Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia.
Administration of certain drugs (for example, antiarrhythmics, antihistamines, antibiotics, antipsychotics) may occasionally affect myocardial repolarization and cause prolongation of the QT interval. We performed a whole genome association study of drug-induced QT prolongation after 14 days of treatment in a phase 3 clinical trial evaluating the efficacy, safety and tolerability of a novel atypical antipsychotic, iloperidone, in patients with schizophrenia. We identified DNA polymorphisms associated with QT prolongation in six loci, including the CERKL and SLCO3A1 genes. Each single nucleotide polymorphism (SNP) defined two genotype groups associated with a low mean QT change (ranging from -0.69 to 5.67 ms depending on the SNP) or a higher mean QT prolongation (ranging from 14.16 to 17.81 ms). The CERKL protein is thought to be part of the ceramide pathway, which regulates currents conducted by various potassium channels, including the hERG channel. It is well established that inhibition of the hERG channel can prolong the QT interval. SLCO3A1 is thought to play a role in the translocation of prostaglandins, which have known cardioprotective properties, including the prevention of torsades de pointes. Our findings also point to genes involved in myocardial infarction (PALLD), cardiac structure and function (BRUNOL4) and cardiac development (NRG3). Results of this pharmacogenomic study provide new insight into the clinical response to iloperidone, developed with the goal of directing therapy to those patients with the optimal benefit/risk ratio.
Volpi
S
S
Vanda Pharmaceuticals Inc., Rockville, MD 20850, USA.
Heaton
C
C
Mack
K
K
Hamilton
J B
JB
Lannan
R
R
Wolfgang
C D
CD
Licamele
L
L
Polymeropoulos
M H
MH
Lavedan
C
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects*; D000067878:CELF Proteins; D002352:Carrier Proteins / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D004311:Double-Blind Method; D004562:Electrocardiography / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007555:Isoxazoles / Q000009:adverse effects*; D016014:Linear Models; D015810:Linkage Disequilibrium; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020880:Neuregulins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D010597:Pharmacogenetics; D010750:Phosphoproteins / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D010879:Piperazines / Q000627:therapeutic use; D010880:Piperidines / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D013844:Thiazoles / Q000627:therapeutic use; D055815:Young Adult
D014150:Antipsychotic Agents; D000067878:CELF Proteins; C422243:CELF4 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007555:Isoxazoles; C486357:NRG3 protein, human; C089765:NUBP1 protein, human; D020880:Neuregulins; D027361:Organic Anion Transporters; C412722:PALLD protein, human; D010750:Phosphoproteins; D010879:Piperazines; D010880:Piperidines; D016601:RNA-Binding Proteins; C479544:SLCO3A1 protein, human; D013844:Thiazoles; C092292:ziprasidone; D017853:Phosphotransferases (Alcohol Group Acceptor); C066324:ceramide kinase; C081732:iloperidone