Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes
The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients. To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and...
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Veröffentlicht in: | The Annals of pharmacotherapy 2012-02, Vol.46 (2), p.208-218 |
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creator | Valentin, Isa Ivette Vazquez, Joan Rivera-Miranda, Giselle Seip, Richard L Velez, Meredith Kocherla, Mohan Bogaard, Kali Cruz-Gonzalez, Iadelisse Cadilla, Carmen L Renta, Jessica Y Feliu, Juan F Ramos, Alga S Alejandro-Cowan, Yirelia Gorowski, Krystyna Ruaño, Gualberto Duconge, Jorge |
description | The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients.
To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm.
A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested.
Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients.
This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm. |
doi_str_mv | 10.1345/aph.1Q190 |
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To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm.
A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested.
Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients.
This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.</description><identifier>ISSN: 1060-0280</identifier><identifier>EISSN: 1542-6270</identifier><identifier>DOI: 10.1345/aph.1Q190</identifier><identifier>PMID: 22274142</identifier><language>eng</language><publisher>United States</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Anticoagulants - administration & dosage ; Aryl Hydrocarbon Hydroxylases - genetics ; Cytochrome P-450 CYP2C9 ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Mixed Function Oxygenases - genetics ; Puerto Rico - ethnology ; Vitamin K Epoxide Reductases ; Warfarin - administration & dosage</subject><ispartof>The Annals of pharmacotherapy, 2012-02, Vol.46 (2), p.208-218</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c2190-24556ec3d19f01823c39290b2b1df0e39c2d3baf48ef898ea50cce57f8fd83a53</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22274142$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Valentin, Isa Ivette</creatorcontrib><creatorcontrib>Vazquez, Joan</creatorcontrib><creatorcontrib>Rivera-Miranda, Giselle</creatorcontrib><creatorcontrib>Seip, Richard L</creatorcontrib><creatorcontrib>Velez, Meredith</creatorcontrib><creatorcontrib>Kocherla, Mohan</creatorcontrib><creatorcontrib>Bogaard, Kali</creatorcontrib><creatorcontrib>Cruz-Gonzalez, Iadelisse</creatorcontrib><creatorcontrib>Cadilla, Carmen L</creatorcontrib><creatorcontrib>Renta, Jessica Y</creatorcontrib><creatorcontrib>Feliu, Juan F</creatorcontrib><creatorcontrib>Ramos, Alga S</creatorcontrib><creatorcontrib>Alejandro-Cowan, Yirelia</creatorcontrib><creatorcontrib>Gorowski, Krystyna</creatorcontrib><creatorcontrib>Ruaño, Gualberto</creatorcontrib><creatorcontrib>Duconge, Jorge</creatorcontrib><title>Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes</title><title>The Annals of pharmacotherapy</title><addtitle>Ann Pharmacother</addtitle><description>The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients.
To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm.
A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested.
Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients.
This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Anticoagulants - administration & dosage</subject><subject>Aryl Hydrocarbon Hydroxylases - genetics</subject><subject>Cytochrome P-450 CYP2C9</subject><subject>Female</subject><subject>Genotype</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mixed Function Oxygenases - genetics</subject><subject>Puerto Rico - ethnology</subject><subject>Vitamin K Epoxide Reductases</subject><subject>Warfarin - administration & dosage</subject><issn>1060-0280</issn><issn>1542-6270</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUV1LHTEQDVJRa33oHyh5K4WuTSa7dzcvhbKoLQreSlvwKWSTiabsTdZkt8V_b_ykfZphzpkzZziEvOXskIu6-aSn60P-nUu2RfZ4U0O1gpa9Kj1bsYpBx3bJ65x_M8YkB7lDdgGgrXkNeySvE1pvZh8DjY7-1cnp5AO1MSMt0PIAZVpG6wXTHOmFNzrQSc8ew5w_0kFntLSsm7gZfNBzTF6PtL9cQy-pDpb-Oj2_6Dm9whDn2wnzG7Lt9Jjx4Knuk5_HRz_6r9XZ-cm3_stZZaD8UkHdNCs0wnLpGO9AGCFBsgEGbh1DIQ1YMWhXd-g62aFumDHYtK5zthO6Efvk86PutAwbtKb4TXpUU_IbnW5V1F79jwR_ra7iHyVE27UAReD9k0CKNwvmWW18NjiOOmBcspLAeV2vGlGYHx6ZJsWcE7qXK5yp-4xUyUg9ZFS47_619cJ8DkXcATDVjmc</recordid><startdate>201202</startdate><enddate>201202</enddate><creator>Valentin, Isa