Association between HLA and Stevens–Johnson Syndrome Induced by Carbamazepine in Southern Han Chinese: Genetic Markers besides B*1502?

Abstract

Previous studies have demonstrated a strong association between carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-induced SJS/TEN) and HLA-B*1502 in Chinese, and HLA-A*3101 but not HLA-B*1502 in Caucasians and Japanese. Cases with CBZ-induced SJS/TEN negative for HLA-B*1502 were reported recently in Southeast Asia. Negative correlations between CBZ-induced SJS/TEN and B*0702 or B*4001 have also been reported, suggesting a possible protective role. Here, we genotyped HLA-B and HLA-A in 18 cases with CBZ-induced SJS/TEN, in comparison with CBZtolerant and normal controls in Southern Han Chinese. A strong association between HLA-B*1502 and CBZ-induced SJS/TEN was found, with 72.2% sensitivity and 87.1% specificity. However, we also found five patients with SJS (5/18, 27.78%) who were negative for HLA-B*1502. HLA-A*2402 was present in nine of 16 cases with SJS (56.25%, including three of five cases negative for HLA-B*1502), which was significantly more frequent than that of CBZ-tolerant controls or the general southern population. Only one case with SJS carried HLA-A*3101. No statistical difference in the mean age, sex ratio and CBZ usage was found between the CBZ-induced SJS/TEN group and the CBZ-tolerant group. In search for possible protective genetic markers in HLA-B*1502-positive but CBZ-tolerant patients, we failed to find any significant factors in the HLA alleles observed. Given the association between HLA-B*1502 and CBZ-induced SJS/TEN, genetic testing before initiating CBZ therapy is suggested in Han Chinese population. However, physicians should also be vigilant about SJS/TEN in those negative for HLA-B*1502. Other factors for the development of CBZ-induced SJS/TEN in HLA-B*1502-negative patients and protective factors in CBZ-tolerant patients should be investigated further.

Stevens-Johnson Syndrome without Skin Lesions: A Rare and Clinically Challenging Disease in the Urgent Setting

“…HLA-B*5701, HLA-B*5801, HLA-B*1502, HLA-A*3101, HLA-A*0206, HLA-B*4403, HLA-A29, HLA-B12, HLA-DR7, and HLA-A2 are linked to SJS drug hypersensitivity reactions. [38][39][40][41] HLA-DQB1*0601, HLA-DQA1*0103, DQB1*0301, and HLA-A*0206 are linked to ocular manifestations in SJS. 42 Genetic influences can explain why SJS occurs in multiple family members even though it is a rare condition 43 or why it recurs in certain individuals.…”

Pediatric Perspective on Pharmacogenomics

“…Recent studies have found a significant association between CBZ-induced SJS HLA-A*3101 but not HLA-B*1502. These cases were reported in different populations including Caucasian [133], Japanese [134] and, most recently, Chinese [135] children.…”

PharmGKB summary

“…Other alleles have shown significant relationships with SJS/TEN within these ethnicities, such as HLAB*07:02 [98] and HLA-A*31:01 [100, 119-121]. Several studies in Japanese, Korean and Han Chinese patients suggest that carriers of the HLA-B*15:11 alleles [101, 105, 122] have an increased risk of developing SCARs. The average allele frequencies for *15:11 in Japanese and Korean populations are higher than for *15:02 , with values of 0.4 - 0.8% for the Japanese, and 1.6% for Koreans [6].…”

“…The average allele frequencies for *15:11 in Japanese and Korean populations are higher than for *15:02 , with values of 0.4 - 0.8% for the Japanese, and 1.6% for Koreans [6]. Both *15:02 and *15:11 are part of the same HLA-B75 serotype [101, 122], and the two alleles share a 98.6% amino acid sequence homology [105]. Therefore, they may share similar structures that lead to the triggering of an immune reaction when carbamazepine is administered [105].…”

“…Both *15:02 and *15:11 are part of the same HLA-B75 serotype [101, 122], and the two alleles share a 98.6% amino acid sequence homology [105]. Therefore, they may share similar structures that lead to the triggering of an immune reaction when carbamazepine is administered [105]. Studies on *07:02, *31:01 and *15:11 are limited compared to those on *15:02 , and research into alleles beyond *15:02 may help improve predictive genetic testing for SJS/TEN.…”