This study aimed to investigate the prevalence and association of HLA-B*15:02 with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-SJS/TEN) in the Indian population in Malaysia, which mostly originated from Southern India. HLA-B alleles in five Indian case patients with CBZ-SJS/TEN and 52 CBZ-tolerant controls, and followed by a pooled sample of seven cases from two centers in Malaysia were analyzed. Positive association for HLA-B*15:02 with CBZ-SJS/TEN was detected in Indians (40% [2/5] vs. 3.8% [2/52], odds ratio [OR] 16.7, p = 0.0349), of which 80% (4/5) of the Indian patients originated from Southern India. A pooled sample of seven cases showed stronger association between HLA-B*15:02 and CBZ-SJS/TEN (57.1% [4/7] vs. 3.8% [2/52], OR 33.3, 95% confidence interval [CI] 4.25-162.21, p = 1.05 × 10(-3)). Subsequent meta-analysis on Indians from Malaysia and India further demonstrated a significant and strong association between HLA-B*15:02 and CBZ-SJS/TEN (OR 38.54; 95% CI 6.83-217.34, p < 1.0 × 10(-4)). Our study is the first on Indians predominantly from Southern India that demonstrated HLA-B*15:02 as a strong risk factor for CBZ-SJS/TEN despite a low population allele frequency. This stressed the importance of testing for HLA-B*15:02, irrespective of the ancestral background, including populations with low allele frequency.
We describe the association of the HLA-B*1502 allele in 27 epilepsy patients (19 Malays, 8 Chinese) treated with carbamazepine (CBZ) at the UKM Medical Center (UKMMC), 6 with CBZ-Steven Johnson Syndrome (CBZ-SJS), 11 with CBZ-induced rash, 2 with suspected phenytoin-induced rash and 8 negative controls. Our study showed that 10 (6 Malay, 4 Chinese) patients were positive for HLA-B*1502. Out of the 10 patients, six were confirmed to have CBZ-SJS (p = 0.0006), while four patients developed a skin rash. However there were 6 Malay patients and 1 Chinese patient that developed a skin rash after CBZ administration who were not positive for the allele, indicating that there might be more that one allele associated with CBZ-induced hypersensitivity. Another 2 patients were suspected of having phenytoin-induced rash, instead of CBZ, and these patients did not have HLA-B*1502. In conclusion, this study confirmed the association of HLA-B*1502 with CBZ-SJS among Malaysian epilepsy patients, however there might be other genes that could be responsible for the CBZ-induced rash.
Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.