Blood group alleles in the cloud
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T he genomics revolution is just starting. In the notso-distant future, accessing a patient’s full exome or genome will likely be routine. Last year, Genomics England finished sequencing 100,000 individual genomes, mainly from National Health Service (NHS) patients with a rare disease or cancer. Next up for the NHS: sequencing 1 million genomes over the next five years. Other large-scale sequencing projects are underway elsewhere. Years ago, HLA matching for stem cell and solid organ transplantation shifted from antibody-based testing to DNAbased testing. Investigators found that HLA antigens that type identically by serology may vary when typed using higher-resolution methods, such as DNA sequencing. We now appreciate that minor HLA antigenic differences can have major clinical consequences. For example, a renal transplant patient might accept a donor kidney carrying a serologically defined HLA “A4” antigen but might reject a different donor kidney carrying a subtly different “A4” antigen. Chou and colleagues made analogous observations about Rh antigens in a study of chronically transfused patients with sickle cell disease. Several patients formed Rh alloantibodies despite being transfused with red blood cell (RBC) units that were phenotypically matched for D, C, and E antigens. Genotyping revealed that many of the sensitized individuals carried variant RH alleles. Thus, the patients’ immune systems saw seemingly matched RBC antigens as foreign, triggering antibody formation. RBC genotyping will probably not eliminate the need for pretransfusion serologic testing, but the importance of genotyping in transfusion medicine will continue to grow. The sheer volume of genomic data will keep growing, too. Researchers have already identified more than 500 different RHD alleles, and more are surely on the way. How to manage all of the incoming DNA data plus accompanying data on clinical significance presents a challenge for journals such as this one. Dr. Connie Westhoff, a longtime Associate Editor at TRANSFUSION, developed a one-page format for researchers to submit reports of newly discovered alleles encoding RBC antigens. These reports contain valuable information, but they are not a great fit for a printed monthly journal. Considered as an isolated research paper in a magazine, a report of a newly discovered A-to-T base substitution in the glycophorin B gene may not generate tremendous interest. That same report, however, becomes far more valuable when viewed in its proper context: contributing to the totality of knowledge about the MNS system. I think that data on new blood group alleles is most useful in electronic form, so that individual reports of alleles can be sensibly grouped and studied in the aggregate. As a first step, beginning this month, TRANSFUSION will publish one-page reports of new alleles online only— these will no longer appear in the print edition of the journal. (Authors: fear not. These reports will be assigned “e” page numbers in TRANSFUSION issues online to allow citation; the reports will be downloadable as pdfs; and authorship/academic credit will be given as always.) In the future, it will be ideal to link all reports of antigens and alleles published in TRANSFUSION and other journals to an open-access, searchable online database encompassing the entirety of transfusion medicine genomics. Such a database does not yet exist, but groups such as the International Society of Blood Transfusion (ISBT) are working on it. Stay tuned!
[1] Matthew S. Lebo,et al. Automated typing of red blood cell and platelet antigens: a whole-genome sequencing study. , 2018, The Lancet. Haematology.
[2] G. Bein,et al. Red cell genotyping precision medicine: a conference summary , 2017, Therapeutic advances in hematology.
[3] C. Westhoff,et al. High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors. , 2013, Blood.