Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population

Takeshi Ozeki, Taisei Mushiroda, Amara Yowang, Atsushi Takahashi, Michiaki Kubo, Yuji Shirakata, Zenro Ikezawa, Masafumi Iijima, Tetsuo Shiohara, Koji Hashimoto, Naoyuki Kamatani, Yusuke Nakamura

研究成果: Article

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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 = 1.18 3 10-13). 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-A*3101 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 = 3.64 3 10-15), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A*3101 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.

元の言語English
記事番号ddq537
ページ(範囲)1034-1041
ページ数8
ジャーナルHuman molecular genetics
20
発行部数5
DOI
出版物ステータスPublished - 01-03-2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Ozeki, T., Mushiroda, T., Yowang, A., Takahashi, A., Kubo, M., Shirakata, Y., Ikezawa, Z., Iijima, M., Shiohara, T., Hashimoto, K., Kamatani, N., & Nakamura, Y. (2011). Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Human molecular genetics, 20(5), 1034-1041. [ddq537]. https://doi.org/10.1093/hmg/ddq537