multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease
Background Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the int...
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| Veröffentlicht in: | Journal of gastroenterology 2010-10, Vol.45 (10), p.1014-1021 |
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| creator | Ban, Hiromistu Andoh, Akira Imaeda, Hirotsugu Kobori, Ayako Bamba, Shigeki Tsujikawa, Tomoyuki Sasaki, Masaya Saito, Yasuharu Fujiyama, Yoshihide |
| description | Background Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients. Methods Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses. Results Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with the MRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype (P = 0.049). Of the 15 patients who experienced leucopenia ( |
| doi_str_mv | 10.1007/s00535-010-0248-y |
| format | Article |
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A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients. Methods Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses. Results Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with the MRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype (P = 0.049). Of the 15 patients who experienced leucopenia (<3 × 10⁹/l), 7 patients carried the MRP4 variant. The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03-10.57, P = 0.036). Conclusions These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.</description><identifier>ISSN: 0944-1174</identifier><identifier>EISSN: 1435-5922</identifier><identifier>DOI: 10.1007/s00535-010-0248-y</identifier><identifier>PMID: 20393862</identifier><language>eng</language><publisher>Japan: Japan : Springer Japan</publisher><subject>6-Mercaptopurine ; Abdominal Surgery ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analysis ; Azathioprine ; Azathioprine - metabolism ; Azathioprine - therapeutic use ; Blood cell count ; Colitis, Ulcerative - drug therapy ; Colitis, Ulcerative - genetics ; Colorectal Surgery ; Crohn Disease - drug therapy ; Crohn Disease - genetics ; Exons ; Female ; Gastroenterology ; Gastrointestinal diseases ; Genetic aspects ; Hepatology ; Humans ; IBD ; Immunosuppressive Agents - metabolism ; Immunosuppressive Agents - therapeutic use ; Inflammatory bowel disease ; Japan ; Male ; Medicine ; Medicine & Public Health ; Mercaptopurine ; Mercaptopurine - metabolism ; Mercaptopurine - therapeutic use ; Middle Aged ; MRP4 ; Multidrug Resistance-Associated Proteins - genetics ; Original Article—Alimentary Tract ; Political aspects ; Polymerase Chain Reaction - methods ; Polymorphism, Single Nucleotide ; Sequence Analysis, DNA ; Single nucleotide polymorphisms ; Surgical Oncology ; Thioguanine ; Young Adult</subject><ispartof>Journal of gastroenterology, 2010-10, Vol.45 (10), p.1014-1021</ispartof><rights>Springer 2010</rights><rights>COPYRIGHT 2010 Springer</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c514t-4d9007036cfdb291bd3e7b43b3cd9bcca0b08174f8944ff23930c61b94d4a09f3</citedby><cites>FETCH-LOGICAL-c514t-4d9007036cfdb291bd3e7b43b3cd9bcca0b08174f8944ff23930c61b94d4a09f3</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/s00535-010-0248-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00535-010-0248-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,781,785,27929,27930,41493,42562,51324</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20393862$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ban, Hiromistu</creatorcontrib><creatorcontrib>Andoh, Akira</creatorcontrib><creatorcontrib>Imaeda, Hirotsugu</creatorcontrib><creatorcontrib>Kobori, Ayako</creatorcontrib><creatorcontrib>Bamba, Shigeki</creatorcontrib><creatorcontrib>Tsujikawa, Tomoyuki</creatorcontrib><creatorcontrib>Sasaki, Masaya</creatorcontrib><creatorcontrib>Saito, Yasuharu</creatorcontrib><creatorcontrib>Fujiyama, Yoshihide</creatorcontrib><title>multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease</title><title>Journal of gastroenterology</title><addtitle>J Gastroenterol</addtitle><addtitle>J Gastroenterol</addtitle><description>Background Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients. Methods Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses. Results Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with the MRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype (P = 0.049). Of the 15 patients who experienced leucopenia (<3 × 10⁹/l), 7 patients carried the MRP4 variant. The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03-10.57, P = 0.036). Conclusions These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.