Carbamazepine (CBZ) causes life‐threating T‐cell‐mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug‐induced liver injury (CBZ‐DILI). In order to evaluate shared or phenotype‐specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta‐analysis of two genomewide association studies (GWAS) on a total of 43 well‐phenotyped Northern and Southern European CBZ‐SCAR cases and 10,701 population controls and a GWAS on 12 CBZ‐DILI cases and 8,438 ethnically matched population controls. HLA‐A*31:01 was identified as the strongest genetic predisposing factor for both CBZ‐SCAR (odds ratio (OR) = 8.0; 95% CI 4.10–15.80; P = 1.2 × 10−9) and CBZ‐DILI (OR = 7.3; 95% CI 2.47–23.67; P = 0.0004) in European populations. The association with HLA‐A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10−9) rather than by Stevens‐Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA‐B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ‐SCAR cases, which needs replication in additional cohorts and functional evaluation.
Background: b-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE. Objective: We sought to identify genetic predisposing factors for immediate reactions to b-lactam antibiotics. Methods: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort. Results: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P 5 2 3 10 214); this was in linkage disequilibrium with HLA-DRB1*10:01 (odds ratio, 2.93; P 5 5.4 3 10 27) and HLA-DQA1*01:05 (odds ratio, 2.93, P 5 5.4 3 10 27). Haplotype analysis identified that HLA-DRB1*10:01 was a risk factor even without the HLA-DQA1*01:05 allele. The association with HLA-DRB1*10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1*10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P 5 4.1 3 10 29). No association with HLA-DRB1*10:01 was identified in 268 patients with delayed hypersensitivity reactions to b-lactams. Conclusions: HLA-DRB1*10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.
The discovery in recent years by gravity wave detectors of dozens of merging binary black holes with masses much greater than one solar mass, when taken with the known population of black holes raises the possibility that it may not be possible to explain their all their origins and growth by credible accretion mechanisms. This paper offers an alternative perspective; that black holes can increase their mass by a quantum process linked to the acceleration of distant matter. Also, the idea that dark matter is predominantly composed of black holes in strongly supported. A testable equation M/M = 2H for the fractional rate of production of dark matter inside a large region of space with radius r and mass M(r), where H is the Hubble Constant, is presented. A mechanism to produce early supermassive black holes is proposed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.