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HLA-B*59:01: a marker for Stevens–Johnson syndrome/toxic epidermal necrolysis caused by methazolamide in Han Chinese

Abstract

Methazolamide is an intraocular pressure-lowering drug that is used in the treatment of glaucoma and other ophthalmologic abnormalities. The use of methazolamide has been shown to cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients of Asian ancestry. Methazolamide-induced SJS/TEN is associated with the presence of HLA-B59 serotype/HLA-B*59:01 in Korean and Japanese populations. To better understand the genetic risk factors for these adverse reactions in the Han Chinese population, we characterized the HLA class I genotypes of eight Chinese patients with methazolamide-induced SJS/TEN from 2008 to 2014. The frequency of HLA-B*59:01 was 87.5% (7/8) in the case patients, which was significantly different from 0% (0/30) in the methazolamide-tolerant patients (odds ratio (OR)=305.0; P=6.3 × 10−7) and 0.35% (1/283) in healthy subjects from the human major histocompatibility complex database (OR=1974.0; P=2.0 × 10−12). HLA-C*01:02, which is closely linked to HLA-B*59:01, had a weaker but notable association with methazolamide-induced SJS/TEN compared with the tolerant controls (OR=12.1; P=0.016) and general population (OR=15.5; P=2.0 × 10−3). The distribution of the HLA-B*59:01-C*01:02 haplotype was also significantly different in cases and controls. This study demonstrated a strong association between HLA-B*59:01 and methazolamide-induced SJS/TEN in the Han Chinese population for the first time. Pretherapy screening for HLA-B*59:01 would be useful to reduce the risk of methazolamide-induced SJS/TEN.

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References

  1. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC . Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129: 92–96.

    Article  CAS  PubMed  Google Scholar 

  2. Roujeau JC, Stern RS . Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331: 1272–1285.

    Article  CAS  PubMed  Google Scholar 

  3. Rzany B, Mockenhaupt M, Baur S, Schroder W, Stocker U, Mueller J et al. Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry. J Clin Epidemiol 1996; 49: 769–773.

    Article  CAS  PubMed  Google Scholar 

  4. Fritsch PO, Sidoroff A . Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Am J Clin Dermatol 2000; 1: 349–360.

    Article  CAS  PubMed  Google Scholar 

  5. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol 2008; 128: 35–44.

    Article  CAS  PubMed  Google Scholar 

  6. Sud RN, Grewal SS . Stevens Johnson syndrome due to Diamox. Indian J Ophthalmol 1981; 29: 101–103.

    CAS  PubMed  Google Scholar 

  7. Flach AJ, Smith RE, Fraunfelder FT . Stevens-Johnson syndrome associated with methazolamide treatment reported in two Japanese-American women. Ophthalmology 1995; 102: 1677–1680.

    Article  CAS  PubMed  Google Scholar 

  8. Shirato S, Kagaya F, Suzuki Y, Joukou S . Stevens-Johnson syndrome induced by methazolamide treatment. Arch Ophthalmol 1997; 115: 550–553.

    Article  CAS  PubMed  Google Scholar 

  9. Cotter JB . Methazolamide-induced Stevens-Johnson syndrome: a warning!. Arch Ophthalmol 1998; 116: 117.

    Article  CAS  PubMed  Google Scholar 

  10. Park YJ, Moon JI, Park CK . Three cases of Stevens-Johnson syndrome associated with methazolamide treatment. J Korean Ophthalmol Soc 1999; 40: 613–618.

    Google Scholar 

  11. Ahn EY, Lee JB, Lee SC, Won YH . Four cases of Stevens–Johnson syndrome associated with methazolamide treatment. Korean J Dermatol 2000; 38: 798–801.

    Google Scholar 

  12. Moon JI, Seo JH, Park CK . Association of HLA type with Stevens–Johnson syndrome induced by methazolamide treatment. J Korean Ophthalmol Soc 2000; 41: 2241–2246.

    Google Scholar 

  13. Sung KH, Jwong Y, Choi HU, Lee SK . Two cases of HLA-B59(+) Stevens–Johnson syndrome (SJS)–toxic epidermal necrolysis (TEN) associated with methazolamide treatment. Korean J Dermatol 2005; 43: 561–563.

    Google Scholar 

  14. Kim SH, Kim M, Lee KW, Kim SH, Kang HR, Park HW et al. HLA-B*59:01 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Pharmacogenomics 2010; 11: 879–884.

    Article  CAS  PubMed  Google Scholar 

  15. Jin RJ, Zhang XY, Jiang JX, Sun LP . One case of methazolamide-induced Stevens-Johnson syndrome [in Chinese]. Chin J Derm Venereol 2012; 26: 363–364.

    Google Scholar 

  16. Yan C, Xue HY, Cai CC . Stevens-Johnson syndrome induced by methazolamide tablet [in Chinese]. Chin J Drug Appl Monit 2012; 9: 179–181.

    Google Scholar 

  17. Roujeau JC . Clinical heterogeneity of drug hypersensitivity. Toxicology 2005; 209: 123–129.

    Article  CAS  PubMed  Google Scholar 

  18. Kitts A, Feolo M, Helmberg W . The Major Histocompatibility Complex Database, dbMHC In: McEntyre J, Ostell J (eds) The NCBI Handbook. National Center for Biotechnology Information NIH: Bethesda, MD, USA, 2003.

