NEXT-GENERATION SEQUENCING IN CLINICAL HISTOCOMPATIBILITY TESTING

November 04, 2021

The human leukocyte antigen (HLA) region is one of the most researched parts of the human genome due to the fact multiple vital genes for immune cell regulation and function are located in that area (Cornaby, Schmitz and Weimer, 2021). Several important immune gene products are encoded by the HLA genes including the major histocompatibility complex (MHC) class I molecules (HLA-A, -B and -C genes), class II molecules (HLA-DPB1, DPA1, DM, DO, DQB1, DQA1, DRB1, and DRA genes) and complement system proteins.

Molecule
 

The most well-known usage for HLA typing in a clinical setting is organ transplant procedures, both hematopoietic stem cell transplant and solid organ transplant. Additionally, allele variants found in HLA genes were found to be linked with the increased susceptibility to various autoimmune and other chronic diseases, such as multiple sclerosis, systematic lupus erythematosus, diabetes mellitus type I, Parkinson’s disease and schizophrenia (Trowsdale and Knight, 2013). Next-generation sequencing (NGS) typing methods are becoming more commonly used in clinical histocompatibility testing owing to their higher resolution, phasing and fewer ambiguities compared to the other methodologies.


Recent studies have begun researching the impact of high-resolution typing of HLA on transplant outcomes, which indicated that this kind of matching decreased the risk of acute graft-versus-host disease in hematopoietic cell transplants and improved the detection of HLA cross-matches in solid organ transplants (Huang et al., 2019; Mayor et al., 2021). NGS has also been found to be the most accurate clinical method for identifying disease risk or resistance and drug hypersensitivities. When considering pharmacogenomics, a variety of HLA alleles variants has been connected to adverse drug reactions (e.g. delayed hypersensitivity reaction, Steven-Johnson Syndrome and increased drug toxicity) (Hammond et al., 2020). As the NGS technology can provide high resolution typing (to the 3rd or higher resolution), it could offer a better understanding of the impact of HLA gene variants and ultimately provide the clinicians with valuable additional medical information about the patient.

References:

Cornaby, C., Schmitz, J. L. and Weimer, E. T. (2021) ‘Next-generation sequencing and clinical histocompatibility testing’, Human Immunology. American Society for Histocompatibility and Immunogenetics, 82(11), pp. 829–837. doi: 10.1016/j.humimm.2021.08.009.

Hammond, S. et al. (2020) ‘T-Cell Activation by Low Molecular Weight Drugs and Factors That Influence Susceptibility to Drug Hypersensitivity’, Chemical Research in Toxicology, 33(1), pp. 77–94. doi: 10.1021/acs.chemrestox.9b00327.

Huang, Y. et al. (2019) ‘Assessing the utilization of high-resolution 2-field HLA typing in solid organ transplantation’, American Journal of Transplantation, 19(7), pp. 1955–1963. doi: 10.1111/ajt.15258.

Mayor, N. P. et al. (2021) ‘Impact of Previously Unrecognized HLA Mismatches Using Ultrahigh Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation’, Journal of Clinical Oncology, 39(21), pp. 2397–2409. doi: 10.1200/JCO.20.03643.

Trowsdale, J. and Knight, J. C. (2013) ‘Major Histocompatibility Complex Genomics and Human Disease’, Annual Review of Genomics and Human Genetics, 14(1), pp. 301–323. doi: 10.1146/annurev-genom-091212-153455.

Nina Fajs, Edinburgh Genetics