Thiopurine S-methyltransferase (TPMT) Activity Is Better Determined by Biochemical Assay Versus Genotyping in the Jewish Population
Background Thiopurine S -methyltransferase (TPMT) is a key enzyme that deactivates thiopurines, into their inactive metabolite, 6-methylmercaptopurine. Intermediate and low TPMT activity may lead to leukopenia following thiopurine treatment. The aim of this study was to determine TPMT activity and T...
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| Veröffentlicht in: | Digestive diseases and sciences 2014-06, Vol.59 (6), p.1207-1212 |
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| container_title | Digestive diseases and sciences |
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| creator | Kasirer, Yair Mevorach, Rephael Renbaum, Paul Algur, Nurit Soiferman, Devora Beeri, Rachel Rachman, Yelana Segel, Reeval Turner, Dan |
| description | Background
Thiopurine
S
-methyltransferase (TPMT) is a key enzyme that deactivates thiopurines, into their inactive metabolite, 6-methylmercaptopurine. Intermediate and low TPMT activity may lead to leukopenia following thiopurine treatment. The aim of this study was to determine TPMT activity and TPMT alleles (genotype–phenotype correlation) in Jews, aiming to develop an evidence-based pharmacogenetic assay for this population.
Methods
TPMT activity was determined in 228 Jewish volunteers by high performance liquid chromatography. Common allelic variants in the Caucasian population [TPMT*2 (G238C), TPMT *3A (G460A and A719G), TPMT* 3B (G460A) and TPMT*3C (A719G)] were tested. Phenotype–genotype correlation was examined and discordant cases were fully sequenced to identify novel genetic variants.
Results
Mean TPMT activity was 15.4 ± 4 U/ml red blood cells (range 1–34). Intermediate activity was found in 33/228 (14 %) subjects and absent activity was found in one sample (0.4 %). Only eight individuals (3.5 % of the entire cohort and 24 % of those with intermediate/low activity) were identified as carriers of a TPMT genetic variant, all of whom had the TPMT*3A allele. Sequencing the entire TPMT coding region and splice junctions in the remainder of the discordant cases did not reveal any novel variants.
Conclusion
Genotyping TPMT in Jews yields a much lower rate of variants than identified in the general Caucasian population. We conclude that a biochemical assay to determine TPMT enzymatic activity should be performed in Jews before starting thiopurine treatment in order to identify low activity subjects. |
| doi_str_mv | 10.1007/s10620-013-3008-z |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_1942215655</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A712942929</galeid><sourcerecordid>A712942929</sourcerecordid><originalsourceid>FETCH-LOGICAL-c444t-928fff0b7d0e3161b9e40db12d9a9fb3cdc429e9a6cef4e44d956bfcfce6d4343</originalsourceid><addsrcrecordid>eNqFkc1u1DAUhSMEokPhAdggS2zKIsV_ccbLaYFSVEQlBraR41xPXCX21HZA6ZYXx6MUhJAQsmRb9neuj-8piucEnxKM69eRYEFxiQkrGcbr8u5BsSJVzUpaifXDYoWJyHtCxFHxJMYbjLGsiXhcHFHOJBZ1tSp-bHvr91OwDtDncoTUz0MKykUDQUVAJ9vrj9tXaKOT_WbTjC4jOoOUIKA3kOcx6zrUzujMet3DaLUa0CZGNaOvEOIU0QU4n-a9dTtkHUo9oA_w3cYeXednB5Wsd0-LR0YNEZ7dr8fFl3dvt-fvy6tPF5fnm6tSc85TKenaGIPbusPAiCCtBI67ltBOKmlapjvNqQSphAbDgfNOVqI12mgQHWecHRcnS9198LcTxNSMNmoYBuXAT7EhklNKKlFV_0crul7XrCIkoy__Qm_8FFz-yIGqs2vC6kydLtRODdBYZ3zuss6jOzTNOzA2n29qQrMJSWUWkEWgg48xgGn2wY4qzA3BzSH9Zkm_yek3h_Sbu6x5cW9lakfofit-xZ0BugAxX7kdhD-8_rPqT54au6U</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1527928137</pqid></control><display><type>article</type><title>Thiopurine S-methyltransferase (TPMT) Activity Is Better Determined by Biochemical Assay Versus Genotyping in the Jewish Population</title><source>MEDLINE</source><source>SpringerNature Journals</source><creator>Kasirer, Yair ; Mevorach, Rephael ; Renbaum, Paul ; Algur, Nurit ; Soiferman, Devora ; Beeri, Rachel ; Rachman, Yelana ; Segel, Reeval ; Turner, Dan</creator><creatorcontrib>Kasirer, Yair ; Mevorach, Rephael ; Renbaum, Paul ; Algur, Nurit ; Soiferman, Devora ; Beeri, Rachel ; Rachman, Yelana ; Segel, Reeval ; Turner, Dan</creatorcontrib><description>Background
