Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients
Background Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to...
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| description | Background
Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to tailor the warfarin dosage in the European, Asian and African-American populations. However, minimal interest was directed towards Middle East countries. The factors affecting warfarin dose requirement could be different in patients from different geographical and ethnic groups, limiting the value of published dosing algorithms.
Objective
The first objective of this study was to examine the contribution of genetic and nongenetic factors on the variability of warfarin dose requirements in the Egyptian population using an easy, cost-effective and rapid analysis of vitamin K epoxide reductase complex subunit 1 (
VKORC1
) and cytochrome P450 (
CYP
)
2C9
single nucleotide polymorphism (SNP) genotyping of patients. A second objective was to develop and validate an algorithm for warfarin dose prediction that is tailored to Egyptian patients.
Methods
Eighty-four patients, 41 males and 43 females, with a median (25th–75th percentiles) age of 39 (31–48) years were recruited in this study. Fifty patients whose international normalised ratio (INR) was in the range of 2–3 were allocated to a study cohort. SYBR Green-based multiplex allele-specific real-time PCR was used for genotyping of
CYP2C9
(1075A>C) and
VKORC1
(1173C>T) polymorphisms. Linear regression analysis, including the variables age, gender,
CYP2C9
and
VKORC1
SNP genotypes, was run to derive the best model for estimating the warfarin dose that achieves an INR of 2–3. The new warfarin dosing algorithm was examined in a second cohort of patients (
n
= 34) to check its validity. The predicted dose requirements for a subgroup of our patients were calculated according to Gage and International Warfarin Pharmacogenetics Consortium (IWPC) algorithms available at
http://www.warfarindosing.org.
Results
In the study cohort, warfarin dose/week in
VKORC1
TT subjects was statistically significantly lower than in
VKORC1
CC/CT subjects (
p
= 0.032), while there was no statistically significant difference in warfarin dose/week between
CYP2C9
*1*1 and *1*3 (
p
= 0.925). A multivariate stepwise linear regression analysis revealed that age and
VKORC1
had independent and significant contributions to the overall variability in wa |
| doi_str_mv | 10.1007/s40291-013-0046-3 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_1566321830</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3446986941</sourcerecordid><originalsourceid>FETCH-LOGICAL-c372t-b99f396ef44f4e9f41e96b311db0d0c33d59e4b06ec8a654c62dd3836d0243fb3</originalsourceid><addsrcrecordid>eNp1kMtOAyEUhonRWG8P4MaQuEYPl6Fl6aVWE41dWF0SZoBxajuMMF349lKrxo0rSM73_yfnQ-iYwhkFGJ4nAUxRApQTACEJ30J7lA4VYQCw_fUfEgqSDdB-SvPMFFKxXTRgfMTVCOgess9m0VjTN6HFwWODpzF0ITmLX0z0JjYtvg6paWt8sahDbPrXJb4063kO9K8OT1zr-qbCD-bNkVm3LhnXH13fmBZPc69r-3SIdrxZJHf0_R6g2c346eqW3D9O7q4u7knFh6wnpVKeK-m8EF445QV1SpacUluChYpzWygnSpCuGhlZiEoya_Ml0gIT3Jf8AJ1uersY3lcu9XoeVrHNKzUtpOSMjjhkim6oKoaUovO6i83SxA9NQa-96o1Xnb3qtVfNc-bku3lVLp39TfyIzADbACmP2trFP6v_bf0ER_GCFA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1566321830</pqid></control><display><type>article</type><title>Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients</title><source>MEDLINE</source><source>Springer Journals</source><creator>Ekladious, Sherif M. M. ; Issac, Marianne Samir M. ; Sharaf, Sahar Abd El-Atty ; Abou-Youssef, Hazem S.</creator><creatorcontrib>Ekladious, Sherif M. M. ; Issac, Marianne Samir M. ; Sharaf, Sahar Abd El-Atty ; Abou-Youssef, Hazem S.</creatorcontrib><description>Background
Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to tailor the warfarin dosage in the European, Asian and African-American populations. However, minimal interest was directed towards Middle East countries. The factors affecting warfarin dose requirement could be different in patients from different geographical and ethnic groups, limiting the value of published dosing algorithms.
Objective
The first objective of this study was to examine the contribution of genetic and nongenetic factors on the variability of warfarin dose requirements in the Egyptian population using an easy, cost-effective and rapid analysis of vitamin K epoxide reductase complex subunit 1 (
VKORC1
) and cytochrome P450 (
CYP
)
2C9
single nucleotide polymorphism (SNP) genotyping of patients. A second objective was to develop and validate an algorithm for warfarin dose prediction that is tailored to Egyptian patients.
