Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia

Molecular Psychiatry volume 14, pages 1024–1031 (2009)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Al Khatib SM, LaPointe NM, Kramer JM, Califf RM . What clinicians should know about the QT interval. JAMA 2003; 289: 2120–2127.

    Article  PubMed  Google Scholar 

  2. Paulussen ADC, Gilissen RAHJ, Armstrong M, Doevendans PA, Verhasselt P, Smeets HJM et al. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J Mol Med 2004; 82: 182–188.

    Article  CAS  PubMed  Google Scholar 

  3. Roden DM . Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350: 1013–1022.

    Article  CAS  PubMed  Google Scholar 

  4. Zareba W, Lin DA . Antipsychotic drugs and QT interval prolongation. Psychiatr Q 2003; 74: 291–306.

    Article  PubMed  Google Scholar 

  5. Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002; 105: 1943–1948.

    Article  CAS  PubMed  Google Scholar 

  6. Farkas A, Coker SJ . Prevention of clofilium-induced torsades de pointes by prostaglandin E2 does not involve ATP-dependent K+ channels. Eur J Pharmacol 2003; 472: 189–196.

    Article  CAS  PubMed  Google Scholar 

  7. Cutler AJ, Kalali AH, Weiden P, Hamilton J, Wolfgang CD . Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol 2008; 28 (Suppl 1): S20–S28.

    Article  CAS  PubMed  Google Scholar 

  8. Di X, Matsuzaki H, Webster TA, Hubbell E, Liu G, Dong S et al. Dynamic model based algorithms for screening and genotyping over 100K SNPs on oligonucleotide microarrays. Bioinformatics 2005; 21: 1958–1963.

    Article  CAS  PubMed  Google Scholar 

  9. BRLMM: an improved genotype calling method for the GeneChip® Human Mapping 500K Array Set. Affymetrix Web site. http://www.affymetrix.com/support/technical/whitepapers/brlmm_whitepaper.pdf. Accessed 26 July 2007.

  10. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc 1995; 57: 289–300.

    Google Scholar 

  11. Weller JI, Song JZ, Heyen DW, Lewin HA, Ron M . A new approach to the problem of multiple comparisons in the genetic dissection of complex traits. Genetics 1998; 150: 1699–1706.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Mosig MO, Lipkin E, Khutoreskaya G, Tchourzyna E, Soller M, Friedmann A . A whole genome scan for quantitative trait loci affecting milk protein percentage in Israeli-Holstein cattle, by means of selective milk DNA pooling in a daughter design, using an adjusted false discovery rate criterion. Genetics 2001; 157: 1683–1698.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Benjamini Y, Yekutieli D . Quantitative trait Loci analysis using the false discovery rate. Genetics 2005; 171: 783–790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  15. Lewontin RC . On measures of gametic disequilibrium. Genetics 1988; 120: 849–852.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bornancin F, Mechtcheriakova D, Stora S, Graf C, Wlachos A, Devay P et al. Characterization of a ceramide kinase-like protein. Biochim Biophys Acta 2005; 1687: 31–43.

    Article  CAS  PubMed  Google Scholar 

  17. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K . dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001; 29: 308–311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chapman H, Ramstrom C, Korhonen L, Laine M, Wann KT, Lindholm D et al. Downregulation of the HERG (KCNH2) K+ channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation. J Cell Sci 2005; 118: 5325–5334.

    Article  CAS  PubMed  Google Scholar 

  19. Hida H, Takeda M, Soliven B . Ceramide inhibits inwardly rectifying K+ currents via a Ras- and Raf-1-dependent pathway in cultured oligodendrocytes. J Neurosci 1998; 18: 8712–8719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chik CL, Li B, Karpinski E, Ho AK . Ceramide inhibits the outward potassium current in rat pinealocytes. J Neurochem 2001; 79: 339–348.

    Article  CAS  PubMed  Google Scholar 

  21. Ceramide kinase-like protein. Human Protein Reference Database Web site. Available at http://www.hprd.org. Accessed 7 August 2007.

  22. UniProtKB/Swiss-Prot entry Q49MI3. ExPASy Web Site. Available at http://www.expasy.org/cgi-bin/niceprot.pl?CERKL_HUMAN. Accessed 8 August 2007.