Thiopurine
S
-methyltransferase (TPMT) is a key enzyme that deactivates thiopurines, into their inactive metabolite, 6-methylmercaptopurine. Intermediate and low TPMT activity may lead to leukopenia following thiopurine treatment. The aim of this study was to determine TPMT activity and TPMT alleles (genotype–phenotype correlation) in Jews, aiming to develop an evidence-based pharmacogenetic assay for this population.
Methods
TPMT activity was determined in 228 Jewish volunteers by high performance liquid chromatography. Common allelic variants in the Caucasian population [TPMT*2 (G238C), TPMT *3A (G460A and A719G), TPMT* 3B (G460A) and TPMT*3C (A719G)] were tested. Phenotype–genotype correlation was examined and discordant cases were fully sequenced to identify novel genetic variants.
Results
Mean TPMT activity was 15.4 ± 4 U/ml red blood cells (range 1–34). Intermediate activity was found in 33/228 (14 %) subjects and absent activity was found in one sample (0.4 %). Only eight individuals (3.5 % of the entire cohort and 24 % of those with intermediate/low activity) were identified as carriers of a TPMT genetic variant, all of whom had the TPMT*3A allele. Sequencing the entire TPMT coding region and splice junctions in the remainder of the discordant cases did not reveal any novel variants.
Conclusion
Genotyping TPMT in Jews yields a much lower rate of variants than identified in the general Caucasian population. We conclude that a biochemical assay to determine TPMT enzymatic activity should be performed in Jews before starting thiopurine treatment in order to identify low activity subjects.</description><identifier>ISSN: 0163-2116</identifier><identifier>EISSN: 1573-2568</identifier><identifier>DOI: 10.1007/s10620-013-3008-z</identifier><identifier>PMID: 24390675</identifier><identifier>CODEN: DDSCDJ</identifier><language>eng</language><publisher>Boston: Springer US</publisher><subject>Adult ; Aged ; Biochemistry ; Ethylenediaminetetraacetic acid ; Female ; Gastroenterology ; Gene Expression Regulation, Enzymologic - physiology ; Genetic aspects ; Genetic Variation ; Genotype ; Hepatology ; High performance liquid chromatography ; Humans ; Jews ; Jews - genetics ; Male ; Medicine ; Medicine & Public Health ; Metabolites ; Methyltransferases - genetics ; Methyltransferases - metabolism ; Middle Aged ; Oncology ; Original Article ; Pharmacogenetics ; Pneumoviridae ; Transferases ; Transplant Surgery</subject><ispartof>Digestive diseases and sciences, 2014-06, Vol.59 (6), p.1207-1212</ispartof><rights>Springer Science+Business Media New York 2014</rights><rights>COPYRIGHT 2014 Springer</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c444t-928fff0b7d0e3161b9e40db12d9a9fb3cdc429e9a6cef4e44d956bfcfce6d4343</citedby><cites>FETCH-LOGICAL-c444t-928fff0b7d0e3161b9e40db12d9a9fb3cdc429e9a6cef4e44d956bfcfce6d4343</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/s10620-013-3008-z$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10620-013-3008-z$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,782,786,27933,27934,41497,42566,51328</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24390675$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kasirer, Yair</creatorcontrib><creatorcontrib>Mevorach, Rephael</creatorcontrib><creatorcontrib>Renbaum, Paul</creatorcontrib><creatorcontrib>Algur, Nurit</creatorcontrib><creatorcontrib>Soiferman, Devora</creatorcontrib><creatorcontrib>Beeri, Rachel</creatorcontrib><creatorcontrib>Rachman, Yelana</creatorcontrib><creatorcontrib>Segel, Reeval</creatorcontrib><creatorcontrib>Turner, Dan</creatorcontrib><title>Thiopurine