Methods
Eighty-four patients, 41 males and 43 females, with a median (25th–75th percentiles) age of 39 (31–48) years were recruited in this study. Fifty patients whose international normalised ratio (INR) was in the range of 2–3 were allocated to a study cohort. SYBR Green-based multiplex allele-specific real-time PCR was used for genotyping of
CYP2C9
(1075A>C) and
VKORC1
(1173C>T) polymorphisms. Linear regression analysis, including the variables age, gender,
CYP2C9
and
VKORC1
SNP genotypes, was run to derive the best model for estimating the warfarin dose that achieves an INR of 2–3. The new warfarin dosing algorithm was examined in a second cohort of patients (
n
= 34) to check its validity. The predicted dose requirements for a subgroup of our patients were calculated according to Gage and International Warfarin Pharmacogenetics Consortium (IWPC) algorithms available at
http://www.warfarindosing.org.
Results
In the study cohort, warfarin dose/week in
VKORC1
TT subjects was statistically significantly lower than in
VKORC1
CC/CT subjects (
p
= 0.032), while there was no statistically significant difference in warfarin dose/week between
CYP2C9
*1*1 and *1*3 (
p
= 0.925). A multivariate stepwise linear regression analysis revealed that age and
VKORC1
had independent and significant contributions to the overall variability in warfarin dose with a
p
-value = 0.013 and 0.042, respectively. Maintenance dose (mg/week) = 65.226 − 0.422 × (age) − 9.474 × (
VKORC1
). The estimated regression equation was able to account for 20.5 % of the overall variability in warfarin maintenance dose. A significant positive correlation, with sufficient strength, was observed between the predicted warfarin dose and the actual prescribed dose (
r
= 0.453,
p
= 0.001). In the validation cohort, after application of the dosing algorithm, correlation between predicted and actual dose was statistically significant (
p
= 0.023). The equation was particularly successful among patients with a dose ≥35 mg/week. The correlation coefficient between the actual and predicted doses for IWPC and Gage were 0.304 and 0.276, respectively. When compared with our algorithm (
r
= 0.279), the difference was non-significant:
p
= 0.903 and 0.990, respectively.
Conclusion
VKORC1
(1173C>T) contributes to the warfarin dose variability. Patients’ age and genetic variants of
VKORC1
account for nearly 20.5 % of the variability in warfarin dose required to achieve an INR of 2–3. The success of a prediction equation based on these variables was proved in a different cohort: the predicted dose correlated significantly with the maintenance dose and the equation was more successful among patients with a dose ≥35 mg/week. The results of the warfarin algorithm we developed were comparable with those of the IWPC and Gage algorithms with the advantage of using one SNP (
VKORC1
1173C>T) only. This represents an economic advantage in our community. Replication of this study in a larger cohort of patients is necessary before translation of this knowledge into clinical guidelines for warfarin prescription.</description><identifier>ISSN: 1177-1062</identifier><identifier>EISSN: 1179-2000</identifier><identifier>DOI: 10.1007/s40291-013-0046-3</identifier><identifier>PMID: 23839801</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Adult ; Age ; Algorithms ; Anticoagulants ; Anticoagulants - administration & dosage ; Aryl Hydrocarbon Hydroxylases - genetics ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cohort Studies ; Cytochrome P-450 CYP2C9 ; Dose-Response Relationship, Drug ; Drug therapy ; Egypt ; Female ; Genetic Variation ; Genotype ; Human Genetics ; Humans ; Laboratories ; Laboratory Medicine ; Male ; Medical records ; Methods ; Middle Aged ; Molecular Medicine ; Original Research Article ; Patient safety ; Pharmacogenetics ; Pharmacotherapy ; Polymorphism ; Polymorphism, Single Nucleotide ; Studies ; Vitamin K Epoxide Reductases - genetics ; Warfarin - administration & dosage</subject><ispartof>Molecular diagnosis & therapy, 2013-12, Vol.17 (6), p.381-390</ispartof><rights>Springer International Publishing Switzerland 2013</rights><rights>Copyright Wolters Kluwer Health Adis International Dec 2013</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-b99f396ef44f4e9f41e96b311db0d0c33d59e4b06ec8a654c62dd3836d0243fb3</citedby><cites>FETCH-LOGICAL-c372t-b99f396ef44f4e9f41e96b311db0d0c33d59e4b06ec8a654c62dd3836d0243fb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s40291-013-0046-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s40291-013-0046-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23839801$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ekladious, Sherif M. M.</creatorcontrib><creatorcontrib>Issac, Marianne Samir M.</creatorcontrib><creatorcontrib>Sharaf, Sahar Abd El-Atty</creatorcontrib><creatorcontrib>Abou-Youssef, Hazem S.</creatorcontrib><title>Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients</title><title>Molecular diagnosis & therapy</title><addtitle>Mol Diagn Ther</addtitle><addtitle>Mol Diagn Ther</addtitle><description>Background
Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to tailor the warfarin dosage in the European, Asian and African-American populations. However, minimal interest was directed towards Middle East countries. The factors affecting warfarin dose requirement could be different in patients from different geographical and ethnic groups, limiting the value of published dosing algorithms.