</description><subject>6-Mercaptopurine</subject><subject>Abdominal Surgery</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Analysis</subject><subject>Azathioprine</subject><subject>Azathioprine - metabolism</subject><subject>Azathioprine - therapeutic use</subject><subject>Blood cell count</subject><subject>Colitis, Ulcerative - drug therapy</subject><subject>Colitis, Ulcerative - genetics</subject><subject>Colorectal Surgery</subject><subject>Crohn Disease - drug therapy</subject><subject>Crohn Disease - genetics</subject><subject>Exons</subject><subject>Female</subject><subject>Gastroenterology</subject><subject>Gastrointestinal diseases</subject><subject>Genetic aspects</subject><subject>Hepatology</subject><subject>Humans</subject><subject>IBD</subject><subject>Immunosuppressive Agents - metabolism</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Inflammatory bowel disease</subject><subject>Japan</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mercaptopurine</subject><subject>Mercaptopurine - metabolism</subject><subject>Mercaptopurine - therapeutic use</subject><subject>Middle Aged</subject><subject>MRP4</subject><subject>Multidrug Resistance-Associated Proteins - genetics</subject><subject>Original Article—Alimentary Tract</subject><subject>Political aspects</subject><subject>Polymerase Chain Reaction - methods</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Sequence Analysis, DNA</subject><subject>Single nucleotide polymorphisms</subject><subject>Surgical Oncology</subject><subject>Thioguanine</subject><subject>Young Adult</subject><issn>0944-1174</issn><issn>1435-5922</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9Uk2P1SAUJUbjPJ_-ADdKdN2Rr76W5WTiZyZxobMmlEIfkxYqUF_6R_y93peOGhNjWBDuPefAuQeEnlNySQlp3mRCal5XhJKKMNFW6wO0owIqtWTsIdoRKURFaSMu0JOc7wihnNTtY3TBCJe8PbAd-jEtY_F9WoYq2exz0cFYPKdYrA9Y4DmO6xTTfPR5wj5jjYM9YadNiQlrY-ISig8DdnAsRx_nJflgcbYh--K_-7Ji0PmkZx1sBmFdvA0l45MvR-i4UU-TBq0Vd_FkR9z7bHW2T9Ejp8dsn93ve3T77u3X6w_Vzef3H6-vbipTU1Eq0UuYA-EH4_qOSdr13Dad4B03veyM0aQjLfh3LUzCOQauiTnQTopeaCId36NXmy44_rbYXNRdXFKAK1UjCWeHBua5R6830KBHq-DRsSRtJp-NuoJ-3R5ke0Zd_gMFq7eTNzFY56H-F4FuBJNizsk6NSc_6bQqStQ5X7XlqyBfdc5XrcB5cf_epZts_5vxK1AAsA2QoRUGm_4Y-p_qy43kdFR6SD6r2y_s_FtoK2XDJP8JSza8vg</recordid><startdate>20101001</startdate><enddate>20101001</enddate><creator>Ban, Hiromistu</creator><creator>Andoh, Akira</creator><creator>Imaeda, Hirotsugu</creator><creator>Kobori, Ayako</creator><creator>Bamba, Shigeki</creator><creator>Tsujikawa, Tomoyuki</creator><creator>Sasaki, Masaya</creator><creator>Saito, Yasuharu</creator><creator>Fujiyama, Yoshihide</creator><general>Japan : Springer Japan</general><general>Springer Japan</general><general>Springer</general><general>Springer Nature B.V</general><scope>FBQ</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>3V.</scope><scope>7RV</scope><scope>7T5</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>H94</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></search><sort><creationdate>20101001</creationdate><title>multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease</title><author>Ban, Hiromistu ; Andoh, Akira ; Imaeda, Hirotsugu ; Kobori, Ayako ; Bamba, Shigeki ; Tsujikawa, Tomoyuki ; Sasaki, Masaya ; Saito, Yasuharu ; Fujiyama, Yoshihide</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c514t-4d9007036cfdb291bd3e7b43b3cd9bcca0b08174f8944ff23930c61b94d4a09f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>6-Mercaptopurine</topic><topic>Abdominal Surgery</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Analysis</topic><topic>Azathioprine</topic><topic>Azathioprine - metabolism</topic><topic>Azathioprine - therapeutic use</topic><topic>Blood cell count</topic><topic>Colitis, Ulcerative - drug therapy</topic><topic>Colitis, Ulcerative - genetics</topic><topic>Colorectal Surgery</topic><topic>Crohn Disease - drug therapy</topic><topic>Crohn Disease - genetics</topic><topic>Exons</topic><topic>Female</topic><topic>Gastroenterology</topic><topic>Gastrointestinal diseases</topic><topic>Genetic aspects</topic><topic>Hepatology</topic><topic>Humans</topic><topic>IBD</topic><topic>Immunosuppressive Agents - metabolism</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Inflammatory bowel disease</topic><topic>Japan</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mercaptopurine</topic><topic>Mercaptopurine - metabolism</topic><topic>Mercaptopurine - therapeutic use</topic><topic>Middle Aged</topic><topic>MRP4</topic><topic>Multidrug Resistance-Associated Proteins - genetics</topic><topic>Original Article—Alimentary Tract</topic><topic>Political