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HLA-B*07:02 and HLA-C*07:02 are associated with trimethoprim-sulfamethoxazole respiratory failure

The Pharmacogenomics Journal volume 22, pages 124–129 (2022)Cite this article

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Abstract

We have identified an underrecognized severe adverse drug reaction (ADR) of trimethoprim-sulfamethoxazole (TMP-SMX) associated respiratory failure in previously healthy children and young adults. We investigated potential genetic risk factors associated with TMP-SMX induced respiratory failure in a cohort of seven patients. We explored whole genome sequence among seven patients representing nearly half of all reported cases worldwide and 63 unrelated control individuals in two stages: (1) human leukocyte antigen (HLA) locus variation as several other ADRs have been associated HLA genetic variants and (2) coding variation to catalog and explore potential rare variants contributing to this devastating reaction. All cases were either heterozygous (carriers) or homozygous for the common HLA-B*07:02–HLA-C*07:02 haplotype. Despite the small sample size, this observation is statistically significant both in conservative comparison to maximum reported population frequencies (binomial P = 0.00017 for HLA-B and P = 0.00028 for HLA-C) and to our control population assessed by same HLA genotyping approach (binomial P = 0.000001 for HLA-B and P = 0.000018 for HLA-C). No gene elsewhere in the genome harnessed shared rare case enriched coding variation. Our results suggests that HLA-B*07:02 and HLA-C*07:02 are necessary for a patient to develop respiratory failure due to TMP-SMX.

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Fig. 1: Overrepresentation of HLA-B*07:02 and HLA-C*07:02 in TMP-SMX associated respiratory failure cases compared to 63 controls and 75,902 population controls of European ancestry.

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References

  1. Frey N, Bircher A, Bodmer M, Jick SS, Meier CR, Spoendlin J. Antibiotic drug use and the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: a population-based case-control study. J Invest Dermatol. 2018;138:1207–9.

    Article  CAS  Google Scholar 

  2. Lin YF, Yang CH, Sindy H, Lin JY, Rosaline Hui CY, Tsai YC, et al. Severe cutaneous adverse reactions related to systemic antibiotics. Clin Infect Dis. 2014;58:1377–85.

    Article  CAS  Google Scholar 

  3. Bjornsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology. 2005;42:481–9.

    Article  Google Scholar 

  4. Keisu M, Wiholm BE, Palmblad J. Trimethoprim-sulphamethoxazole-associated blood dyscrasias. Ten years’ experience of the Swedish spontaneous reporting system. J Intern Med. 1990;228:353–60.

    Article  CAS  Google Scholar 

  5. Pirmohamed M, Friedmann PS, Molokhia M, Loke YK, Smith C, Phillips E, et al. Phenotype standardization for immune-mediated drug-induced skin injury. Clin Pharm Ther. 2011;89:896–901.

    Article  CAS  Google Scholar 

  6. Li YJ, Phillips E, Dellinger A, Nicoletti P, Schutte R, Li D, et al. HLA-B*14:01 and HLA-B*35:01 are associated with trimethoprim-sulfamethoxazole induced liver injury. Hepatology. 2021;73:268–81.

    Article  CAS  Google Scholar 

  7. Wang CW, Tassaneeyakul W, Chen CB, Chen WT, Teng YC, Huang CY, et al. Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians. J Allergy Clin Immunol. 2021;147:1402–12.

    Article  CAS  Google Scholar 

  8. Miller JO, Taylor J, Goldman JL. Severe acute respiratory failure in healthy adolescents exposed to trimethoprim-sulfamethoxazole. Pediatrics. 2019;143:e20183242.

  9. Miller JO, Shih AR, Mino-Kenudson M, Taylor MS, Goldman JL. Trimethoprim-sulfamethoxazole-associated fulminant respiratory failure in children and young adults. Am J respiratory Crit care Med. 2021;203:918–21.

    Article  CAS  Google Scholar 

  10. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharm Ther. 1981;30:239–45.

