Influence of NOS1AP Risk Variants on the Corrected QT (QTc) Interval in the Pharmacotherapy of Schizophrenia

Abstract

Introduction The variants of the gene for nitric oxide synthase 1 adaptor protein (NOS1AP) are associated with schizophrenia and cardiovascular deficits involving corrected QT (QTc) interval prolongation. Here, we investigated a possible pharmacogenetic effect of antipsychotic treatment on QTc length in interaction with two NOS1AP variants (rs12143842 and rs10494366) whose minor alleles are associated with increased QTc interval length.

Methods We conducted a retrospective analysis of electrocardiographic (ECG) and genotype data of 239 patients diagnosed with schizophrenia. We converted antipsychotics dosage to chlorpromazine equivalents and defined daily doses. We analysed the effects of the minor (i. e. rs12143842-CT/TT and rs10494366-GT/GG) and major (i. e. rs12143842-CC and rs10494366-TT) allele genotypes to QTc interval for female and male participants separately.

Results As expected, rs12143842 and rs10494366 exhibit strong linkage disequilibrium. Both polymorphisms had no direct effect on antipsychotic use or QTc interval. However, there was a continuous increase in QTc interval with increasing antipsychotic dosage in males. For both variants, positive correlation of QTc length with antipsychotic dosage was found in homozygous male carriers of the major alleles (i. e. rs12143842-CC and rs10494366-TT), but not in minor allele carriers. There was no significant interaction between antipsychotic dosage and QTc interval for either genotype in female patients.

Conclusions In this study, a significant interaction was found between both NOS1AP variants, rs12143842 and rs10494366, and antipsychotic treatment on the QTc interval in a sex-dependent manner. Our findings might be relevant for adequate antipsychotic treatment in rs12143842 and rs10494366 major allele carriers.

Key words

NOS1AP - CAPON - QTc interval - antipsychotic treatment - pharmacogenetic interaction

