Dataset Information

HLA-A*11:01 is associated with levetiracetam-induced psychiatric adverse events.

ABSTRACT: Levetiracetam (LEV) is effective for focal and generalized epilepsy and is used worldwide because of its relatively few drug interactions and favorable tolerability. However, some psychiatric adverse events (PAEs) have been reported, resulting in drug withdrawal. The pathophysiology of LEV-induced PAE has not yet been elucidated. In this study, we investigated the relationship between PAEs and human leukocyte antigen (HLA) genes. Eleven epilepsy patients, who developed PAEs after the administration of LEV and spontaneously improved after drug withdrawal, were enrolled retrospectively. Genomic DNA from the peripheral blood was extracted, and four-digit allele genotyping of HLA genes was performed. The genotype frequencies of HLA genes were compared to those of 80 patients in which LEV was well tolerated, as well as to 485 individuals from the general Korean population. The frequency of the HLA-A*1101 allele was significantly higher in the LEV-induced PAEs group compared to both the LEV-tolerant group (p = 0.021, OR 4.80, 95% CI 1.30-17.74) and the general Korean population (p = 0.015, OR 4.62, 95% CI 1.38-15.45). This study is the first attempt at investigating the relationship between the HLA system and LEV-induced PAE. The results of this study suggest that the HLA-A*1101 allele could be a risk factor for the development of PAEs.

SUBMITTER: Yang TW

PROVIDER: S-EPMC6051654 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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HLA-A*11:01 is associated with levetiracetam-induced psychiatric adverse events.

Yang Tae-Won TW Moon Jangsup J Kim Tae-Joon TJ Jun Jin-Sun JS Lim Jung-Ah JA Lee Soon-Tae ST Jung Keun-Hwa KH Park Kyung-Il KI Jung Ki-Young KY Chu Kon K Lee Sang Kun SK

PloS one 20180718 7

Levetiracetam (LEV) is effective for focal and generalized epilepsy and is used worldwide because of its relatively few drug interactions and favorable tolerability. However, some psychiatric adverse events (PAEs) have been reported, resulting in drug withdrawal. The pathophysiology of LEV-induced PAE has not yet been elucidated. In this study, we investigated the relationship between PAEs and human leukocyte antigen (HLA) genes. Eleven epilepsy patients, who developed PAEs after the administrat ...[more]

PMID: 30020991

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.

Project description:Importance:Levetiracetam is a commonly used antiepileptic drug, yet psychiatric adverse effects are common and may lead to treatment discontinuation. Objective:To derive prediction models to estimate the risk of psychiatric adverse effects from levetiracetam use. Design, Setting, and Participants:Retrospective open cohort study. All patients meeting the case definition for epilepsy after the Acceptable Mortality Reporting date in The Health Improvement Network (THIN) database based in the United Kingdom (inclusive January 1, 2000, to May 31, 2012) who received a first-ever prescription for levetiracetam were included. Of 11 194 182 patients registered in THIN, this study identified 7400 presumed incident cases (66.1 cases per 100 000 persons) over a maximum of 12 years' follow-up. The index date was when patients received their first prescription code for levetiracetam, and follow-up lasted 2 years or until an event, loss to follow-up, or censoring. The analyses were performed on April 22, 2018. Exposure:A presumed first-ever prescription for levetiracetam. Main Outcomes and Measures:The outcome of interest was a Read code for any psychiatric sign, symptom, or disorder as reached through consensus by 2 authors. This study used regression techniques to derive 2 prediction models, one for the overall population and one for those without a history of a psychiatric sign, symptom, or disorder during the study period. Results:Among 1173 patients with epilepsy receiving levetiracetam, the overall median age was 39 (interquartile range, 25-56) years, and 590 (50.3%) were female. A total of 14.1% (165 of 1173) experienced a psychiatric symptom or disorder within 2 years of index prescription. The odds of reporting a psychiatric symptom were significantly elevated for women (odds ratio [OR], 1.41; 95% CI, 0.99-2.01; P = .05) and those with a preexposure history of higher social deprivation (OR, 1.15; 95% CI, 1.01-1.31; P = .03), depression (OR, 2.20; 95% CI, 1.49-3.24; P < .001), anxiety (OR, 1.74; 95% CI, 1.11-2.72; P = .02), or recreational drug use (OR, 2.02; 95% CI, 1.20-3.37; P = .008). The model performed well after stratified k = 5-fold cross-validation (area under the curve [AUC], 0.68; 95% CI, 0.58-0.79). There was a gradient in risk, with probabilities increasing from 8% for 0 risk factors to 11% to 17% for 1, 17% to 31% for 2, 30% to 42% for 3, and 49% when all risk factors were present. For those free of a preexposure psychiatric code, a second model performed comparably well after k = 5-fold cross-validation (AUC, 0.72; 95% CI, 0.54-0.90). Specificity was maximized using threshold cutoffs of 0.10 (full model) and 0.14 (second model); a score below these thresholds indicates safety of prescription. Conclusions and Relevance:This study derived 2 simple models that predict the risk of a psychiatric adverse effect from levetiracetam. These algorithms can be used to guide prescription in clinical practice.

