ABCMdb

PMID: 16330681

Wojnowski L, Kulle B, Schirmer M, Schluter G, Schmidt A, Rosenberger A, Vonhof S, Bickeboller H, Toliat MR, Suk EK, Tzvetkov M, Kruger A, Seifert S, Kloess M, Hahn H, Loeffler M, Nurnberg P, Pfreundschuh M, Trumper L, Brockmoller J, Hasenfuss G
NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity.
Circulation. 2005 Dec 13;112(24):3754-62. Epub 2005 Dec 5., 2005-12-13 [PubMed]

Sentences

No. Mutations Sentence Comment

10 ABCC1 p.Gly671Val In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Login to comment 16 ABCC1 p.Gly671Val ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Login to comment 117 ABCC1 p.Gly671Val ABCC1 p.Gly671Val ABCC1 p.Gly671Val ABCC1 p.Gly671Val Distribution of Genotypes and Probability Values for Gene Variants Showing Associations With Cardiotoxicity After Doxorubicin Treatment Cardiotoxicity Gene Variant Genotype Distribution P vs Controls Genotypes* n Freidlin Test Fisher Test Acute CYBA His72Tyr(rs4673) CC/CT/TT 13/28/3 0.048 0.054 RAC2 7508T3A(rs13058338) TT/TA/AA 15/23/5 0.002 0.005 NCF4-212A3G(rs1883112) GG/GA/AA 10/22/9 0.372 0.519 MRP1 Gly671Val GG/GT/TT 33/8/1 0.001 0.005 MRP2 Val1188Glu(rs8187694) TT/TA/AA 36/8/0 0.049 0.06 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 36/8/0 0.049 0.06 Chronic CYBA His72Tyr(rs4673) CC/CT/TT 13/27/3 0.062 0.074 RAC2 7508T3A(rs13058338) TT/TA/AA 24/15/4 0.28 0.747 NCF4-212A3G(rs1883112) GG/GA/AA 14/14/15 0.007 0.013 MRP1 Gly671Val GG/GT/TT 39/4/0 0.586 0.537 MRP2 Val1188Glu(rs8187694) TT/TA/AA 37/6/0 0.274 0.269 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 37/6/0 0.274 0.269 Chronic or acute CYBA His72Tyr(rs4673) CC/CT/TT 26/55/6 0.009 0.01 RAC2 7508T3A(rs13058338) TT/TA/AA 39/38/9 0.013 0.04 NCF4-212A3G(rs1883112) GG/GA/AA 24/36/24 0.022 0.031 MRP1 Gly671Val GG/GT/TT 72/12/1 0.012 0.029 MRP2 Val1188Glu(rs8187694) TT/TA/AA 73/14/0 0.044 0.05 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 73/14/0 0.044 0.05 None (controls) CYBA His72Tyr(rs4673) CC/CT/TT 164/154/45 1 1 RAC2 7508T3A(rs13058338) TT/TA/AA 211/132/19 1 1 NCF4-212A3G(rs1883112) GG/GA/AA 106/186/62 1 1 MRP1 Gly671Val GG/GT/TT 331/24/1 1 1 MRP2 Val1188Glu(rs8187694) TT/TA/AA 331/32/0 1 1 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 331/32/0 1 1 *Genotype(s) predisposing to ACT is underlined. Login to comment 122 ABCC1 p.Gly671Val ABCC1 p.Gly671Val ABCC1 p.Gly671Val ABCC1 p.Gly671Val Distribution of Genotypes and Probability Values for Gene Variants Showing Associations With Cardiotoxicity After Doxorubicin Treatment Cardiotoxicity Gene Variant Genotype Distribution P vs Controls Genotypes* n Freidlin Test Fisher Test Acute CYBA His72Tyr(rs4673) CC/CT/TT 13/28/3 0.048 0.054 RAC2 7508T3A(rs13058338) TT/TA/AA 15/23/5 0.002 0.005 NCF4-212A3G(rs1883112) GG/GA/AA 10/22/9 0.372 0.519 MRP1 Gly671Val GG/GT/TT 33/8/1 0.001 0.005 MRP2 Val1188Glu(rs8187694) TT/TA/AA 36/8/0 0.049 0.06 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 36/8/0 0.049 0.06 Chronic CYBA His72Tyr(rs4673) CC/CT/TT 13/27/3 0.062 0.074 RAC2 7508T3A(rs13058338) TT/TA/AA 24/15/4 0.28 0.747 NCF4-212A3G(rs1883112) GG/GA/AA 14/14/15 0.007 0.013 MRP1 Gly671Val GG/GT/TT 39/4/0 0.586 0.537 MRP2 Val1188Glu(rs8187694) TT/TA/AA 37/6/0 0.274 0.269 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 37/6/0 0.274 0.269 Chronic or acute CYBA His72Tyr(rs4673) CC/CT/TT 26/55/6 0.009 0.01 RAC2 7508T3A(rs13058338) TT/TA/AA 39/38/9 0.013 0.04 NCF4-212A3G(rs1883112) GG/GA/AA 24/36/24 0.022 0.031 MRP1 Gly671Val GG/GT/TT 72/12/1 0.012 0.029 MRP2 Val1188Glu(rs8187694) TT/TA/AA 