Publication History

Received: 24 January 2022
Received: 14 March 2022

Accepted: 18 March 2022

Article published online:
22 June 2022

• References

• 1 Fan Z, Wu Y, Shen J. et al. Schizophrenia and the risk of cardiovascular diseases: A meta-analysis of thirteen cohort studies. J Psychiatr Res 2013; 47: 1549-1556 DOI: 10.1016/j.jpsychires.2013.07.011.
• 2 Olfson M, Gerhard T, Huang C. et al. Premature mortality among adults with schizophrenia in the United States. JAMA Psychiatry 2015; 72: 1172-1181 DOI: 10.1001/jamapsychiatry.2015.1737.
• 3 Westman J, Eriksson SV, Gissler M. et al. Increased cardiovascular mortality in people with schizophrenia: A 24-year national register study. Epidemiol Psychiatr Sci 2018; 27: 519-527 DOI: 10.1017/S2045796017000166.
• 4 Jindal R, MacKenzie EM, Baker GB. et al. Cardiac risk and schizophrenia. J Psychiatry Neurosci 2005; 30: 393-395 Im Internet:/pmc/articles/PMC1277021/; Stand: 11.05.2021
• 5 Trinkley KE, Lee Page R, Lien H. et al. QT interval prolongation and the risk of torsades de pointes: Essentials for clinicians. Curr Med Res Opin 2013; 29: 1719-1726 DOI: 10.1185/03007995.2013.840568.
• 6 Brzustowicz LM. NOS1AP in schizophrenia. Curr Psychiatry Rep 2008; 10: 158-163 DOI: 10.1007/s11920-008-0027-0.
• 7 Freudenberg F, Alttoa A, Reif A. Neuronal nitric oxide synthase (NOS1) and its adaptor, NOS1AP, as a genetic risk factors for psychiatric disorders. Genes Brain Behav 2015; 14: 46-63 DOI: 10.1111/gbb.12193.
• 8 Xu B, Wratten N, Charych EI. et al. Increased expression in dorsolateral prefrontal cortex of CAPON in schizophrenia and bipolar disorder. PLoS Med 2005; 2: e263 DOI: 10.1371/journal.pmed.0020263.
• 9 Hadzimichalis NM, Previtera ML, Moreau MP. et al. NOS1AP protein levels are altered in BA46 and cerebellum of patients with schizophrenia. Schizophr Res 2010; DOI: 10.1016/j.schres.2010.05.009.
• 10 Greenwood TA, Lazzeroni LC, Murray SS. et al. Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the consortium on the genetics of schizophrenia. Am J Psychiatry 2011; 168: 930-946 DOI: 10.1176/appi.ajp.2011.10050723.
• 11 Eijgelsheim M, Aarnoudse ALHJ, Rivadeneira F. et al. Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration. Hum Mol Genet 2009; 18: 347-357 DOI: 10.1093/hmg/ddn341.
• 12 Lehtinen AB, Newton-Cheh C, Ziegler JT. et al. Association of NOS1AP genetic variants with QT interval duration in families from the Diabetes Heart Study. Diabetes. 2008; 57: 1108-1114 DOI: 10.2337/db07-1365.
• 13 Tobin MD, Kähönen M, Braund P. et al. Gender and effects of a common genetic variant in the NOS1 regulator NOS1AP on cardiac repolarization in 3761 individuals from two independent populations. Int J Epidemiol 2008; 37: 1132-1141 DOI: 10.1093/ije/dyn091.
• 14 Aarnoudse AJLHJ, Newton-Cheh C, De Bakker PIW. et al. Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam Study. Circulation 2007; 116: 10-16 DOI: 10.1161/CIRCULATIONAHA.106.676783.
• 15 Post W, Shen H, Damcott C. et al. Associations between genetic variants in the NOS1AP (CAPON) gene and cardiac repolarization in the Old Order Amish. Hum Hered 2007; 64: 214-219 DOI: 10.1159/000103630.
• 16 Arking DE, Pfeufer A, Post W. et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 2006; 38: 644-651 DOI: 10.1038/ng1790.
• 17 Chang K-C, Barth AS, Sasano T. et al. CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart. Proc Natl Acad Sci USA 2008; 105: 4477-4482 DOI: 10.1073/pnas.0709118105.
• 18 Earle N, Ingles J, Bagnall RD. et al. NOS1AP polymorphisms modify QTc interval duration but not cardiac arrest risk in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2015; 26: 1346-1351 DOI: 10.1111/JCE.12827.
• 19 Beach SR, Celano CM, Noseworthy PA. et al. QTc prolongation, torsades de pointes, and psychotropic medications. Psychosomatics 2013; 54: 1-13 DOI: 10.1016/j.psym.2012.11.001.
• 20 Buckley NA, Sanders P. Cardiovascular adverse effects of antipsychotic drugs. Drug Saf 2000; 23: 215-228 DOI: 10.2165/00002018-200023030-00004.
• 21 Åberg K, Adkins DE, Liu Y. et al. Genome-wide association study of antipsychotic-induced QTc interval prolongation. Pharmacogenomics J 2012; 12: 165-172 DOI: 10.1038/TPJ.2010.76.
• 22 Lonsdale J, Thomas J, Salvatore M. et al. The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013; 45: 580-585 DOI: 10.1038/ng.2653.
• 23 Rautaharju PM, Surawicz B, Gettes LS. AHA/ACCF/HRS Recommendations for the standardization and interpretation of the electrocardiogram. Part IV: The ST segment, T and U waves, and the QT interval A scientific statement from the American Heart Association Electrocardiography and Arrhythmias Co. J Am Coll Cardiol 2009; 53: 982-991 DOI: 10.1016/j.jacc.2008.12.014.
