HLA-B Alleles and Lamotrigine-Induced Cutaneous Adverse Drug Reactions in the Han Chinese Population

Abstract

Lamotrigine (LTG) is a commonly used antiepileptic drug. However, the use of LTG is limited because of its cutaneous adverse drug reactions (cADRs) ranging from mild maculopapular eruption (MPE) to severe Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between HLA-B*1502 and carbamazepine-induced SJS ⁄ TEN has been identified in Chinese and Thai. Although three of seven cases with HLA-B*1502 have been reported in LTG-induced SJS ⁄ TEN so far, the relationship between HLA-B*1502 and LTG-induced SJS ⁄ TEN needs further investigation. It is also unclear whether there is a specific genetic marker associated with LTG-induced MPE in Chinese. In this study, we genotyped 43 Han Chinese patients treated with LTG (14 cases with LTG-induced cADRs and 29 LTG-tolerant controls), using PCR-SSP for HLA-B*1502 testing and low-resolution genotyping, as well as sequencing for four-digit genotyping. The two cases with SJS were negative for HLA-B*1502, with B1301 ⁄ 1301 and 4601 ⁄ 5610, respectively. Combining the data with previous studies, there was no significant difference in the frequency of subjects with HLA-B*1502 between the LTG-induced SJS ⁄ TEN group and the LTG-tolerant group (p = 0.08, OR 4.23, 95% CI 0.94-18.97). In the MPE group, only one was positive for HLA-B*1502. There was no significant difference in the frequency of a specific HLA-B allele between the MPE group and the LTG-tolerant group either. In this study, no significant association between HLA-B*1502 and LTG-induced SJS or MPE was found. Given the small sample size and only HLA-B locus genotyping, further large-scale studies are required to explore genetic associations with LTG-induced cADRs.

Safety of lamotrigine in paediatrics: a systematic review

“…36 The protective mechanism of the introduction of small incremental doses, although not fully understood, is believed to involve the desensitisation of antigen presenting cells and T lymphocytes 37. Human leucocyte antigen (HLA) B genotyping may be useful in determining the predisposition to LTG-induced rash, but the level of HLA involvement is not fully determined 38. Comedication with valproic acid is also a significant predictor of rash in LTG-treated patients 33.…”

HLA and Pharmacogenetics of Drug Hypersensitivity

“…Studies into lamotrigine associated DHS however, have produced conflicting results. Several studies could not show a link between lamotrigine-induced SJS and the carriage of HLA-B*1502 in the Han Chinese [66,67]. Others, which have examined oxcarbazepine-, phenytoin-and lamotrigine-induced SJS/TEN together, have reported expression of HLA-B*1502 in 33% of lamotrigine SJS cases, yet the reported differences from controls did not reach statistical significance [64].…”

PharmGKB summary

“…However, studies linking HLA-B*15:02 with oxcarbazepine-induced SJS or MPE have shown mixed results [131, 146-148]. Though no individual studies have found significant associations between *15:02 and lamotrigine-induced adverse reactions [130, 131, 149, 150], a meta-analysis of four studies did find a significantly increased risk for SJS/TEN for patients carrying *15:02 who receive lamotrigine [118]. …”