Ivette</creator><creator>Vazquez, Joan</creator><creator>Rivera-Miranda, Giselle</creator><creator>Seip, Richard L</creator><creator>Velez, Meredith</creator><creator>Kocherla, Mohan</creator><creator>Bogaard, Kali</creator><creator>Cruz-Gonzalez, Iadelisse</creator><creator>Cadilla, Carmen L</creator><creator>Renta, Jessica Y</creator><creator>Feliu, Juan F</creator><creator>Ramos, Alga S</creator><creator>Alejandro-Cowan, Yirelia</creator><creator>Gorowski, Krystyna</creator><creator>Ruaño, Gualberto</creator><creator>Duconge, Jorge</creator><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><scope>5PM</scope></search><sort><creationdate>201202</creationdate><title>Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes</title><author>Valentin, Isa Ivette ; Vazquez, Joan ; Rivera-Miranda, Giselle ; Seip, Richard L ; Velez, Meredith ; Kocherla, Mohan ; Bogaard, Kali ; Cruz-Gonzalez, Iadelisse ; Cadilla, Carmen L ; Renta, Jessica Y ; Feliu, Juan F ; Ramos, Alga S ; Alejandro-Cowan, Yirelia ; Gorowski, Krystyna ; Ruaño, Gualberto ; Duconge, Jorge</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2190-24556ec3d19f01823c39290b2b1df0e39c2d3baf48ef898ea50cce57f8fd83a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Anticoagulants - administration & dosage</topic><topic>Aryl Hydrocarbon Hydroxylases - genetics</topic><topic>Cytochrome P-450 CYP2C9</topic><topic>Female</topic><topic>Genotype</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mixed Function Oxygenases - genetics</topic><topic>Puerto Rico - ethnology</topic><topic>Vitamin K Epoxide Reductases</topic><topic>Warfarin - administration & dosage</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Valentin, Isa Ivette</creatorcontrib><creatorcontrib>Vazquez, Joan</creatorcontrib><creatorcontrib>Rivera-Miranda, Giselle</creatorcontrib><creatorcontrib>Seip, Richard L</creatorcontrib><creatorcontrib>Velez, Meredith</creatorcontrib><creatorcontrib>Kocherla, Mohan</creatorcontrib><creatorcontrib>Bogaard, Kali</creatorcontrib><creatorcontrib>Cruz-Gonzalez, Iadelisse</creatorcontrib><creatorcontrib>Cadilla, Carmen L</creatorcontrib><creatorcontrib>Renta, Jessica Y</creatorcontrib><creatorcontrib>Feliu, Juan F</creatorcontrib><creatorcontrib>Ramos, Alga S</creatorcontrib><creatorcontrib>Alejandro-Cowan, Yirelia</creatorcontrib><creatorcontrib>Gorowski, Krystyna</creatorcontrib><creatorcontrib>Ruaño, Gualberto</creatorcontrib><creatorcontrib>Duconge, Jorge</creatorcontrib><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Annals of pharmacotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Valentin, Isa Ivette</au><au>Vazquez, Joan</au><au>Rivera-Miranda, Giselle</au><au>Seip, Richard L</au><au>Velez, Meredith</au><au>Kocherla, Mohan</au><au>Bogaard, Kali</au><au>Cruz-Gonzalez, Iadelisse</au><au>Cadilla, Carmen L</au><au>Renta, Jessica Y</au><au>Feliu, Juan F</au><au>Ramos, Alga S</au><au>Alejandro-Cowan, Yirelia</au><au>Gorowski, Krystyna</au><au>Ruaño, Gualberto</au><au>Duconge, Jorge</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes</atitle><jtitle>The Annals of pharmacotherapy</jtitle><addtitle>Ann Pharmacother</addtitle><date>2012-02</date><risdate>2012</risdate><volume>46</volume><issue>2</issue><spage>208</spage><epage>218</epage><pages>208-218</pages><issn>1060-0280</issn><eissn>1542-6270</eissn><abstract>The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients.
To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm.
A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested.
Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients.
This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.</abstract><cop>United States</cop><pmid>22274142</pmid><doi>10.1345/aph.1Q190</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adult Aged Aged, 80 and over Anticoagulants - administration & dosage Aryl Hydrocarbon Hydroxylases - genetics Cytochrome P-450 CYP2C9 Female Genotype Humans Male Middle Aged Mixed Function Oxygenases - genetics Puerto Rico - ethnology Vitamin K Epoxide Reductases Warfarin - administration & dosage |
title | Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes |
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