• 24 Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353-370
• 25 Molnar J, Weiss JS, Rosenthal JE. The missing second: What is the correct unit for the Bazett corrected Qt interval?. Am J Cardiol 1995; 75: 537-538 DOI: 10.1016/S0002-9149(99)80603-1.
• 26 Gardner DM, Murphy AL, O’Donnell H. et al. International consensus study of antipsychotic dosing. Am J Psychiatry 2010; 167: 686-693 DOI: 10.1176/appi.ajp.2009.09060802.
• 27 Leucht S, Samara M, Heres S. et al. Dose equivalents for antipsychotic drugs: The DDD method. Schizophr Bull 2016; 42: S90-S94 DOI: 10.1093/schbul/sbv167.
• 28 Leisch F, Man M. Package “genetics”. Population Genetics. 2021 https://cran.r-project.org/web/packages/genetics/genetics.pdf
• 29 Salama G, Bett GCL. Sex differences in the mechanisms underlying long QT syndrome. Am J Physiol – Hear Circ Physiol 2014; 307: H640 DOI: 10.1152/ajpheart.00864.2013.
• 30 Fujii K, Ozeki Y, Okayasu H. et al. QT is longer in drug-free patients with schizophrenia compared with age-matched healthy Subjects. PLoS One 2014; 9: e98555 DOI: 10.1371/journal.pone.0098555.
• 31 Machiela MJ, Chanock SJ. LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 2015; 31: 3555-3557 DOI: 10.1093/bioinformatics/btv402.
• 32 Khatib R, Sabir FRN, Omari C. et al. Managing drug-induced QT prolongation in clinical practice. Postgrad Med J 2021; 97: 452-458 DOI: 10.1136/postgradmedj-2020-138661.
• 33 Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002; 62: 1649-1671 DOI: 10.2165/00003495-200262110-00006.
• 34 Hommers L, Scherf-Clavel M, Stempel R. et al. Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age. J Psychopharmacol 2021; 35: 1127-1133 DOI: 10.1177/02698811211003477.
• 35 Funada A, Hayashi K, Ino H. et al. Assessment of QT intervals and prevalence of short QT syndrome in Japan. Clin Cardiol 2008; 31: 270-274 DOI: 10.1002/clc.20208.
• 36 Mason JW, Ramseth DJ, Chanter DO. et al. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects. J Electrocardiol 2007; 40 DOI: 10.1016/j.jelectrocard.2006.09.003.
• 37 Yang FDe, Wang XQ, Liu XP. et al. Sex difference in QTc prolongation in chronic institutionalized patients with schizophrenia on long-term treatment with typical and atypical antipsychotics. Psychopharmacology (Berl) 2011; 216: 9-16 DOI: 10.1007/s00213-011-2188-5.
• 38 Leung A, Chue P. Sex differences in schizophrenia, a review of the literature. Acta Psychiatr Scand 2000; 401: 3-38 DOI: 10.1111/J.0065-1591.2000.0AP25.X.
• 39 Seeman MV. The pharmacodynamics of antipsychotic drugs in women and men. Front Psychiatry 2021; 12: 468 DOI: 10.3389/FPSYT.2021.650904/BIBTEX.
• 40 Ramos-Ríos R, Arrojo-Romero M, Paz-Silva E. et al. QTc interval in a sample of long-term schizophrenia inpatients. Schizophr Res 2010; 116: 35-43 DOI: 10.1016/J.SCHRES.2009.09.041.
• 41 Rijcken CAW, Monster TBM, Brouwers JRBJ. et al. Chlorpromazine equivalents versus defined daily doses: How to compare antipsychotic drug doses?. J Clin Psychopharmacol 2003; 23: 657-659 DOI: 10.1097/01.jcp.0000096247.29231.3a.
• 42 Nosè M, Tansella M, Thornicroft G. et al. Is the defined daily dose system a reliable tool for standardizing antipsychotic dosages?. Int Clin Psychopharmacol 2008; 23: 287-290 DOI: 10.1097/YIC.0b013e328303ac75.
• 43 Javaid JI. Clinical pharmacokinetics of antipsychotics. J Clin Pharmacol 1994; 34: 286-295 DOI: 10.1002/J.1552-4604.1994.TB01995.X.
• 44 Carrascal-Laso L, Isidoro-García M, Ramos-Gallego I. et al. Review: Influence of the CYP450 genetic variation on the treatment of psychotic disorders. J Clin Med 2021; 10 DOI: 10.3390/JCM10184275.
• 45 Vandael E, Vandenberk B, Vandenberghe J. et al. Risk factors for QTc-prolongation: Systematic review of the evidence. Int J Clin Pharm 2017; 39: 16-25 DOI: 10.1007/S11096-016-0414-2.
• 46 Sedlak T, Shufelt C, Iribarren C. et al. Sex hormones and the QT interval: A review. J Women’s Heal 2012; 21: 933 DOI: 10.1089/JWH.2011.3444.
• 47 Sala M, Vicentini A, Brambilla P. et al. QT interval prolongation related to psychoactive drug treatment: A comparison of monotherapy versus polytherapy. Ann Gen Psychiatry 2005; 4 DOI: 10.1186/1744-859X-4-1.
• 48 Elliott A, Johan Mørk T, Højlund M. et al. QTc interval in patients with schizophrenia receiving antipsychotic treatment as monotherapy or polypharmacy. CNS Spectr 2018; 23: 278-283 DOI: 10.1017/S1092852917000402.
• 49 Meid AD, Bighelli I, Mächler S. et al. Combinations of QTc-prolonging drugs: Towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature. Ther Adv Psychopharmacol 2017; 7: 251 DOI: 10.1177/2045125317721662.