73/14/0 0.044 0.05 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 73/14/0 0.044 0.05 None (controls) CYBA His72Tyr(rs4673) CC/CT/TT 164/154/45 1 1 RAC2 7508T3A(rs13058338) TT/TA/AA 211/132/19 1 1 NCF4-212A3G(rs1883112) GG/GA/AA 106/186/62 1 1 MRP1 Gly671Val GG/GT/TT 331/24/1 1 1 MRP2 Val1188Glu(rs8187694) TT/TA/AA 331/32/0 1 1 MRP2Cys1515Tyr(rs8187710) GG/GA/AA 331/32/0 1 1 *Genotype(s) predisposing to ACT is underlined. Login to comment 126 ABCC1 p.Gly671Val The predisposing allele A of the MRP1 variant Gly671Val conferred an OR of 3.6 (95% CI, 1.6 to 8.4). Login to comment 131 ABCC1 p.Gly671Val The predisposing allele A of the MRP1 variant Gly671Val conferred an OR of 3.6 (95% CI, 1.6 to 8.4). Login to comment 132 ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu The 2 missense mutations in MRP2, Val1188Glu (rs8187694) and Cys1515Tyr (rs8187710), yielded identical frequencies and relationships with acute ACT, as characterized by an OR of 2.3 (95% CI, 1.0 to 5.4). Login to comment 136 ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu All associations except 1 (the Val1188Glu and Cys1515Tyr haplotype) were still significant when chronic cases were defined more conservatively (ejection fraction Ͻ45% instead of Ͻ50%). Login to comment 194 ABCC1 p.Arg433Ser As opposed to polarized cells, in the cardiomyocytes MRP1 is found in the cytoplasm in addition to plasma membrane.37 It has been postulated that such an expression may permit sequestration of doxorubicin in lysosomes, ie, away from its target the nucleus.40 A low-frequency protein variant of MRP1 (Arg433Ser) has been shown to affect resistance to anthracyclines in vitro but has not been found in our study.41 The effect on doxorubicin resistance or transport of the variant 671Val, which shows an association with acute ACT in this study, has not been investigated.42 MRP2 has a substrate spectrum similar to that of MRP1 and increases the resistance to doxorubicin when overexpressed in HEK-293 cells.43 Physiologically, the MRP2 protein is expressed in the apical membrane of polarized cells in the liver and in the kidney, and there is no evidence for its expression in the heart. Login to comment 199 ABCC1 p.Arg433Ser As opposed to polarized cells, in the cardiomyocytes MRP1 is found in the cytoplasm in addition to plasma membrane.37 It has been postulated that such an expression may permit sequestration of doxorubicin in lysosomes, ie, away from its target the nucleus.40 A low-frequency protein variant of MRP1 (Arg433Ser) has been shown to affect resistance to anthracyclines in vitro but has not been found in our study.41 The effect on doxorubicin resistance or transport of the variant 671Val, which shows an association with acute ACT in this study, has not been investigated.42 MRP2 has a substrate spectrum similar to that of MRP1 and increases the resistance to doxorubicin when overexpressed in HEK-293 cells.43 Physiologically, the MRP2 protein is expressed in the apical membrane of polarized cells in the liver and in the kidney, and there is no evidence for its expression in the heart. Login to comment 202 ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu The 2 missense variants associating with ACT, Val1188Glu (rs8187694), and Cys1515Tyr (rs8187710), were initially described in the Japanese.48 No data on their functional significance have been published, and the specific variant relevant to doxorubicin treatment cannot be inferred from our results because of the 100% LD between the 2 missense mutations in our cohort. Login to comment