HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans

Abstract

Background: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.

Methods: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.

Results: The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).

Conclusions: The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).

Figure 1. Results of a Genomewide Association Study of Samples from Case Subjects with Carbamazepine-Induced Hypersensitivity Syndrome and Control Subjects

Panel A shows a Manhattan plot for logistic regression with a strong signal in the HLA-A region on chromosome 6. Each dot represents a P value for the comparison of 22 case subjects with the hypersensitivity syndrome and 2691 healthy control subjects from the Wellcome Trust Case Control Consortium. Panel B shows P values for single-nucleotide polymorphisms (SNPs) in the HLA-A region. There is a strong association between carbamazepine-induced hypersensitivity syndrome and the HLA-A*3101 allele, with identification of the allele in 40.0% of case subjects and only 4.9% of control subjects. The x axis shows the SNP position on chromosome 6 (National Center for Biotechnology Information build 36). The left y axis shows the negative log₁₀ of P values for the comparison between case subjects and control subjects, as calculated with logistic regression. The right y axis shows the recombination rate on chromosome 6 between 29 and 31 Mb. The diamonds show the degree of linkage disequilibrium (LD) in the samples.

Figure 2. Distribution of the HLA-A*3101 Allele across the Spectrum of Clinical Phenotypes of Case Subjects with Carbamazepine- Induced Hypersensitivity and Control Subjects without Adverse Reactions to Carbamazepine

Subjects were recruited at centers collaborating with the University of Liverpool and Walton Centre for Neurology (UK) or centers affiliated with the EPIGEN consortium. The sample obtained from one patient with acute generalized exanthematous pustulosis (AGEP) was analyzed with the samples for the group of case subjects with the hypersensitivity syndrome. Since there were no observations of the HLA-A*3101 allele in the three case subjects with the hypersensitivity syndrome in the EPIGEN cohort, 0.5 was added to each value in a two-by-two contingency table to estimate an odds ratio. One patient with the Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) was of mixed European and Thai ancestry. Study weighting (indicated by different sizes of squares) refers to the proportion of subjects who were recruited from each study cohort. Diamonds indicate pooled odds ratios. The horizontal lines indicate 95% confidence intervals. The abbreviation df denotes degrees of freedom, and I² is the percentage of total variation that is due to heterogeneity rather than chance.