S-methyltransferase (TPMT) Activity Is Better Determined by Biochemical Assay Versus Genotyping in the Jewish Population</title><title>Digestive diseases and sciences</title><addtitle>Dig Dis Sci</addtitle><addtitle>Dig Dis Sci</addtitle><description>Background
Thiopurine
S
-methyltransferase (TPMT) is a key enzyme that deactivates thiopurines, into their inactive metabolite, 6-methylmercaptopurine. Intermediate and low TPMT activity may lead to leukopenia following thiopurine treatment. The aim of this study was to determine TPMT activity and TPMT alleles (genotype–phenotype correlation) in Jews, aiming to develop an evidence-based pharmacogenetic assay for this population.
Methods
TPMT activity was determined in 228 Jewish volunteers by high performance liquid chromatography. Common allelic variants in the Caucasian population [TPMT*2 (G238C), TPMT *3A (G460A and A719G), TPMT* 3B (G460A) and TPMT*3C (A719G)] were tested. Phenotype–genotype correlation was examined and discordant cases were fully sequenced to identify novel genetic variants.
Results
Mean TPMT activity was 15.4 ± 4 U/ml red blood cells (range 1–34). Intermediate activity was found in 33/228 (14 %) subjects and absent activity was found in one sample (0.4 %). Only eight individuals (3.5 % of the entire cohort and 24 % of those with intermediate/low activity) were identified as carriers of a TPMT genetic variant, all of whom had the TPMT*3A allele. Sequencing the entire TPMT coding region and splice junctions in the remainder of the discordant cases did not reveal any novel variants.
Conclusion
Genotyping TPMT in Jews yields a much lower rate of variants than identified in the general Caucasian population. We conclude that a biochemical assay to determine TPMT enzymatic activity should be performed in Jews before starting thiopurine treatment in order to identify low activity subjects.</description><subject>Adult</subject><subject>Aged</subject><subject>Biochemistry</subject><subject>Ethylenediaminetetraacetic acid</subject><subject>Female</subject><subject>Gastroenterology</subject><subject>Gene Expression Regulation, Enzymologic - physiology</subject><subject>Genetic aspects</subject><subject>Genetic Variation</subject><subject>Genotype</subject><subject>Hepatology</subject><subject>High performance liquid chromatography</subject><subject>Humans</subject><subject>Jews</subject><subject>Jews - genetics</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolites</subject><subject>Methyltransferases - genetics</subject><subject>Methyltransferases - metabolism</subject><subject>Middle Aged</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pharmacogenetics</subject><subject>Pneumoviridae</subject><subject>Transferases</subject><subject>Transplant