TY - JOUR
T1 - Genome-wide association study of metamizole-induced agranulocytosis in european populations
AU - EuDAC collaborators
AU - Cismaru, Anca Liliana
AU - Rudin, Deborah
AU - Ibañez, Luisa
AU - Liakoni, Evangelia
AU - Bonadies, Nicolas
AU - Kreutz, Reinhold
AU - Carvajal, Alfonso
AU - Lucena, Maria Isabel
AU - Martin, Javier
AU - Ponce, Esther Sancho
AU - Molokhia, Mariam
AU - Eriksson, Niclas
AU - Krähenbühl, Stephan
AU - Largiadèr, Carlo R.
AU - Haschke, Manuel
AU - Hallberg, Pär
AU - Wadelius, Mia
AU - Amstutz, Ursula
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - Dipyrone
KW - Drug-induced agranulocytosis
KW - Genome-wide association study
KW - Metamizole
KW - Pharmacogenetics
UR - http://www.scopus.com/inward/record.url?scp=85094893701&partnerID=8YFLogxK
U2 - 10.3390/genes11111275
DO - 10.3390/genes11111275
M3 - Article
AN - SCOPUS:85094893701
SN - 2073-4425
VL - 11
SP - 1
EP - 21
JO - Genes
JF - Genes
IS - 11
M1 - 1275
ER -