Objective
The first objective of this study was to examine the contribution of genetic and nongenetic factors on the variability of warfarin dose requirements in the Egyptian population using an easy, cost-effective and rapid analysis of vitamin K epoxide reductase complex subunit 1 (
VKORC1
) and cytochrome P450 (
CYP
)
2C9
single nucleotide polymorphism (SNP) genotyping of patients. A second objective was to develop and validate an algorithm for warfarin dose prediction that is tailored to Egyptian patients.
Methods
Eighty-four patients, 41 males and 43 females, with a median (25th–75th percentiles) age of 39 (31–48) years were recruited in this study. Fifty patients whose international normalised ratio (INR) was in the range of 2–3 were allocated to a study cohort. SYBR Green-based multiplex allele-specific real-time PCR was used for genotyping of
CYP2C9
(1075A>C) and
VKORC1
(1173C>T) polymorphisms. Linear regression analysis, including the variables age, gender,
CYP2C9
and
VKORC1
SNP genotypes, was run to derive the best model for estimating the warfarin dose that achieves an INR of 2–3. The new warfarin dosing algorithm was examined in a second cohort of patients (
n
= 34) to check its validity. The predicted dose requirements for a subgroup of our patients were calculated according to Gage and International Warfarin Pharmacogenetics Consortium (IWPC) algorithms available at
http://www.warfarindosing.org.
Results
In the study cohort, warfarin dose/week in
VKORC1
TT subjects was statistically significantly lower than in
VKORC1
CC/CT subjects (
p
= 0.032), while there was no statistically significant difference in warfarin dose/week between
CYP2C9
*1*1 and *1*3 (
p
= 0.925). A multivariate stepwise linear regression analysis revealed that age and
VKORC1
had independent and significant contributions to the overall variability in warfarin dose with a
p
-value = 0.013 and 0.042, respectively. Maintenance dose (mg/week) = 65.226 − 0.422 × (age) − 9.474 × (
VKORC1
). The estimated regression equation was able to account for 20.5 % of the overall variability in warfarin maintenance dose. A significant positive correlation, with sufficient strength, was observed between the predicted warfarin dose and the actual prescribed dose (
r
= 0.453,
p
= 0.001). In the validation cohort, after application of the dosing algorithm, correlation between predicted and actual dose was statistically significant (
p
= 0.023). The equation was particularly successful among patients with a dose ≥35 mg/week. The correlation coefficient between the actual and predicted doses for IWPC and Gage were 0.304 and 0.276, respectively. When compared with our algorithm (
r
= 0.279), the difference was non-significant:
p
= 0.903 and 0.990, respectively.
Conclusion
VKORC1
(1173C>T) contributes to the warfarin dose variability. Patients’ age and genetic variants of
VKORC1
account for nearly 20.5 % of the variability in warfarin dose required to achieve an INR of 2–3. The success of a prediction equation based on these variables was proved in a different cohort: the predicted dose correlated significantly with the maintenance dose and the equation was more successful among patients with a dose ≥35 mg/week. The results of the warfarin algorithm we developed were comparable with those of the IWPC and Gage algorithms with the advantage of using one SNP (
VKORC1
1173C>T) only. This represents an economic advantage in our community. Replication of this study in a larger cohort of patients is necessary before translation of this knowledge into clinical guidelines for warfarin prescription.</description><subject>Adult</subject><subject>Age</subject><subject>Algorithms</subject><subject>Anticoagulants</subject><subject>Anticoagulants - administration & dosage</subject><subject>Aryl Hydrocarbon Hydroxylases - genetics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cohort Studies</subject><subject>Cytochrome P-450 CYP2C9</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug therapy</subject><subject>Egypt</subject><subject>Female</subject><subject>Genetic Variation</subject><subject>Genotype</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Laboratories</subject><subject>Laboratory Medicine</subject><subject>Male</subject><subject>Medical records</subject><subject>Methods</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Original Research Article</subject><subject>Patient