Surgery</subject><issn>0163-2116</issn><issn>1573-2568</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkc1u1DAUhSMEokPhAdggS2zKIsV_ccbLaYFSVEQlBraR41xPXCX21HZA6ZYXx6MUhJAQsmRb9neuj-8piucEnxKM69eRYEFxiQkrGcbr8u5BsSJVzUpaifXDYoWJyHtCxFHxJMYbjLGsiXhcHFHOJBZ1tSp-bHvr91OwDtDncoTUz0MKykUDQUVAJ9vrj9tXaKOT_WbTjC4jOoOUIKA3kOcx6zrUzujMet3DaLUa0CZGNaOvEOIU0QU4n-a9dTtkHUo9oA_w3cYeXednB5Wsd0-LR0YNEZ7dr8fFl3dvt-fvy6tPF5fnm6tSc85TKenaGIPbusPAiCCtBI67ltBOKmlapjvNqQSphAbDgfNOVqI12mgQHWecHRcnS9198LcTxNSMNmoYBuXAT7EhklNKKlFV_0crul7XrCIkoy__Qm_8FFz-yIGqs2vC6kydLtRODdBYZ3zuss6jOzTNOzA2n29qQrMJSWUWkEWgg48xgGn2wY4qzA3BzSH9Zkm_yek3h_Sbu6x5cW9lakfofit-xZ0BugAxX7kdhD-8_rPqT54au6U</recordid><startdate>20140601</startdate><enddate>20140601</enddate><creator>Kasirer, Yair</creator><creator>Mevorach, Rephael</creator><creator>Renbaum, Paul</creator><creator>Algur, Nurit</creator><creator>Soiferman, Devora</creator><creator>Beeri, Rachel</creator><creator>Rachman, Yelana</creator><creator>Segel, Reeval</creator><creator>Turner, Dan</creator><general>Springer US</general><general>Springer</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>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20140601</creationdate><title>Thiopurine S-methyltransferase (TPMT) Activity Is Better Determined by Biochemical Assay Versus Genotyping in the Jewish Population</title><author>Kasirer, Yair ; 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Thiopurine
S
-methyltransferase (TPMT) is a key enzyme that deactivates thiopurines, into their inactive metabolite, 6-methylmercaptopurine. Intermediate and low TPMT activity may lead to leukopenia following thiopurine treatment. The aim of this study was to determine TPMT activity and TPMT alleles (genotype–phenotype correlation) in Jews, aiming to develop an evidence-based pharmacogenetic assay for this population.
Methods
TPMT activity was determined in 228 Jewish volunteers by high performance liquid chromatography. Common allelic variants in the Caucasian population [TPMT*2 (G238C), TPMT *3A (G460A and A719G), TPMT* 3B (G460A) and TPMT*3C (A719G)] were tested. Phenotype–genotype correlation was examined and discordant cases were fully sequenced to identify novel genetic variants.
Results
Mean TPMT activity was 15.4 ± 4 U/ml red blood cells (range 1–34). Intermediate activity was found in 33/228 (14 %) subjects and absent activity was found in one sample (0.4 %). Only eight individuals (3.5 % of the entire cohort and 24 % of those with intermediate/low activity) were identified as carriers of a TPMT genetic variant, all of whom had the TPMT*3A allele. Sequencing the entire TPMT coding region and splice junctions in the remainder of the discordant cases did not reveal any novel variants.
Conclusion
Genotyping TPMT in Jews yields a much lower rate of variants than identified in the general Caucasian population. We conclude that a biochemical assay to determine TPMT enzymatic activity should be performed in Jews before starting thiopurine treatment in order to identify low activity subjects.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>24390675</pmid><doi>10.1007/s10620-013-3008-z</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0163-2116 |
| ispartof | Digestive diseases and sciences, 2014-06, Vol.59 (6), p.1207-1212 |
| issn | 0163-2116 1573-2568 |
| language | eng |
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| source | MEDLINE; SpringerNature Journals |
| subjects | Adult Aged Biochemistry Ethylenediaminetetraacetic acid Female Gastroenterology Gene Expression Regulation, Enzymologic - physiology Genetic aspects Genetic Variation Genotype Hepatology High performance liquid chromatography Humans Jews Jews - genetics Male Medicine Medicine & Public Health Metabolites Methyltransferases - genetics Methyltransferases - metabolism Middle Aged Oncology Original Article Pharmacogenetics Pneumoviridae Transferases Transplant Surgery |
| title | Thiopurine S-methyltransferase (TPMT) Activity Is Better Determined by Biochemical Assay Versus Genotyping in the Jewish Population |
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