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SNP-based HLA allele tagging, imputation and association with antiepileptic drug-induced cutaneous reactions in Hong Kong Han Chinese

The Pharmacogenomics Journal volume 18, pages 340–346 (2018)Cite this article

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Abstract

Human leukocyte antigen (HLA) genes control the regulation of the human immune system and are involved in immune-related diseases. Population surveys on relationships between single nucleotide polymorphisms (SNP) and HLA alleles are essential to conduct genetic association between HLA variants and diseases. Samples were obtained from our in-house database for epilepsy genetics and pharmacogenetics research. Using 184 epilepsy patients with both genome-wide SNP array and HLA-A/B candidate gene sequencing data, we sought tagging SNPs that completely represent sixHLA risk alleles; in addition, a Hong Kong population-specific reference panel was constructed for SNP-based HLA imputation. The performance of our new panel was compared to a recent Han Chinese panel. Finally, genetic associations of HLA variants with mild skin rash were performed on the combined sample of 408 patients. Common SNPs rs2571375 and rs144295468 were found to successfully tag HLA risk alleles A*31:01 and B*13:01, respectively. HLA-B*15:02 can be predicted by rs144012689 with >95% sensitivity and specificity. The imputation reference panel for the Hong Kong population had comparable performance to the Han Chinese panel due to the large sample size for common HLA alleles, though it retained discordance for imputing rare alleles. No significant genetic associations were found between HLA genetic variants and mild skin rash induced by aromatic antiepileptic drugs. This study provides new information on the genetic structure of HLA regions in the Hong Kong population by identifying tagging SNPs and serving as a reference panel. Moreover, our comprehensive genetic analyses revealed no significant association between HLA alleles and mild skin rash in Hong Kong Han Chinese.

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References

  1. 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: 1166–1172.

    Article  CAS  Google Scholar 

  2. Gragert L, Madbouly A, Freeman J, Maiers M . Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry. Hum Immunol 2013; 74: 1313–1320.

    Article  CAS  Google Scholar 

  3. Kaniwa N, Saito Y . Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury. J Hum Genet 2013; 58: 317–326.

    Article  CAS  Google Scholar 

  4. Daly AK . Pharmacogenomics of adverse drug reactions. Genome Med 2013; 5: 5.

    Article  CAS  Google Scholar 

  5. Chen P, Lin JJ, Lu CS, Ong CT, Hsieh PF, Yang CC et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 2011; 364: 1126–1133.

    Article  CAS  Google Scholar 

  6. 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: 1134–1143.

    Article  CAS  Google Scholar 

  7. Hirsch LJ, Arif H, Nahm EA, Buchsbaum R, Resor SR, Bazil CW . Cross-sensitivity of skin rashes with antiepileptic drug use. Neurology 2008; 71: 1527–1534.

    Article  CAS  Google Scholar 

  8. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol (vol 102, pg 4134, 2005). Proc Natl Acad Sci USA 2005; 102: 6237–6237.

    CAS  Google Scholar 

  9. Chen ZB, Liew D, Kwan P . Effects of a HLA-B*15:02 screening policy on antiepileptic drug use and severe skin reactions. Neurology 2014; 83: 2077–2084.

    Article  CAS  Google Scholar 

  10. 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: 4443–4451.

    Article  CAS  Google Scholar 

  11. 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: 467–472.

    Article  Google Scholar 

  12. Guo Y, Baum LW, Sham PC, Wong V, Ng PW, Lui CH et al. Two-stage genome-wide association study identifies variants in CAMSAP1L1 as susceptibility loci for epilepsy in Chinese. Hum Mol Genet 2012; 21: 1184–1189.

    Article  CAS  Google Scholar 

  13. International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address e-auea. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol 2014; 13: 893–903.

    Article  Google Scholar 

  14. Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 2007; 48: 1015–1018.

    Article  CAS  Google Scholar 

  15. Reich D, Price AL, Patterson N . Principal component analysis of genetic data. Nat Genet 2008; 40: 491–492.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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: 740–746.

    Article  CAS  Google Scholar 

  18. 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: 559–575.

    Article  CAS  Google Scholar 

  19. 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: 740–746.

    Article  CAS  Google Scholar 

  20. Gabriel S, Ziaugra L, Tabbaa D. SNP . Genotyping using the sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet 2009; 60: 2.12.11–12.12.16.

    Google Scholar 

  21. Hsieh AR, Chang SW, Chen PL, Chu CC, Hsiao CL, Yang WS et al. Predicting HLA genotypes using unphased and flanking single-nucleotide polymorphisms in Han Chinese population. BMC genomics 2014; 15: 81.

    Article  Google Scholar 

  22. Li SYS, Wang HW, Smith A, Zhang B, Zhang XY, Schoch G et al. Predicting multiallelic genes using unphased and flanking single nucleotide polymorphisms. Genet Epidemiol 2011; 35: 85–92.

    Article  CAS  Google Scholar 

  23. 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.

    Article  Google Scholar 

  24. Park JH, Wacholder S, Gail MH, Peters U, Jacobs KB, Chanock SJ et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet 2010; 42: 570–575.

    Article  CAS  Google Scholar 

  25. Chung WH, Chang WC, Lee YS, Wu YY, Yang CH, Ho HC et al. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA 2014; 312: 525–534.

    Article  Google Scholar 

  26. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 2010; 11: 446–450.

    Article  CAS  Google Scholar 

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Acknowledgements

This project is supported by the Hong Kong Health and Medical Research Fund (HMRF 01120186 grant to Patrick Kwan) and General Research Fund (HKU 7623/08M and HKU 7630/12M grants to Stacey Cherny). We would like to give special thanks to Drs Wanling Yang and Ching-Lung Cheung from the Centre for Genomic Sciences at the University of Hong Kong, and Mark McCormack from the Royal College of Surgeons of Ireland for their advice on HLA analysis. We thank all the neurologists who recruited the patients, and the patients for participating in the study.

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Authors and Affiliations

  1. Center for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    H Gui, P C Sham & S S Cherny

  2. Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA

    H Gui

  3. Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China

    M Kwok & P Kwan

  4. Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    L Baum, P C Sham & S S Cherny

  5. The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China

    P C Sham & S S Cherny

  6. Departments of Medicine and Neurology, The University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia

    P Kwan

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  1. H Gui
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Correspondence to P Kwan or S S Cherny.

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Gui, H., Kwok, M., Baum, L. et al. SNP-based HLA allele tagging, imputation and association with antiepileptic drug-induced cutaneous reactions in Hong Kong Han Chinese. Pharmacogenomics J 18, 340–346 (2018). https://doi.org/10.1038/tpj.2017.11

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  • DOI: https://doi.org/10.1038/tpj.2017.11

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