target and metabolizing enzyme genes, in addition to nongenetic factors, were important determinants of warfarin dose requirements.
Clinical Pharmacology & Therapeutics (2006) 79, 291–302; doi: 10.1016/j.clpt.2005.11.011</abstract><cop>New York, NY</cop><pub>Nature Publishing</pub><pmid>16580898</pmid><doi>10.1016/j.clpt.2005.11.011</doi><tpages>12</tpages></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adult Aged Aged, 80 and over Anticoagulants - administration & dosage Anticoagulants - metabolism Anticoagulants - therapeutic use Aryl Hydrocarbon Hydroxylases - genetics Biological and medical sciences Blood Coagulation Factors - genetics Cytochrome P-450 CYP2C9 DNA Primers Factor VII - genetics Factor X - genetics Female Genotype Humans International Normalized Ratio Male Medical sciences Middle Aged Mixed Function Oxygenases - genetics Pharmacology. Drug treatments Polymerase Chain Reaction Polymorphism, Genetic Prothrombin - genetics Vitamin K Epoxide Reductases Warfarin - administration & dosage Warfarin - metabolism Warfarin - therapeutic use |
| title | Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements |
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