Christopher C. Porter, MD
The pace of discovery and translation in hematology research can, at times, seem painstakingly slow. However, key advances in the annotation of the human genome and the development of high-throughput methods of defining genetic loci may accelerate this pace. In a session organized by the Scientific Committee on Hematopathology and Clinical Laboratory Hematology, investigators described the state of the art in genomic interrogation as it relates to benign and malignant hematology, as well as hematopoietic stem cell transplantation (HSCT).
The session titled “Genome-Wide Association Studies in Hematology,” which took place yesterday and will take place again this morning at 7:30 a.m. in Room 230 of the Orange County Convention Center, featured presentations from Drs. Willem Ouwehand, Mary Relling, and Steven McCarroll. The session chair, Dr. Mark Flemming, suggested that attendees should begin to understand “the principles of genome-wide association studies and how the results may be translated to clinical medicine.”
Dr. Ouwehand began the session with a historical perspective and then described the experience of the HaemGen consortium in identifying common variants at several genetic loci which are associated with clinically relevant hematologic parameters. Investigators associated with six European population-based studies identified 70 single nucleotide polymorphisms (SNPs) associated with platelet count and/or platelet volume. Some are in genes known to be involved with platelet function, and others have been validated in animal models. Interestingly, two SNPs in a risk locus for CAD at chromosome 12q24.12 were both associated with platelet count in the primary analyses.
Dr. Relling then discussed the role of genome-wide interrogations in addressing the etiology and responsiveness to therapy of childhood acute lymphoblastic leukemia (ALL). She presented work from a collaborative effort among individuals at St. Jude Children’s Research Hospital and members of the Children’s Oncology Group, in which they identified SNPs significantly associated with ALL, including two in the ARID5B gene that distinguish between hyperdiploid ALL and other subtypes, suggesting that germline polymorphisms influence the susceptibility to and subtype of pediatric ALL. Using similar methodology, they have also found that SLC01B1 SNPs are associated with methotrexate pharmacokinetics known to be important in ALL treatment response.
Dr. McCarroll finished the session by describing the extent to which genomic studies have identified the variation in antigen repertoire among individuals in a population and the implications of this phenomenon for donor selection for HSCT. Interestingly, some polymorphisms are significant and common enough that some individuals may completely lack a protein-coding gene that is expressed in others. He proceeded to describe the results of an international collaboration, in which investigators found that one such gene deletion is associated with graft-versus-host disease after HSCT. He concluded his talk by suggesting a strategy for identifying the genetic bases of histocompatibility barriers among individuals based on the emerging understanding of genomic variation.
A common theme among the discussions was the necessity and utility of large-scale collaboration and unbiased genome-scale research in discovering molecules with relevance to hematologists. The work highlighted the importance of big science in answering big questions.
Dr. Porter indicated no relevant conflicts of interest.