| Autor: |
Lacaze P; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia. paul.lacaze@monash.edu., Ronaldson KJ; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia., Zhang EJ; MRC Centre for Drug Safety Science, Wolfson Centre for Personalised Medicine, University of Liverpool, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, UK., Alfirevic A; MRC Centre for Drug Safety Science, Wolfson Centre for Personalised Medicine, University of Liverpool, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, UK., Shah H; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Newman L; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Strahl M; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Smith M; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Bousman C; Departments of Medical Genetics, Psychiatry, and Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada., Francis B; Department of Biostatistics, University of Liverpool, Liverpool, UK., Morris AP; Department of Biostatistics, University of Liverpool, Liverpool, UK.; Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK., Wilson T; Medical Genomics Facility, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Rossello F; University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, VIC, Australia., Powell D; Bioinformatics Platform, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia., Vasic V; Medical Genomics Facility, Hudson Institute of Medical Research, Melbourne, VIC, Australia., Sebra R; Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., McNeil JJ; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia., Pirmohamed M; MRC Centre for Drug Safety Science, Wolfson Centre for Personalised Medicine, University of Liverpool, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, UK. |
| Abstrakt: |
Clozapine is the most effective antipsychotic drug for schizophrenia, yet it can cause life-threatening adverse drug reactions, including myocarditis. The aim of this study was to determine whether schizophrenia patients with clozapine-induced myocarditis have a genetic predisposition compared with clozapine-tolerant controls. We measured different types of genetic variation, including genome-wide single-nucleotide polymorphisms (SNPs), coding variants that alter protein expression, and variable forms of human leucocyte antigen (HLA) genes, alongside traditional clinical risk factors in 42 cases and 67 controls. We calculated a polygenic risk score (PRS) based on variation at 96 different genetic sites, to estimate the genetic liability to clozapine-induced myocarditis. Our genome-wide association analysis identified four SNPs suggestive of increased myocarditis risk (P < 1 × 10 -6 ), with odds ratios ranging 5.5-13.7. The SNP with the lowest P value was rs74675399 (chr19p13.3, P = 1.21 × 10 -7 ; OR = 6.36), located in the GNA15 gene, previously associated with heart failure. The HLA-C*07:01 allele was identified as potentially predisposing to clozapine-induced myocarditis (OR = 2.89, 95% CI: 1.11-7.53), consistent with a previous report of association of the same allele with clozapine-induced agranulocytosis. Another seven HLA alleles, including HLA-B*07:02 (OR = 0.25, 95% CI: 0.05-1.2) were found to be putatively protective. Long-read DNA sequencing provided increased resolution of HLA typing and validated the HLA associations. The PRS explained 66% of liability (P value = 9.7 × 10 -5 ). Combining clinical and genetic factors together increased the proportion of variability accounted for (r 2 0.73, P = 9.8 × 10 -9 ). However, due to the limited sample size, individual genetic associations were not statistically significant after correction for multiple testing. We report novel candidate genetic associations with clozapine-induced myocarditis, which may have potential clinical utility, but larger cohorts are required for replication. |
