Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cross-ethnicity tagging SNPs for HLA alleles associated with adverse drug reaction

Abstract

Reduction of adverse drug reaction (ADR) incidence through screening of predisposing human leucocyte antigen (HLA) alleles is a promising approach for many widely used drugs. However, application of these associations has been limited by the cost burden of HLA genotyping. Use of single nucleotide polymorphisms (SNPs) that can approximate (β€˜tag’) HLA alleles of interest has been proposed as a cost-effective and simple alternative to conventional genotyping. However, most reported SNP tags have not been validated and there is concern regarding clinical utility of this approach due to tagging inconsistency across different populations. We assess the ability of 67 previously reported and 378 novel tagging SNPs, identified here in 5 HLA reference panels, to tag 15 ADR-associated HLA alleles in a panel of 955 ethnically diverse samples. Tags for 8 HLA alleles of interest were identified with 100% sensitivity and >95% specificity. These SNPs may act as a reliable genotyping approach for the routine screening of patients, without the need to account for patient ethnicity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Yip VL, Alfirevic A, Pirmohamed M. Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review. Clin Rev Allergy Immunol. 2015;48:165–75.

    ArticleΒ  CASΒ  Google ScholarΒ 

  2. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200–5.

    ArticleΒ  CASΒ  Google ScholarΒ 

  3. Chen Z, Liew D, Kwan P. Effects of a HLA-B*15:02 screening policy on antiepileptic drug use and severe skin reactions. Neurology. 2014;83:2077–84.

    ArticleΒ  CASΒ  Google ScholarΒ 

  4. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92:414–7.

    ArticleΒ  CASΒ  Google ScholarΒ 

  5. US Food and Drug Administration. Genomics - Table of Pharmacogenomic Biomarkers in Drug Labeling.

  6. Hughes DA, Vilar FJ, Ward CC, Alfirevic A, Park BK, Pirmohamed M. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics. 2004;14:335–42.

    ArticleΒ  Google ScholarΒ 

  7. Young B, Squires K, Patel P, Dejesus E, Bellos N, Berger D, et al. First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS. 2008;22:1673–5.

    ArticleΒ  CASΒ  Google ScholarΒ 

  8. Plumpton CO, Alfirevic A, Pirmohamed M, Hughes DA. Cost effectiveness analysis of HLA-B*58:01 genotyping prior to initiation of allopurinol for gout. Rheumatology. 2017;56:1729–39.

    ArticleΒ  CASΒ  Google ScholarΒ 

  9. Chen Z, Liew D, Kwan P. Real-world efficiency of pharmacogenetic screening for carbamazepine-induced severe cutaneous adverse reactions. PLoS ONE. 2014;9:e96990.

    ArticleΒ  Google ScholarΒ 

  10. Varney MD, Castley AS, Haimila K, Saavalainen P. Methods for diagnostic HLA typing in disease association and drug hypersensitivity. Methods Mol Biol. 2012;882:27–46.

    ArticleΒ  CASΒ  Google ScholarΒ 

  11. Mayor NP, Robinson J, McWhinnie AJ, Ranade S, Eng K, Midwinter W, et al. HLA typing for the next generation. PLoS ONE. 2015;10:e0127153.

    ArticleΒ  Google ScholarΒ 

  12. Plumpton CO, Roberts D, Pirmohamed M, Hughes DA. A systematic review of economic evaluations of pharmacogenetic testing for prevention of adverse drug reactions. Pharmacoeconomics. 2016;34:771–93.

    ArticleΒ  Google ScholarΒ 

  13. Monsuur AJ, de Bakker PI, Zhernakova A, Pinto D, Verduijn W, Romanos J, et al. Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide polymorphisms. PLoS ONE. 2008;3:e2270.

    ArticleΒ  Google ScholarΒ 

  14. de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 2006;38:1166–72.

    ArticleΒ  Google ScholarΒ 

  15. Barker JM, Triolo TM, Aly TA, Baschal EE, Babu SR, Kretowski A, et al. Two single nucleotide polymorphisms identify the highest-risk diabetes HLA genotype: potential for rapid screening. Diabetes. 2008;57:3152–5.

    ArticleΒ  CASΒ  Google ScholarΒ 

  16. Koskinen L, Romanos J, Kaukinen K, Mustalahti K, Korponay-Szabo I, Barisani D, et al. Cost-effective HLA typing with tagging SNPs predicts celiac disease risk haplotypes in the Finnish, Hungarian, and Italian populations. Immunogenetics. 2009;61:247–56.

    ArticleΒ  CASΒ  Google ScholarΒ 

  17. Vu CL, Chan J, Todaro M, Skafidas S, Kwan P. Point-of-care molecular diagnostic devices: an overview. Pharmacogenomics. 2015;16:1399–409.