safety</subject><subject>Pharmacogenetics</subject><subject>Pharmacotherapy</subject><subject>Polymorphism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Studies</subject><subject>Vitamin K Epoxide Reductases - genetics</subject><subject>Warfarin - administration & dosage</subject><issn>1177-1062</issn><issn>1179-2000</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kMtOAyEUhonRWG8P4MaQuEYPl6Fl6aVWE41dWF0SZoBxajuMMF349lKrxo0rSM73_yfnQ-iYwhkFGJ4nAUxRApQTACEJ30J7lA4VYQCw_fUfEgqSDdB-SvPMFFKxXTRgfMTVCOgess9m0VjTN6HFwWODpzF0ITmLX0z0JjYtvg6paWt8sahDbPrXJb4063kO9K8OT1zr-qbCD-bNkVm3LhnXH13fmBZPc69r-3SIdrxZJHf0_R6g2c346eqW3D9O7q4u7knFh6wnpVKeK-m8EF445QV1SpacUluChYpzWygnSpCuGhlZiEoya_Ml0gIT3Jf8AJ1uersY3lcu9XoeVrHNKzUtpOSMjjhkim6oKoaUovO6i83SxA9NQa-96o1Xnb3qtVfNc-bku3lVLp39TfyIzADbACmP2trFP6v_bf0ER_GCFA</recordid><startdate>201312</startdate><enddate>201312</enddate><creator>Ekladious, Sherif M. M.</creator><creator>Issac, Marianne Samir M.</creator><creator>Sharaf, Sahar Abd El-Atty</creator><creator>Abou-Youssef, Hazem S.</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><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>3V.</scope><scope>4T-</scope><scope>7QO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>201312</creationdate><title>Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients</title><author>Ekladious, Sherif M. M. ; Issac, Marianne Samir M. ; Sharaf, Sahar Abd El-Atty ; Abou-Youssef, Hazem S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-b99f396ef44f4e9f41e96b311db0d0c33d59e4b06ec8a654c62dd3836d0243fb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Age</topic><topic>Algorithms</topic><topic>Anticoagulants</topic><topic>Anticoagulants - administration & dosage</topic><topic>Aryl Hydrocarbon Hydroxylases - genetics</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Cohort Studies</topic><topic>Cytochrome P-450 CYP2C9</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug therapy</topic><topic>Egypt</topic><topic>Female</topic><topic>Genetic Variation</topic><topic>Genotype</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Laboratories</topic><topic>Laboratory Medicine</topic><topic>Male</topic><topic>Medical records</topic><topic>Methods</topic><topic>Middle Aged</topic><topic>Molecular Medicine</topic><topic>Original Research Article</topic><topic>Patient safety</topic><topic>Pharmacogenetics</topic><topic>Pharmacotherapy</topic><topic>Polymorphism</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Studies</topic><topic>Vitamin K Epoxide Reductases - genetics</topic><topic>Warfarin - administration & dosage</topic><toplevel>online_resources</toplevel><creatorcontrib>Ekladious, Sherif M. M.</creatorcontrib><creatorcontrib>Issac, Marianne Samir M.</creatorcontrib><creatorcontrib>Sharaf, Sahar Abd El-Atty</creatorcontrib><creatorcontrib>Abou-Youssef, Hazem S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Docstoc</collection><collection>Biotechnology Research Abstracts</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Molecular diagnosis & therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ekladious, Sherif M. M.</au><au>Issac, Marianne Samir M.</au><au>Sharaf, Sahar Abd El-Atty</au><au>Abou-Youssef, Hazem S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients</atitle><jtitle>Molecular diagnosis & therapy</jtitle><stitle>Mol Diagn Ther</stitle><addtitle>Mol Diagn Ther</addtitle><date>2013-12</date><risdate>2013</risdate><volume>17</volume><issue>6</issue><spage>381</spage><epage>390</epage><pages>381-390</pages><issn>1177-1062</issn><eissn>1179-2000</eissn><abstract>Background
Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to tailor the warfarin dosage in the European, Asian and African-American populations. However, minimal interest was directed towards Middle East countries. The factors affecting warfarin dose requirement could be different in patients from different geographical and ethnic groups, limiting the value of published dosing algorithms.
Objective
The first objective of this study was to examine the contribution of genetic and nongenetic factors on the variability of warfarin dose requirements in the Egyptian population using an easy, cost-effective and rapid analysis of vitamin K epoxide reductase complex subunit 1 (
VKORC1
) and cytochrome P450 (
CYP
)
2C9
single nucleotide polymorphism (SNP) genotyping of patients. A second objective was to develop and validate an algorithm for warfarin dose prediction that is tailored to Egyptian patients.
