3c6d676a6515bd3ccdb5943b8a5aae8a pmc_33138277.pdf 7275e4b18caf7a81c97466f1663fdaa5ced2a5d0 pmc_33138277.pdf 0d16c1357c6cd4a101f0ad636bc16b7297fc15d3b4c179724b287514b607c844 pmc_33138277.pdf Title: Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations Subject: Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 10-7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41–6.68, p = 1.01 10-7) and rs4427239 (OR = 5.47, 95%CI: 2.81–10.65, p = 5.75 10-7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA. Keywords: drug-induced agranulocytosis; metamizole; dipyrone; genome-wide association study; pharmacogenetics Author: Anca Liliana Cismaru, Deborah Rudin, Luisa Ibañez, Evangelia Liakoni, Nicolas Bonadies, Reinhold Kreutz, Alfonso Carvajal, Maria Isabel Lucena, Javier Martin, Esther Sancho Ponce, Mariam Molokhia, Niclas Eriksson, EuDAC collaborators, Stephan Krähenbühl, Carlo R. Largiadèr, Manuel Haschke, Pär Hallberg, Mia Wadelius and Ursula Amstutz Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Thu Oct 29 07:18:19 2020 CET ModDate: Thu Oct 29 15:48:07 2020 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1837355 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WYEKQU+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 PDPHZD+Pxsy Type 1 Builtin yes yes no 15 0 SXQPWE+VnURWPalladioL Type 1 Custom yes yes no 19 0 RJXPCQ+URWPalladioL-Ital Type 1 Custom yes yes no 23 0 HOXOJJ+URWPalladioL-Bold Type 1 Custom yes yes no 28 0 FTKFJW+URWPalladioL-Roma Type 1 Custom yes yes no 32 0 PCCCDW+Rpxr Type 1 Builtin yes yes no 36 0 QTLELQ+Pxbsy Type 1 Builtin yes yes no 40 0 KONDUX+EuphemiaUCAS-Bold Type 1C WinAnsi yes 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LastModified: 2023-03-31 11:43:31 CEST Size: 1837355 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 655 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Ethical Statement Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Study Design and Participants Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Genotype Data and Quality Control Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Multidimensional Scaling and Identification of Genetic Outliers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Imputation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Candidate Gene and Genome-Wide Association Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Cohort Characteristics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Association Analyses in the Discovery Cohort (MIA/MIN-CH and MIA-CH) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Children: Item: Title: Candidate Gene Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Genome-Wide Association Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Replication in Independent Cohorts Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: GWAS Meta-Analysis across Independent Cohorts Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Info: Title: Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations Author: Anca Liliana Cismaru, Deborah Rudin, Luisa Ibañez, Evangelia Liakoni, Nicolas Bonadies, Reinhold Kreutz, Alfonso Carvajal, Maria Isabel Lucena, Javier Martin, Esther Sancho Ponce, Mariam Molokhia, Niclas Eriksson, EuDAC collaborators, Stephan Krähenbühl, Carlo R. Largiadèr, Manuel Haschke, Pär Hallberg, Mia Wadelius and Ursula Amstutz Subject: Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 10-7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41 6.68, p = 1.01 10-7) and rs4427239 (OR = 5.47, 95%CI: 2.81 10.65, p = 5.75 10-7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA. 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Subtype: Link Rect: 76, 565, 166, 596 Annotation: Subtype: Link Rect: 234, 559, 407, 570 Checksum: bd01d538 Type: CRC32 Checksum: 3c6d676a6515bd3ccdb5943b8a5aae8a Type: MD5 Checksum: 7275e4b18caf7a81c97466f1663fdaa5ced2a5d0 Type: SHA-1