Project description:Phenytoin (PHT) is one of the most commonly reported aromatic anti-epileptic drugs (AEDs) to cause cutaneous adverse reactions (CADRs), particularly severe cutaneous adverse reactions (SCARs). Although human leukocyte antigen (HLA)-B*15:02 is associated with PHT-induced Steven Johnson syndrome/toxic epidermal necrosis (SJS/TEN) in East Asians, the association is much weaker than it is reported for carbamazepine (CBZ). In this study, we investigated the association of pharmacogenetic variants of the HLA B gene and CYP2C9*3 with PHT-CADRs in South Indian epileptic patients. This prospective case-controlled study included 25 PHT-induced CADRs, 30 phenytoin-tolerant patients, and 463 (HLA-B) and 82 (CYP2C9*3) normal-controls from previous studies included for the case and normal-control comparison. Six SCARs cases and 19 mild-moderate reactions were observed among the 25 cases. Pooled data analysis was performed for the HLA B*51:01 and PHT-CADRs associations. The Fisher exact test and multivariate binary logistic regression analysis were used to identify the susceptible alleles associated with PHT-CADRs. Multivariate analysis showed that CYP2C9*3 was significantly associated with overall PHT-CADRs (OR = 12.00, 95% CI 2.759-84.87, p = 003). In subgroup analysis, CYP2C9*3 and HLA B*55:01 were found to be associated with PHT-SCARs (OR = 12.45, 95% CI 1.138-136.2, p = 0.003) and PHT-maculopapular exanthema (MPE) (OR = 4.041, 95% CI 1.125-15.67, p = 0.035), respectively. Pooled data analysis has confirmed the association between HLA B*51:01/PHT-SCARs (OR = 6.273, 95% CI 2.24-16.69, p = <0.001) and HLA B*51:01/PHT-overall CADRs (OR = 2.323, 95% CI 1.22-5.899, p = 0.037). In this study, neither the case nor the control groups had any patients with HLA B*15:02. The risk variables for PHT-SCARs, PHT-overall CADRs, and PHT-MPE were found to be HLA B*51:01, CYP2C9*3, and HLA B*55:01, respectively. These alleles were identified as the risk factors for the first time in the South Indian Tamil population for PHT-CADRs. Further investigation is warranted to establish the clinical relevance of these alleles in this population with larger sample size.