Methods
Eighty-four patients, 41 males and 43 females, with a median (25th–75th percentiles) age of 39 (31–48) years were recruited in this study. Fifty patients whose international normalised ratio (INR) was in the range of 2–3 were allocated to a study cohort. SYBR Green-based multiplex allele-specific real-time PCR was used for genotyping of
CYP2C9
(1075A>C) and
VKORC1
(1173C>T) polymorphisms. Linear regression analysis, including the variables age, gender,
CYP2C9
and
VKORC1
SNP genotypes, was run to derive the best model for estimating the warfarin dose that achieves an INR of 2–3. The new warfarin dosing algorithm was examined in a second cohort of patients (
n
= 34) to check its validity. The predicted dose requirements for a subgroup of our patients were calculated according to Gage and International Warfarin Pharmacogenetics Consortium (IWPC) algorithms available at
http://www.warfarindosing.org.
Results
In the study cohort, warfarin dose/week in
VKORC1
TT subjects was statistically significantly lower than in
VKORC1
CC/CT subjects (
p
= 0.032), while there was no statistically significant difference in warfarin dose/week between
CYP2C9
*1*1 and *1*3 (
p
= 0.925). A multivariate stepwise linear regression analysis revealed that age and
VKORC1
had independent and significant contributions to the overall variability in warfarin dose with a
p
-value = 0.013 and 0.042, respectively. Maintenance dose (mg/week) = 65.226 − 0.422 × (age) − 9.474 × (
VKORC1
). The estimated regression equation was able to account for 20.5 % of the overall variability in warfarin maintenance dose. A significant positive correlation, with sufficient strength, was observed between the predicted warfarin dose and the actual prescribed dose (
r
= 0.453,
p
= 0.001). In the validation cohort, after application of the dosing algorithm, correlation between predicted and actual dose was statistically significant (
p
= 0.023). The equation was particularly successful among patients with a dose ≥35 mg/week. The correlation coefficient between the actual and predicted doses for IWPC and Gage were 0.304 and 0.276, respectively. When compared with our algorithm (
r
= 0.279), the difference was non-significant:
p
= 0.903 and 0.990, respectively.
Conclusion
VKORC1
(1173C>T) contributes to the warfarin dose variability. Patients’ age and genetic variants of
VKORC1
account for nearly 20.5 % of the variability in warfarin dose required to achieve an INR of 2–3. The success of a prediction equation based on these variables was proved in a different cohort: the predicted dose correlated significantly with the maintenance dose and the equation was more successful among patients with a dose ≥35 mg/week. The results of the warfarin algorithm we developed were comparable with those of the IWPC and Gage algorithms with the advantage of using one SNP (
VKORC1
1173C>T) only. This represents an economic advantage in our community. Replication of this study in a larger cohort of patients is necessary before translation of this knowledge into clinical guidelines for warfarin prescription.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>23839801</pmid><doi>10.1007/s40291-013-0046-3</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1177-1062 |
| ispartof | Molecular diagnosis & therapy, 2013-12, Vol.17 (6), p.381-390 |
| issn | 1177-1062 1179-2000 |
| language | eng |
| recordid | cdi_proquest_journals_1566321830 |
| source | MEDLINE; Springer Journals |
| subjects | Adult Age Algorithms Anticoagulants Anticoagulants - administration & dosage Aryl Hydrocarbon Hydroxylases - genetics Biomedical and Life Sciences Biomedicine Cancer Research Cohort Studies Cytochrome P-450 CYP2C9 Dose-Response Relationship, Drug Drug therapy Egypt Female Genetic Variation Genotype Human Genetics Humans Laboratories Laboratory Medicine Male Medical records Methods Middle Aged Molecular Medicine Original Research Article Patient safety Pharmacogenetics Pharmacotherapy Polymorphism Polymorphism, Single Nucleotide Studies Vitamin K Epoxide Reductases - genetics Warfarin - administration & dosage |
| title | Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-11T16%3A31%3A22IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Validation%20of%20a%20Proposed%20Warfarin%20Dosing%20Algorithm%20Based%20on%20the%20Genetic%20Make-Up%20of%20Egyptian%20Patients&rft.jtitle=Molecular%20diagnosis%20&%20therapy&rft.au=Ekladious,%20Sherif%20M.%20M.&rft.date=2013-12&rft.volume=17&rft.issue=6&rft.spage=381&rft.epage=390&rft.pages=381-390&rft.issn=1177-1062&rft.eissn=1179-2000&rft_id=info:doi/10.1007/s40291-013-0046-3&rft_dat=%3Cproquest_cross%3E3446986941%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1566321830&rft_id=info:pmid/23839801&rfr_iscdi=true |