    ArticleΒ  CASΒ  Google ScholarΒ 

  18. He Y, Hoskins JM, Clark S, Campbell NH, Wagner K, Motsinger-Reif AA, et al. Accuracy of SNPs to predict risk of HLA alleles associated with drug-induced hypersensitivity events across racial groups. Pharmacogenomics. 2015;16:817–24.

    ArticleΒ  CASΒ  Google ScholarΒ 

  19. Sanchez-Giron F, Villegas-Torres B, Jaramillo-Villafuerte K, Silva-Zolezzi I, Fernandez-Lopez JC, Jimenez-Sanchez G, et al. Association of the genetic marker for abacavir hypersensitivity HLA-B*5701 with HCP5rs2395029 in Mexican Mestizos. Pharmacogenomics. 2011;12:809–14.

    ArticleΒ  CASΒ  Google ScholarΒ 

  20. Galvan CA, Elbarcha OC, Fernandez EJ, Beltramo DM, Soria NW. Rapid HCP5 single-nucleotide polymorphism genotyping: a simple allele-specific PCR method for prediction of hypersensitivity reaction to abacavir. Clin Chim Acta. 2011;412:1382–4.

    ArticleΒ  CASΒ  Google ScholarΒ 

  21. Badulli C, Sestini R, Sbarsi I, Baroncelli M, Pizzochero C, Martinetti M, et al. Tag SNPs of the ancestral haplotype 57.1 do not substitute HLA-B*57:01 typing for eligibility to abacavir treatment in the Italian population. Pharmacogenomics. 2012;13:247–9.

    ArticleΒ  CASΒ  Google ScholarΒ 

  22. Melis R, Lewis T, Millson A, Lyon E, McMillin GA, Slev PR, et al. Copy number variation and incomplete linkage disequilibrium interfere with the HCP5 genotyping assay for abacavir hypersensitivity. Genet Test Mol Biomarkers. 2012;16:1111–4.

    ArticleΒ  CASΒ  Google ScholarΒ 

  23. Liu X, Sun J, Yu H, Chen H, Wang J, Zou H, et al. Tag SNPs for HLA-B alleles that are associated with drug response and disease risk in the Chinese Han population. Pharmacogenomics J. 2015;15:467–72.

    ArticleΒ  Google ScholarΒ 

  24. Maekawa K, Nakamura R, Kaniwa N, Mizusawa S, Kitamoto A, Kitamoto T, et al. Development of a simple genotyping method for the HLA-A*31:01-tagging SNP in Japanese. Pharmacogenomics. 2015;16:1689–99.

    ArticleΒ  CASΒ  Google ScholarΒ 

  25. Tohkin M, Kaniwa N, Saito Y, Sugiyama E, Kurose K, Nishikawa J, et al. A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Pharmacogenomics J. 2013;13:60–9.

    ArticleΒ  CASΒ  Google ScholarΒ 

  26. Zhou F, Cao H, Zuo X, Zhang T, Zhang X, Liu X, et al. Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease. Nat Genet. 2016;48:740–6.

    ArticleΒ  CASΒ  Google ScholarΒ 

  27. Ghattaoraya GS, Dundar Y, Gonzalez-Galarza FF, Maia MH, Santos EJ, da Silva AL, et al. A web resource for mining HLA associations with adverse drug reactions: HLA-ADR. Database (Oxford). e002882, 2016;2016.

  28. Saunders CL, Abel GA, El Turabi A, Ahmed F, Lyratzopoulos G. Accuracy of routinely recorded ethnic group information compared with self-reported ethnicity: evidence from the English Cancer Patient Experience survey. BMJ Open. 2013;3.

    ArticleΒ  Google ScholarΒ 

  29. Payne PW. Ancestry-based pharmacogenomics, adverse reactions and carbamazepine: is the FDA warning correct? Pharmacogenomics J. 2014;14:473–80.

    ArticleΒ  CASΒ  Google ScholarΒ 

  30. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    ArticleΒ  CASΒ  Google ScholarΒ 

  31. Mack SJ, Cano P, Hollenbach JA, He J, Hurley CK, Middleton D, et al. Common and well-documented HLA alleles: 2012 update to the CWD catalogue. Tissue Antigens. 2013;81:194–203.

    ArticleΒ  CASΒ  Google ScholarΒ 

  32. Gonzalez-Galarza FF, Takeshita LY, Santos EJ, Kempson F, Maia MH, da Silva AL, et al. Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations. Nucleic Acids Res. 2015;43 Database issue:D784–8.

    ArticleΒ  CASΒ  Google ScholarΒ 

  33. Gui H, Kwok M, Baum L, Sham PC, Kwan P, Cherny SS. SNP-based HLA allele tagging, imputation and association with antiepileptic drug-induced cutaneous reactions in Hong Kong Han Chinese. Pharmacogenomics J. 2018;2:340–346

    ArticleΒ  Google ScholarΒ 

  34. Berry KJ, Mielke PW Jr. A generalization of Cohen’s kappa agreement measure to interval measurement and multiple raters. Educ Psychol Meas. 1988;48:921–33.

