Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
Genes (Basel). 2020 Oct 29;11(11):1275. doi: 10.3390/genes11111275.
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 ( < 1 × 10) 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, = 1.01 × 10) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, = 5.75 × 10), of which the latter is located in the 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.
粒细胞缺乏症是一种罕见而严重的药物特异性不良反应，发生于扑热息痛（在瑞士和德国等国家广泛使用的一种镇痛药）。值得注意的是，其潜在机制尚未完全阐明，也没有已知的预测因素可以识别出高危患者。为了确定扑热息痛诱导的粒细胞缺乏症（MIA）和中性粒细胞减少症（MIN）的遗传易感性变异，我们进行了一项回顾性多中心合作研究，包括来自三个欧洲人群的病例和对照。使用来自瑞士队列的全基因组基因分型数据（45 例病例，191 例对照）进行关联分析，随后在两个独立的欧洲队列（41 例病例，273 例对照）和联合发现荟萃分析中进行了复制。在瑞士队列或联合荟萃分析中均未观察到全基因组显著关联（ < 1 × 10），也未确定候选基因提示免疫介导的机制。在所有队列的 MIA 病例联合荟萃分析中，在 9 号染色体上确定了两个候选基因座，rs55898176（OR = 4.01，95%CI：2.41-6.68， = 1.01 × 10）和 rs4427239（OR = 5.47，95%CI：2.81-10.65， = 5.75 × 10），后者位于先前与造血相关的基因中。这是首次针对 MIA 的全基因组关联研究，确定了具有生物学意义的提示性关联，这些关联可能作为 GWAS 后分析的垫脚石，以进一步深入了解 MIA 的发病机制。
