Association of HLA-A and B alleles with antiepileptic drug-induced severe cutaneous adverse drug reactions in a multi–ethnic Malaysian population / Amy Khor Hui Ping

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), a type of severe cutaneous adverse drugs reaction, are an immune-mediated hypersensitivity reaction. Common high risk drugs causing SJS and TEN are aromatic antiepileptic drugs (AEDs) particularly Carbamazepine (CBZ), Phenytoin (PHT) and Lamotrigine (LTG). CBZ is a widely prescribed first-line treatment for epilepsy in Malaysia and therefore is the main causal drug for SJS/TEN cases. A strong association was discovered between HLA-B*15:02 and CBZ-induced SJS/TEN in Taiwan Han Chinese, subsequently the association was replicated in other populations in Southeast Asia including Hong Kong, China, Thailand, Vietnam, India and Malaysia. Malaysia population is composed of heterogeneous multi-ethnic demographic from Austronesia (Malay), Southern India and Southern China. Studies from Malaysia reported the association in Malay and Chinese ethnic groups with one study on Malay CBZSJS/ TEN that found HLA-B*15:02 in 75% of the cases compared to 15.7% in general Malay population. While another study included a mixture of Malay and Chinese CBZSJS/ TEN cases all of which were positive for HLA-B*15:02 but without appropriate drug tolerant control. Furthermore, no study was performed in Malaysia’s Indian ethnic group. Ethnicity specific HLA-A and -B allele association conferring susceptibility to CBZ, PHT and LTG-induced SJS/TEN was investigated in Malaysia three major ethnic groups in this study. AEDs-SJS/TEN cases and AEDs tolerant controls were recruited from two hospitals across Malaysia and HLA-A and -B genotyping were performed. The carrier frequencies of specific HLA-A and -B alleles were compared between 36 AEDs- SJS/TEN cases and 273 AEDs-tolerant controls, stratified by ethnicity and causal drugs. Significant association between HLA-B*15:02 and CBZ-SJS/TEN was detected in the three major ethnic groups: Malay (87.5% versus 12.5%; p = 2.00 x 10-8; Odds ratio (OR) = 49.0; 95% confidence interval (CI) = 9.4-256.8), Chinese (66.7% versus 12.3%; p = 0.0047; OR = 14.3; 95% CI = 2.4-86.0) and Indian (33.3% versus 3.5%; p = 0.042; OR = 13.8; 95% CI = 1.5-125.0). Combined analysis of all ethnic groups showed a significant association with ORCMH of 26.6 (95% CI 12.8-55.3; PCMH = 2.31 x 10-26). For HLA-A, association of HLA-A*31:01 with CBZ-SJS/TEN was discovered in Indians for the first time (p = 0.023; OR = 10.4; 95% CI = 1.6-65.8). This allele was not found in Malay and Chinese CBZ-SJS/TEN groups. Logistic regression analysis demonstrated that HLA-A*31:01 has an independent effect after conditioning for HLA-B*15:02 (P = 0.019; OR 11.7; 95% CI 1.5-9.1). No association was found in PHT and LTG-SJS cases for the three ethnic groups, probably due to limited sample size. In conclusion, this study replicated the association between HLA-B*15:02 and CBZ-SJS/TEN in Malay, Chinese and Indian populations in Malaysia and further demonstrated a new association between HLA-A*31:01 and CBZ-induced SJS/TEN in Indians