The importance of establishing genetic phase in clinical medicine

Abstract

Haplotyping or determination of genetic phase has always played a pivotal role in MHC (HLA studies) both in helping to understand inheritance patterns in diseases such as type 1 diabetes (T1D) and in ensuring better matching in transplantation scenarios such as haematopoietic stem cell transplantation (HSCT), using donors genetically related to the patient. In recent years the need to establish genetic phase in a number of clinical scenarios has become apparent. These include: Genetic phasing for hematopoietic stem cell transplants using unrelated donors, where the HLA haplotypes are not known but where haplotype-matched recipients fare better clinically than allele matched, but haplotype mismatched patients. The use of checkpoint inhibitors is one of the most innovative and exciting developments in cancer treatment in years. An example is the use of the monoclonal ipilimumab to block the CTLA-4 receptor which is known to contain polymorphic sites. Until the phase of these polymorphisms is known it will not be possible to determine how effectively this monoclonal will perform in individual patients. The role of miRNA single strand molecules and their effect on gene expression. Thousands of non-coding genes have been identified and have been shown to be polymorphic, as have their target genes. Genetic phasing of polymorphism both in the miRNA source genes and their targets is clearly a fertile area of research In areas such a drug metabolism where the polymorphic family of CYP genes is responsible for the metabolism of the majority of prescription drugs, determining phase of SNPs is critical to understanding drug metabolism and efficacy. In multigenic disease studies combinations of single nucleotide polymorphisms (SNPs) in participating genes require accurate phasing in order to fully appreciate their role in the disease process. In addition, the level of expression of genes (point 3) is also important in understanding disease processes at the functional level. This review outlines the techniques that are currently available for approximating phase and discusses the clinical relevance of establishing genetic phase in areas of clinical medicine outlined in points 1-3.