Interdisciplinary Training

Indika Rajapakse

Gene-gene interactions: methods and applications for transplant research

My research focus is on potential genetic associations with clinical outcomes after Allogeneic Hematopoietic Cell Transplantation (HCT). The HCT population identified for this research is particularly useful for the discovery of genetic risk factors, because many patients are suffering from post-transplant diseases and identification of genetic risk factors may help us to discover new tools for assessing prognosis, new treatment protocols to improve prognosis outcome, and new insights into mechanisms of chronic diseases after HCT. From analytic perspective, our research has a sufficient power due to relatively high prevalence of several disease phenotypes. Our population, consisting of paired patients and donors, also provides a unique opportunity to assess the potential for genome-genome interaction between the recipient and donor genome.

The goals of this project are to identify, by genome-wide association analysis, donor and recipient genetic components affecting patient outcome following HCT. Utilizing archived biological material and an extensive HCT clinical outcome database maintained by the FHCRC Clinical Science Division, Dr. John Hansen and his colleagues have been studying the Immunogenetics aspect of HCT for the past several decades. Recently, they and other investigators have successfully established that several Single Nucleotide Polymorphisms (SNP) markers within immune regulator genes modify the risk of severe Graft-Versus-Host Disease (GVHD) and transplant-related mortality. Recognizing the complexity of the involved regulatory pathways, I expect that gene-gene interactions will play an essential role in modifying phenotype and determining how these genetic variations affect HCT outcome. Through this proposed research project, I will focus on the design and analysis of genetic associations with two specific aims:

Aim 1: Develop methods for the analysis of gene-gene interactions in the context of HCT. We will examine SNP by SNP interactions between genes as well as haplotype by haplotype interactions between genes. Furthermore, we will distinguish between cis- and trans-interactions.

Aim 2: Analyze genome-genome interactions between recipient and donor. Successful HCT requires sustained engraftment of donor cells in a recipient, so we must consider both recipient's and donor's genomes in assessing genetic associations with clinical outcome. To assess genome-genome interactions, we will examine allelic/genotypic and haplotypic/diplotypic interactions within a locus or across loci.

By developing novel methods and tools to study genetic interactions, we will have an opportunity of identifying interactions that significantly contribute to the risk of GVHD following HCT. In addition to its clinical relevance, this study will provide insight into how a complex phenotype emerges from the interaction of multiple genetic components.