  23. Adachi H, Suzuki T, Abe M, Asano N, Mizutamari H, Tanemoto M et al. Molecular characterization of human and rat organic anion transporter OATP-D. Am J Physiol Renal Physiol 2003; 285: F1188–F1197.

    Article  CAS  PubMed  Google Scholar 

  24. Thiemermann C, Zacharowski K . Selective activation of E-type prostanoid3-receptors reduces myocardial infarct size: a novel insight into the cardioprotective effects of prostaglandins. Pharmacol Ther 2000; 87: 61–67.

    Article  CAS  PubMed  Google Scholar 

  25. Ladd AN, Charlet BN, Cooper TA . The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol Cell Biol 2001; 21: 1285–1296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu X, Timchenko NA, Timchenko LT . Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. Hum Mol Genet 1999; 8: 53–60.

    Article  CAS  PubMed  Google Scholar 

  27. Ladd AN, Taffet G, Hartley C, Kearney DL, Cooper TA . Cardiac tissue-specific repression of CELF activity disrupts alternative splicing and causes cardiomyopathy. Mol Cell Biol 2005; 25: 6267–6278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Philips AV, Timchenko LT, Cooper TA . Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 1998; 280: 737–741.

    Article  CAS  PubMed  Google Scholar 

  29. Li D, Bachinski LL, Roberts R . Genomic organization and isoform-specific tissue expression of human NAPOR (CUGBP2) as a candidate gene for familial arrhythmogenic right ventricular dysplasia. Genomics 2001; 74: 396–401.

    Article  CAS  PubMed  Google Scholar 

  30. Ladd AN, Stenberg MG, Swanson MS, Cooper TA . Dynamic balance between activation and repression regulates pre-mRNA alternative splicing during heart development. Dev Dyn 2005; 233: 783–793.

    Article  CAS  PubMed  Google Scholar 

  31. Carteron C, Ferrer-Montiel A, Cabedo H . Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival. J Cell Sci 2006; 119: 898–909.

    Article  CAS  PubMed  Google Scholar 

  32. Panchal H, Wansbury O, Parry S, Ashworth A, Howard B . Neuregulin3 alters cell fate in the epidermis and mammary gland. BMC Dev Biol 2007; 7: 105.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Révillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat JP . ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol 2008; 19: 73–80.

    Article  PubMed  Google Scholar 

  34. Zhao Y-Y, Sawyer DR, Baliga RR, Opel DJ, Han X, Marchionni MA et al. Neuregulins promote survival and growth of cardiac myocytes: persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem 1998; 273: 10261–10269.

    Article  CAS  PubMed  Google Scholar 

  35. Shiffman D, Ellis SG, Rowland CM, Malloy MJ, Luke MM, Iakoubova OA et al. Identification of four gene variants associated with myocardial infarction. Am J Hum Genet 2005; 77: 596–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jin L, Kern MJ, Otey CA, Wamhoff BR, Somlyo AV . Angiotensin II, focal adhesion kinase, and PRX1 enhance smooth muscle expression of lipoma preferred partner and its newly identified binding partner paladin to promote cell migration. Circ Res 2007; 100: 817–825.

    Article  CAS  PubMed  Google Scholar 

  37. Arking DE, Pfeufer A, Post W, Kao WHL, Newton-Cheh C, Ikeda M et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 2006; 38: 644–651.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the patients for participating in this study. We thank Michael Di Marino, Ingeborg Holt and Nan Wang for their assistance in the statistical analysis, and Andrew Thompson for his technical support. We also thank Dr Paolo Baroldi and Chip Clark for their critical review of the article. This study was funded and submitted by Vanda Pharmaceuticals Inc. Study design, data collection, data analysis and data interpretation were completed by the authors, who are employees of Vanda Pharmaceuticals Inc.

Author information

Authors and Affiliations

  1. Vanda Pharmaceuticals Inc., Rockville, MD, USA

    S Volpi, C Heaton, K Mack, J B Hamilton, R Lannan, C D Wolfgang, L Licamele, M H Polymeropoulos & C Lavedan

Authors
  1. S Volpi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Heaton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Mack
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J B Hamilton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Lannan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C D Wolfgang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L Licamele
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M H Polymeropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C Lavedan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Lavedan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Volpi, S., Heaton, C., Mack, K. et al. Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia. Mol Psychiatry 14, 1024–1031 (2009). https://doi.org/10.1038/mp.2008.52

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.52

Keywords

This article is cited by

Search

Advanced search

Quick links