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.

FIGURE 1

PRISMA flowchart for identification of eligible studies. HLA, human leukocyte antigen.

FIGURE 2

Forest plot for the association of HLA‐B*15:02 with carbamazepine‐induced cutaneous adverse drug reactions. cADRs, cutaneous adverse drug reactions; HLA, human leukocyte antigen; M‐H, Mantel–Haenssel method.

FIGURE 3

Forest plot for the association of HLA‐B*15:02 with carbamazepine‐induced different forms of cutaneous adverse drug reactions. cADRs, cutaneous adverse drug reactions; DRESS, drug reaction with eosinophilia and systemic symptoms; HLA, human leukocyte antigen; M‐H, Mantel–Haenssel method; MPE, maculopapular exanthema; SJS, Stevens−Johnson syndrome; TEN, toxic epidermal necrolysis.

FIGURE 4

Forest plot for the association of HLA‐B*15:02 with carbamazepine‐induced cutaneous adverse drug reactions in different ethnicities. cADRs, cutaneous adverse drug reactions; HLA, human leukocyte antigen; M‐H, Mantel–Haenssel method.

FIGURE 5

Forest plot for the association of HLA‐B*15:21, HLA‐B*38:02 or HLA‐B*40:01 with carbamazepine‐induced cutaneous adverse drug reactions. cADRs, cutaneous adverse drug reactions; HLA, human leukocyte antigen; M‐H, Mantel–Haenssel method.

FIGURE 6

Forest plot for the association of HLA‐B*15:11, HLA‐A*24:02, or HLA‐A*31:01 with carbamazepine‐induced cutaneous adverse drug reactions. cADRs, cutaneous adverse drug reactions; HLA, human leukocyte antigen; M‐H, Mantel–Haenssel method.