    ArticleΒ  Google ScholarΒ 

  35. Machiela MJ, Chanock SJ. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;31:3555–7.

    ArticleΒ  CASΒ  Google ScholarΒ 

  36. Ha NT, Freytag S, Bickeboeller H. Coverage and efficiency in current SNP chips. Eur J Human Genet. 2014;22:1124–30.

    ArticleΒ  CASΒ  Google ScholarΒ 

  37. Motyer A, Vukcevic D, Dilthey A, Donnelly P, McVean G, Leslie S. Practical use of methods for imputation of HLA alleles from SNP Genotype Data. bioRxiv. 2016: 091009.

  38. McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperaviciute D, Carrington M, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011;364:1134–43.

    ArticleΒ  CASΒ  Google ScholarΒ 

  39. Ozeki T, Mushiroda T, Yowang A, Takahashi A, Kubo M, Shirakata Y, et al. Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Hum Mol Genet. 2011;20:1034–41.

    ArticleΒ  CASΒ  Google ScholarΒ 

  40. Cristallo AF, Schroeder J, Citterio A, Santori G, Ferrioli GM, Rossi U, et al. A study of HLA class I and class II 4-digit allele level in Stevens-Johnson syndrome and toxic epidermal necrolysis. Int J Immunogenet. 2011;38:303–9.

    ArticleΒ  CASΒ  Google ScholarΒ 

  41. Kang HR, Jee YK, Kim YS, Lee CH, Jung JW, Kim SH, et al. Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet Genomics. 2011;21:303–7.

    ArticleΒ  CASΒ  Google ScholarΒ 

  42. Zhang FR, Liu H, Irwanto A, Fu XA, Li Y, Yu GQ, et al. HLA-B*13:01 and the dapsone hypersensitivity syndrome. N Engl J Med. 2013;369:1620–8.

    ArticleΒ  CASΒ  Google ScholarΒ 

  43. 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.

    ArticleΒ  CASΒ  Google ScholarΒ 

  44. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia. 2010;51:2461–5.

    ArticleΒ  CASΒ  Google ScholarΒ 

  45. Cornejo Castro EM, Carr DF, Jorgensen AL, Alfirevic A, Pirmohamed M. HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity: a systematic review of the literature and meta-analysis. Pharmacogenet Genomics. 2015;25:186–98.

    ArticleΒ  CASΒ  Google ScholarΒ 

  46. Chen PL, Shih SR, Wang PW, Lin YC, Chu CC, Lin JH, et al. Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study. Nat Commun. 2015;6:7633.

    ArticleΒ  Google ScholarΒ 

  47. Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006;16:297–306.

    ArticleΒ  CASΒ  Google ScholarΒ 

  48. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358:568–79.

    ArticleΒ  Google ScholarΒ 

  49. Kim SH, Kim M, Lee KW, Kim SH, Kang HR, Park HW, et al. HLA-B*5901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Pharmacogenomics. 2010;11:879–84.

    ArticleΒ  CASΒ  Google ScholarΒ 

  50. Schaid DJ, Spraggs CF, McDonnell SK, Parham LR, Cox CJ, Ejlertsen B, et al. Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury. J Clin Oncol. 2014;32:2296–303.

    ArticleΒ  CASΒ  Google ScholarΒ 

  51. Jia X, Han B, Onengut-Gumuscu S, Chen WM, Concannon PJ, Rich SS, et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS ONE. 2013;8:e64683.

    ArticleΒ  CASΒ  Google ScholarΒ 

  52. Pillai NE, Okada Y, Saw WY, Ong RT, Wang X, Tantoso E, et al. Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations. Hum Mol Genet. 2014;23:4443–51.

    ArticleΒ  CASΒ  Google ScholarΒ 

  53. Kim K, Bang SY, Lee HS, Bae SC. Construction and application of a Korean reference panel for imputing classical alleles and amino acids of human leukocyte antigen genes. PLoS ONE. 2014;9:e112546.

    ArticleΒ  Google ScholarΒ 

  54. Gourraud PA, Khankhanian P, Cereb N, Yang SY, Feolo M, Maiers M, et al. HLA diversity in the 1000 genomes dataset. PLoS ONE. 2014;9:e97282.

    ArticleΒ  Google ScholarΒ 

  55. Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68–74.

    ArticleΒ  Google ScholarΒ 

Download references

Acknowledgements

We thank Adam Kowalczyk for his help in reviewing this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael Erlichster.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Erlichster, M., Goudey, B., Skafidas, E. et al. Cross-ethnicity tagging SNPs for HLA alleles associated with adverse drug reaction. Pharmacogenomics J 19, 230–239 (2019). https://doi.org/10.1038/s41397-018-0039-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-018-0039-z

Search

Quick links