    Article  CAS  Google Scholar 

  11. Gonzalez-Galarza FF, McCabe A, Santos E, Jones J, Takeshita L, Ortega-Rivera ND, et al. Allele frequency net database (AFND) 2020 update: gold-standard data classification, open access genotype data and new query tools. Nucleic Acids Res. 2020;48:D783–8.

    CAS  PubMed  Google Scholar 

  12. Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR, et al. Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clin Pharm Ther. 2008;84:362–9.

    Article  CAS  Google Scholar 

  13. Larjo A, Eveleigh R, Kilpelainen E, Kwan T, Pastinen T, Koskela S, et al. Accuracy of programs for the determination of human leukocyte antigen alleles from next-generation sequencing data. Front Immunol. 2017;8:1815.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Gonzalez-Galarza FF, McCabe A, Melo Dos Santos EJ, Jones AR, Middleton D. A snapshot of human leukocyte antigen (HLA) diversity using data from the Allele Frequency Net Database. Hum Immunol. 2020;82:496–504.

    Article  Google Scholar 

  16. Alfirevic A, Gonzalez-Galarza F, Bell C, Martinsson K, Platt V, Bretland G, et al. In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers. Genome Med. 2012;4:51.

    Article  CAS  Google Scholar 

  17. Abacavir sulfate drug insert. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020977s024,020978s028lbl.pdf.

  18. Carbamazepine drug insert. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016608s101,018281s048lbl.pdf.

  19. Karnes JH, Miller MA, White KD, Konvinse KC, Pavlos RK, Redwood AJ, et al. Applications of Immunopharmacogenomics: predicting, preventing, and understanding immune-mediated adverse drug reactions. Annu Rev Pharm Toxicol. 2019;59:463–86.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank the patients and families who contributed to this work.

Funding

The research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM129783 (JLG). Imputed HLA control data for Fig. 1 was provided under the scope of P50GM115305 (EJP).

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Authors and Affiliations

  1. Department of Pediatrics, Children’s Mercy Hospital, University of Missouri–Kansas City, Kansas City, MO, USA

    Jennifer L. Goldman & Jenna O. Miller

  2. Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, University of Missouri–Kansas City, Kansas City, MO, USA

    Neil Miller & Tomi Pastinen

  3. Canadian Center for Computational Genomics, McGill University and Genome Quebec Innovation Center, Montreal, QC, Canada

    Robert Eveleigh

  4. Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia

    Andrew Gibson & Elizabeth J. Phillips

  5. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Elizabeth J. Phillips

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  1. Jennifer L. Goldman
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Contributions

Participated in research design: JLG, JOM, NM, RE, AG, EJP, and TP. Conducted experiments: NM, RE, AG, EJP, and TP. Performed data analysis: JLG, NM, RE, AG, EJP, and TP. Wrote or contributed to the writing of the manuscript: JLG, JOM, NM, RE, AG, EJP, and TP.

Corresponding author

Correspondence to Jennifer L. Goldman.

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Competing interests

EJP reports grants from National Institutes of Health (P50GM115305, R01HG010863, R01AI152183, R21AI139021, U01AI154659) and from the National Health and Medical Research Council of Australia. She receives Royalties from Uptodate and consulting fees from Janssen, Vertex, Biocryst and Regeneron. She is co-director of IIID Pty Ltd that holds a patent for HLA-B*57:01 testing for abacavir hypersensitivity, and has a patent pending for Detection of Human Leukocyte Antigen-A*32:01 in connection with Diagnosing Drug Reaction with Eosinophilia and Systemic Symptoms without any financial remuneration and not directly related to the submitted work.

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Goldman, J.L., Miller, J.O., Miller, N. et al. HLA-B*07:02 and HLA-C*07:02 are associated with trimethoprim-sulfamethoxazole respiratory failure. Pharmacogenomics J 22, 124–129 (2022). https://doi.org/10.1038/s41397-022-00266-8

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