    Google Scholar 

  19. Haldane JB . The estimation and significance of the logarithm of a ratio of frequencies. Ann Hum Genet 1956; 20: 309–311.

    Article  CAS  PubMed  Google Scholar 

  20. Maenaka K, Maenaka T, Tomiyama H, Takiguchi M, Stuart DI, Jones EY . Nonstandard peptide binding revealed by crystal structures of HLA-B*5101 complexed with HIV immunodominant epitopes. J Immunol 2000; 165: 3260–3267.

    Article  CAS  PubMed  Google Scholar 

  21. Eswar N, Webb B, Marti-Renom M, Madhusudhan M, Eramian D, Shen M et al. Comparative protein structure modeling using Modeller. Curr Protoc Protein Sci 2007; Chapter 2: Unit 2.9.

    PubMed  Google Scholar 

  22. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009; 30: 2785–2791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Trott O, Olson AJ . AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455–461.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML . Comparison of simple potential functions for simulating liquid water. J Chem Phys 1983; 79: 926.

    Article  CAS  Google Scholar 

  25. Darden T, York D, Pedersen L . Particle Mesh Ewald—an N.Log(N) Method for Ewald Sums in Large Systems. J Chem Phys 1993; 98: 10089–10092.

    Article  CAS  Google Scholar 

  26. Ryckaert JP, Ciccotti G, Berendsen HJC . Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 1977; 23: 327–341.

    Article  CAS  Google Scholar 

  27. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W et al. A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J Comput Chem 2003; 24: 1999–2012.

    Article  CAS  PubMed  Google Scholar 

  28. Salomon-Ferrer R, Case DA, Walker RC . An overview of the Amber biomolecular simulation package. Wiley Interdiscip Rev-Comput Mol Sci 2013; 3: 198–210.

    Article  CAS  Google Scholar 

  29. U.S. Food Drug Adm Information for Healthcare Professionals: Dangerous or Even Fatal Skin Reactions—Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, and generics). U.S. Food Drug Adm.: Silver Spring, MD, USA, 2007.

  30. U.S. Food Drug Adm Information for Healthcare Professionals: Abacavir (marketed as Ziagen) and Abacavir-Containing Medications. U.S. Food Drug Adm.: Silver Spring, MD, USA, 2008.

  31. Ha JH, Song JY, Kim HO, Kim JW . A case of Stevens-Johnson syndrome caused by acetazolamide. Korean J Dermatol 2003; 41: 248–250.

    Google Scholar 

  32. Her Y, Kil MS, Park JH, Kim CW, Kim SS . Stevens-Johnson syndrome induced by acetazolamide. J Dermatol 2011; 38: 272–275.

    Article  PubMed  Google Scholar 

  33. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR . Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res 2011; 39: D913–D919.

    Article  CAS  PubMed  Google Scholar 

  34. Ross CJ, Katzov-Eckert H, Dube MP, Brooks B, Rassekh SR, Barhdadi A et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet 2009; 41: 1345–1349.

    Article  CAS  PubMed  Google Scholar 

  35. Nelson MR, Bacanu SA, Mosteller M, Li L, Bowman CE, Roses AD et al. Genome-wide approaches to identify pharmacogenetic contributions to adverse drug reactions. Pharmacogenomics J 2009; 9: 23–33.

    Article  CAS  PubMed  Google Scholar 

  36. Daly AK . Genome-wide association studies in pharmacogenomics. Nat Rev Genet 2010; 11: 241–246.

    Article  CAS  PubMed  Google Scholar 

  37. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004; 428: 486.

    Article  CAS  PubMed  Google Scholar 

  38. Uetrecht J, Naisbitt DJ . Idiosyncratic adverse drug reactions: current concepts. Pharmacol Rev 2013; 65: 779–808.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Yun J, Marcaida MJ, Eriksson KK, Jamin H, Fontana S, Pichler WJ et al. Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01. J Immunol 2014; 192: 2984–2993.

    Article  CAS  PubMed  Google Scholar 

  40. Illing PT, Vivian JP, Dudek NL, Kostenko L, Chen Z, Bharadwaj M et al. Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 2012; 486: 554–558.

    Article  CAS  PubMed  Google Scholar 

  41. Ostrov DA, Grant BJ, Pompeu YA, Sidney J, Harndahl M, Southwood S et al. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire. Proc Natl Acad Sci USA 2012; 109: 9959–9964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wei CY, Chung WH, Huang HW, Chen YT, Hung SI . Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Clin Immunol 2012; 129: 1562–1569.

    Article  CAS  PubMed  Google Scholar 

  43. Chessman D, Kostenko L, Lethborg T, Purcell AW, Williamson NA, Chen Z et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 2008; 28: 822–832.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 81472873, 81071287, 30971582 and 31371274) and the Shanghai Municipal Commission of Science and Technology Program (14DJ1400100).

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Correspondence to X Luo or Q Xing.

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Yang, F., Xuan, J., Chen, J. et al. HLA-B*59:01: a marker for Stevens–Johnson syndrome/toxic epidermal necrolysis caused by methazolamide in Han Chinese. Pharmacogenomics J 16, 83–87 (2016). https://doi.org/10.1038/tpj.2015.25

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