title: A model of prediction system for adverse cardiovascular reactions by calcineurin inhibitors among patients with renal transplants using gene-based single-nucleotide polymorphisms.
abstract: The application of pharmacogenomic information to diagnostic assays is expected to improve the prediction of drug efficacy and toxicity, leading to appropriate therapeutic regimens for individual patients. Cardiovascular events are common and severe adverse drug reactions (ADRs) among transplant patients treated with calcineurin inhibitors (CNIs). We conducted case-control association studies using 50,947 gene-based single-nucleotide polymorphisms (SNPs) to identify genetic variations that might be associated with cardiovascular risk factors in 72 renal transplant recipients with CNI therapy. The overall incidence of cardiovascular events was 13.9% (10/72) among patients receiving cyclosporine or tacrolimus; arrhythmias in six patients (8.3%), ischemic heart diseases in two patients (2.8%), and heart failure in two patients (2.8%). On the basis of results of the genome-wide association studies, we attempted to establish a scoring system to predict individual risks for cardiovascular toxicity of cyclosporine and tacrolimus. Estimation of the predictive performance was carried out by the use of internal leave-one-out cross-validation test. When we combined arrhythmia, ischemic heart disease and heart failure cases as subjects with a cardiotoxicity phenotype, nine of ten ADR patients and 50 of 62 non-ADR patients were correctly classified into the respective categories using the top eight SNPs. In addition, the proportion of individuals in the control population (n=246) with scores over the cut-off (11.0%) was close to the cardiovascular ADR frequency (8.3%) among renal transplant patients in the previous clinical study. Our results open the possibility that prediction of CNI-induced cardiovascular complications can lead to better prognosis and quality of life among kidney-transplant patients, and to improved immunosuppressive regimens.
authors.affiliation: Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.affiliation: Laboratory for SNP Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Laboratory of Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Takasaki
authors.affiliation: Laboratory of Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.|Division of Genomic Medicine, Department of Applied Biomedical Engineering and Science, and Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.affiliation: Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Beck
authors.affiliation: Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tahara
authors.affiliation: Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.|Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Laboratory for SNP Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. ohnishi@ims.u-tokyo.ac.jp.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Ohnishi
mesh_terms: D065095:Calcineurin Inhibitors; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000235:genetics*; D016022:Case-Control Studies; D016572:Cyclosporine / Q000009:adverse effects*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D016030:Kidney Transplantation; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D016559:Tacrolimus / Q000009:adverse effects*
chemical_list: D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D016559:Tacrolimus