Project description:An inefficient immune response against Epstein-Barr virus (EBV) infection is related to the pathogenesis of a subgroup of classical Hodgkin lymphomas (cHL). Some EBV immune-evasion mechanisms target HLA presentation, including the non-classical HLA-E molecule. HLA-E can be recognized by T cells via the TCR, and it also regulates natural killer (NK) cell signaling through the inhibitory CD94/NKG2A receptor. Some evidences indicate that EBV-infected B-cells promote the proliferation of NK subsets bearing CD94/NKG2A, suggesting a relevant function of these cells in EBV control. Variations in CD94/NKG2A-HLA-E interactions could affect NK cell-mediated immunity and, consequently, play a role in EBV-driven transformation and lymphomagenesis. The two most common HLA-E alleles, E*01:01 and E*01:03, differ by a single amino acid change that modifies the molecule function. We hypothesized that the functional differences in these variants might participate in the pathogenicity of EBV.We studied two series of cHL patients, both with EBV-positive and-negative cases, and a cohort of unrelated controls, to assess the impact of HLA-E variants on EBV-related cHL susceptibility.We found that the genotypes with at least one copy of E*01:01 (i.e., E*01:01 homozygous and heterozygous) were underrepresented among cHL patients from both series compared to controls (72.6% and 71.6% vs 83%, p = 0.001). After stratification by EBV status, we found low rates of E*01:01-carriers mainly among EBV-positive cases (67.6%). These reduced frequencies are seen independently of other factors such as age, gender, HLA-A*01 and HLA-A*02, HLA alleles positively and negatively associated with the disease (adjusted OR = 0.4, p = 0.001). Furthermore, alleles from both HLA loci exert a cumulative effect on EBV-associated cHL susceptibility.These results indicate that E*01:01 is a novel protective genetic factor in EBV-associated cHL and support a role for HLA-E recognition on the control of EBV infection and lymphomagenesis.

Project description:HLA-B*13:01 allele has been identified as the genetic determinant of dapsone hypersensitivity syndrome (DHS) among leprosy and non-leprosy patients in several studies. Dapsone hydroxylamine (DDS-NHOH), an active metabolite of dapsone, has been believed to be responsible for DHS. However, studies have not highlighted the importance of other genetic polymorphisms in dapsone-induced severe cutaneous adverse reactions (SCAR). We investigated the association of HLA alleles and cytochrome P450 (CYP) alleles with dapsone-induced SCAR in Thai non-leprosy patients. A prospective cohort study, 16 Thai patients of dapsone-induced SCARs (5 SJS-TEN and 11 DRESS) and 9 Taiwanese patients of dapsone-induced SCARs (2 SJS-TEN and 7 DRESS), 40 dapsone-tolerant controls, and 470 general Thai population were enrolled. HLA class I and II alleles were genotyped using polymerase chain reaction-sequence specific oligonucleotides (PCR-SSOs). CYP2C9, CYP2C19, and CYP3A4 genotypes were determined by the TaqMan real-time PCR assay. We performed computational analyses of dapsone and DDS-NHOH interacting with HLA-B*13:01 and HLA-B*13:02 alleles by the molecular docking approach. Among all the HLA alleles, only HLA-B*13:01 allele was found to be significantly associated with dapsone-induced SCARs (OR = 39.00, 95% CI = 7.67-198.21, p = 5.3447 × 10-7), SJS-TEN (OR = 36.00, 95% CI = 3.19-405.89, p = 2.1657 × 10-3), and DRESS (OR = 40.50, 95% CI = 6.38-257.03, p = 1.0784 × 10-5) as compared to dapsone-tolerant controls. Also, HLA-B*13:01 allele was strongly associated with dapsone-induced SCARs in Asians (OR = 36.00, 95% CI = 8.67-149.52, p = 2.8068 × 10-7) and Taiwanese (OR = 31.50, 95% CI = 4.80-206.56, p = 2.5519 × 10-3). Furthermore, dapsone and DDS-NHOH fit within the extra-deep sub pocket of the antigen-binding site of the HLA-B*13:01 allele and change the antigen-recognition site. However, there was no significant association between genetic polymorphism of cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) and dapsone-induced SCARs (SJS-TEN and DRESS). The results of this study support the specific genotyping of the HLA-B*13:01 allele to avoid dapsone-induced SCARs including SJS-TEN and DRESS before initiating dapsone therapy in the Asian population.

Dataset Information

HLA-A*11:01 is associated with levetiracetam-induced psychiatric adverse events.

Publications

HLA-A*11:01 is associated with levetiracetam-induced psychiatric adverse events.

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