Associations of HLA genetic variants with carbamazepine‐induced cutaneous adverse drug reactions: An updated meta‐analysis

Abstract

Aggregated risk of carbamazepine (CBZ)‐induced cutaneous adverse drug reactions (cADRs) with different HLA variants are unclear and limited in terms of the power of studies . This study aimed to assess the aggregated risk of CBZ‐induced cADRs associated with carrying the following HLA variants: HLA‐B*15:02 , HLA‐B*15:11 , HLA‐B*15:21 , HLA‐B*38:02 , HLA‐B*40:01 , HLA‐B*46:01 , HLA‐B*58:01 , HLA‐A*24:02 , and HLA‐A*31:01 . Literature was searched in different databases following PRISMA guidelines. The outcomes were measured as odds ratio (OR) using RevMan software by a random/fixed effects model, where p < 0.05 was set as statistical significance. In total, 46 case–control studies met the inclusion criteria and were included in this analysis consisting of 1817 cases and 6614 controls. It was found that case‐patients who carried the HLA‐B*15:02 allele were associated with a significantly increased risk of CBZ‐induced Stevens−Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) compared to controls (OR 26.01; 95% CI 15.88–42.60; p < 0.00001). The aggregated risk of cADRs was slightly higher in Asian compared to Caucasian patients (Asians: OR 14.84; 95% CI 8.95–24.61; p < 0.00001; Caucasians: OR 11.65; 95% CI 1.68–80.70; p = 0.01). Further, HLA‐B*15:11 , HLA‐B*15:21 , or HLA‐A*31:01 allele was also associated with significantly increased risk of CBZ‐induced cADRs ( HLA‐B*15:11: OR 6.08; 95% CI 2.28–16.23; p = 0.0003; HLA‐B*15:21: OR 5.37; 95% CI 2.02–14.28; p = 0.0008; HLA‐A*31:01: OR 5.92; 95% CI 4.35–8.05; p < 0.00001). Other HLA variants were not found to have any significant associations with CBZ‐induced cADRs. Strong associations between the HLA‐B*15:02 , HLA‐B*15:11 , HLA‐B*15:21 , or HLA‐A*31:01 allele with CBZ‐induced cADRs have been established in this analysis. Pharmacogenetic testing of particular HLA alleles before initiation of CBZ therapy may be beneficial to patients and may help to eradicate cADRs substantially.

Unraveling the genetic link: an umbrella review on HLA-B*15:02 and antiepileptic drug-induced Stevens–Johnson syndrome/toxic epidermal necrolysis

“…Each antiepileptic was analyzed separately. For carbamazepine, there were 42 case–control studies [14–54] and 7 meta-analyses [41,55–60]. For lamotrigine, there were 30 case–control studies [16,18,20,28,36,41,44,48,51,61–74] and three meta-analyses [68,70,72].…”

“…A total of seven relevant meta-analyses were identified [41, [55][56][57][58]60,84]. Four of these studies were found to be of critically low quality.…”

“…This is likely due to the nature of older studies [60,84] having smaller sample sizes, which can lead to over/ underestimation of effect sizes. The most recent studies from Biswas [55] and Rashid [56] include a larger sample size and, therefore, are more likely to represent a more precise measure of the true population risk. The most recent study conducted by Biswas et al [55] encompassed 38 studies involving 1346 cases, 2504 tolerant controls and 564 population controls.…”

Pharmacogenomics and non-genetic factors affecting drug response in autism spectrum disorder in Thai and other populations: current evidence and future implications

“…Since epilepsy appears to be prevalent in ASD patients, antiepileptic drugs, e.g., carbamazepine, might be commonly prescribed to children with ASD. The pharmacogenomic response of carbamazepine in ASD patients has not been assessed yet; however, an association of HLA-B (OMIM ID: 142830) pharmacogenomics with carbamazepine-induced SJS/TEN has already been well established ( Kloypan et al, 2021 ; Biswas et al, 2022a ) and needs further consideration in ASD patients.…”

Polygenic risk scores: An overview from bench to bedside for personalised medicine

“…Efficacy end-points used in pharmacogenomic studies require specific tools, such as the Montgomery-Asberg Depression Rating Scale for depression studies, which will not be available in biobanks. For safety end-points, stratification based on severity may be important as some of the single gene variants have been associated with severe, but not the milder, phenotypes (Biswas et al, 2022). Another major issue which needs to be considered in pharmacogenomic PRSs is polypharmacy (i.e.…”