aspects</topic><topic>Polymerase Chain Reaction - methods</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Sequence Analysis, DNA</topic><topic>Single nucleotide polymorphisms</topic><topic>Surgical Oncology</topic><topic>Thioguanine</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ban, Hiromistu</creatorcontrib><creatorcontrib>Andoh, Akira</creatorcontrib><creatorcontrib>Imaeda, Hirotsugu</creatorcontrib><creatorcontrib>Kobori, Ayako</creatorcontrib><creatorcontrib>Bamba, Shigeki</creatorcontrib><creatorcontrib>Tsujikawa, Tomoyuki</creatorcontrib><creatorcontrib>Sasaki, Masaya</creatorcontrib><creatorcontrib>Saito, Yasuharu</creatorcontrib><creatorcontrib>Fujiyama, Yoshihide</creatorcontrib><collection>AGRIS</collection><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>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</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 Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</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>Journal of gastroenterology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ban, Hiromistu</au><au>Andoh, Akira</au><au>Imaeda, Hirotsugu</au><au>Kobori, Ayako</au><au>Bamba, Shigeki</au><au>Tsujikawa, Tomoyuki</au><au>Sasaki, Masaya</au><au>Saito, Yasuharu</au><au>Fujiyama, Yoshihide</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease</atitle><jtitle>Journal of gastroenterology</jtitle><stitle>J Gastroenterol</stitle><addtitle>J Gastroenterol</addtitle><date>2010-10-01</date><risdate>2010</risdate><volume>45</volume><issue>10</issue><spage>1014</spage><epage>1021</epage><pages>1014-1021</pages><issn>0944-1174</issn><eissn>1435-5922</eissn><abstract>Background Multidrug resistance protein 4 (MRP4) functions as an efflux pump of nucleoside monophosphate analogs, such as 6-mercaptopurine (6-MP) and 6-thioguanine nucleotide (6-TGN). A single-nucleotide polymorphism in human MRP4 (rs3765534) dramatically reduces MRP4 function and results in the intracellular accumulation of 6-TGN. In this study, we investigated the association between MRP4 G2269A polymorphism and thiopurine sensitivity in Japanese IBD patients. Methods Direct sequencing of the MRP4 exon 18 was performed. The TPMT A719G and ITPase C94A polymorphisms were determined by polymerase-chain reaction-restriction fragment length polymorphism analyses. Results Of the 279 samples analyzed (44 healthy volunteers and 235 IBD patients), 68 samples showed a heterozygote of MRP4 G2269A and 7 carried a homozygote. The allelic frequency of MRP4 G2269A was 14.7%. In 130 IBD patients treated with azathioprine/6-MP, the white blood cell count was significantly lower in patients with the MRP4 variant alone (n = 26) than in patients with a wild allelotype (n = 74) (P = 0.014) or in patients with the ITPase variant alone (n = 22) (P = 0.0095). The 6-TGN levels were significantly higher in patients with the MRP4 variant alone than in patients with the wild allelotype (P = 0.049). Of the 15 patients who experienced leucopenia (<3 × 10⁹/l), 7 patients carried the MRP4 variant. The odds ratio of carrying the MRP4 variant alone and having leukopenia was 3.30 (95% confidence interval 1.03-10.57, P = 0.036). Conclusions These results suggest that MRP4 G2269A might be a new factor accounting for thiopurine sensitivity in Japanese patients with IBD.</abstract><cop>Japan</cop><pub>Japan : Springer Japan</pub><pmid>20393862</pmid><doi>10.1007/s00535-010-0248-y</doi><tpages>8</tpages></addata></record> |
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| subjects | 6-Mercaptopurine Abdominal Surgery Adolescent Adult Aged Aged, 80 and over Analysis Azathioprine Azathioprine - metabolism Azathioprine - therapeutic use Blood cell count Colitis, Ulcerative - drug therapy Colitis, Ulcerative - genetics Colorectal Surgery Crohn Disease - drug therapy Crohn Disease - genetics Exons Female Gastroenterology Gastrointestinal diseases Genetic aspects Hepatology Humans IBD Immunosuppressive Agents - metabolism Immunosuppressive Agents - therapeutic use Inflammatory bowel disease Japan Male Medicine Medicine & Public Health Mercaptopurine Mercaptopurine - metabolism Mercaptopurine - therapeutic use Middle Aged MRP4 Multidrug Resistance-Associated Proteins - genetics Original Article—Alimentary Tract Political aspects Polymerase Chain Reaction - methods Polymorphism, Single Nucleotide Sequence Analysis, DNA Single nucleotide polymorphisms Surgical Oncology Thioguanine Young Adult |
| title | multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease |
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