Carbamazepine&HLA-A*3101



Scientific Studies & Publication
Carbamazepine & HLA-A*3101
2011 \| 2009

2011
*Title 1: HLA-A3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans N Engl J Med 2011;364:1134-43. Mark McCormack, B.A., Ana Alfirevic, M.D., Ph.D., Stephane Bourgeois, Ph.D., John J. Farrell, M.S., Dalia Kasperavičiūtė, Ph.D., Mary Carrington, Ph.D., Graeme J. Sills, Ph.D., Tony Marson, M.B., Ch.B,, M.D., Xiaoming Jia, M.Eng., Paul I.W. de Bakker, Ph.D., Krishna Chinthapalli M.B., B.S., Mariam Molokhia, M.B., Ch.B., Ph.D., Michael R. Johnson, D.Phil., Gerard D. O’Connor, M.R.C.P.I., Elijah Chaila, M.R.C.P.I., Saud Alhusaini, M.B., Kevin V. Shianna, Ph.D., Rodney A. Radtke, M.D., Erin L. Heinzen, Ph.D., Nicole Walley, B.S., Massimo Pandolfo, M.D., Ph.D., Werner Pichler, M.D., B. Kevin Park, Ph.D., Chantal Depondt, M.D., Ph.D., Sanjay M. Sisodiya, M.D., Ph.D., David B. Goldstein, Ph.D., Panos Deloukas, Ph.D., Norman Delanty, B.M., Gianpiero L. Cavalleri, Ph.D., and Munir Pirmohamed, Ph.D., F.R.C.P. Background:*Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B1502 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-A3101 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 HLAA 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.)


*Title 2: Genome-wide association study identifies HLA-A3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population** Human Molecular Genetics, 2011, Vol. 20, No. 5 1034–1041 Takeshi Ozeki, Taisei Mushiroda, Amara Yowang, Atsushi Takahashi, Michiaki Kubo, Yuji Shirakata, Zenro Ikezawa, Masafumi Iijima, Tetsuo Shiohara, Koji Hashimoto, Naoyuki Kamatani and Yusuke Nakamura An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P-value for association with CBZ-induced cADRs (P=1.1810^-13). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A3101 was present in 60.7% (37/61) of the patients with CBZ-induced cADRs, but in only 12.5% (47/376) of the CBZ-tolerant controls (odds ratio=10.8, 95% confidence interval 5.9–19.6, P=3.6410^-15), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.


Title 3: HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions but not with carbamazepine-induced lymphocyte proliferation in a Japanese population J Dermatol. 2011 Dec 29. doi: 10.1111/j.1346-8138.2011.01457.x. [Epub ahead of print] Niihara H, Kakamu T, Fujita Y, Kaneko S, Morita E. Carbamazepine (CBZ) is the most frequent culprit drug for severe cutaneous adverse drug reactions (ADR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). A strong association between human leukocyte antigen (HLA)-B1502 and CBZ-induced SJS/TEN has been reported in Han Chinese, Thai, Malaysian and Indian populations, but not in Caucasian or Japanese populations. Recent studies showed an association between HLA-A3101 and CBZ-induced ADR in Caucasian and Japanese populations. We conducted a case-control study to determine HLA genotyping of patients with CBZ-induced ADR in a Japanese population. Fifteen patients with CBZ-induced ADR and 33 subjects who had taken CBZ for more than 3months without evidence of any ADR as a control were enrolled. In addition, the results of a CBZ-induced lymphocyte stimulation test were compared between the groups. A strong association was found between HLA-A31 and CBZ-induced ADR (P< 0.001), and a weak association was found between HLA-A11 and HLA-B51 with CBZ-induced ADR. No HLA-B*1502 was found in either patients or control subjects. The mean CBZ-induced lymphocyte stimulation index was significantly high in patients with CBZ-induced ADR compared with CBZ-tolerant patients (P < 0.001); however, no significant difference was seen between HLA-A31-positive subjects and HLA-A31-negative subjects in either group. These findings suggest that HLA-A31 is strongly associated with CBZ-induced ADR in the Japanese, but does not determine CBZ-induced lymphocyte proliferation.


Title 4: Personalizing carbamazepine therapy Genome Med. 2011; 3(5): 28. Mushiroda T, Nakamura Y. The anticonvulsant carbamazepine has a high incidence of cutaneous adverse drug reactions. A recent prospective clinical trial in Taiwan has indicated that HLA-B1502 screening will reduce the incidence of life-threatening adverse reactions to carbamazepine, while a genome-wide association study has identified the HLA-A3101 allele as a genetic risk factor for the full spectrum of carbamazepine-induced cutaneous adverse drug reactions in a European population. These studies should aid future decision-making for personalized use of carbamazepine treatment.


2009
Title 1 : Carbamazepine hypersensitivity syndrome triggered by a human herpes virus reactivation in a genetically predisposed patient Int Arch Allergy Immunol. 2009;149(2):173-7 Calligaris L, Stocco G, De Iudicibus S, Marino S, Decorti G, Barbi E, Carrozzi M, Marchetti F, Bartoli F, Ventura A. A case of severe hypersensitivity syndrome, triggered by carbamazepine in the presence of a concomitant active human herpes virus (HHV) 6 and 7 infection is described. To further understand the molecular mechanism of this adverse reaction, analyses of the genetic variants of human leukocyte antigen (HLA) and of the epoxide hydrolase gene (EPHX1), previously associated with carbamazepine hypersensitivity, were performed. A lymphocyte transformation test (LTT) was conducted in order to detect drug-specific lymphocytes. In the hypersensitive patient, 2 genetic factors previously associated with intolerance to carbamazepine were detected: the allele HLA-A*3101 and homozygosity for the variant allele of SNP rs1051740 in EPHX1. Drug-specific lymphocytes could be detected by LTT when the HHV was active (positive PCR for viral DNA and increased anti-HHV 6 IgG titer), but not when it was no longer active. In conclusion, we document a case of severe carbamazepine hypersensitivity triggered by viral reactivation in a patient presenting the interaction of 2 unfavorable genetic factors.