Genome-Wide Association Study in Acquired Aplastic Anemia
Abstract
Aplastic anemia (AA) is a bone marrow failure disorder resulting in a lack of production of blood cells that puts patients at risk of severe infection, bleeding, and complications of anemia. In the past, this was fatal in nearly all patients, but now treatments exist with either immunosuppression or a bone marrow transplant. AA is caused because stem cells that give rise to all blood components, the hematopoietic stem cells (HSC), are targets for destruction in the bone marrow. The known causes of HSC destruction are (1) constitutional or inherited genetic defects in production of HSCs, (2) direct chemical and physical damage by drugs, toxins, or radiation, and (3) an attack of HSCs by the patient’s own immune cells called T-lymphocytes. Immune AA is both the commonest and most poorly understood mechanism causing AA. There is a large discrepancy in incidence of AA between Europe and Asia; in Asia rates are approximately 4-6 per million, compared to 2 per million in Europe. The reasons for this difference remain unclear. Epidemiological studies have looked at the effects of environmental exposures, drugs, and toxins but none have provided significant results. Genetic susceptibility has also been investigated as a risk factor for AA but studies have been small and not reproducible. Genome-wide association study (GWAS) is an ideal approach, as it compiles genetic information from numerous individuals and looks to find associations with specific traits or diseases. GWAS has been successfully used to identify important genes that act as markers of risk, that aid with diagnosis, and that act as potential targets for drug treatments in many other diseases. One previous GWAS performed in AA looking at 802 patients identified immune genetic markers that are associated with AA. Our hypothesis is that genetic susceptibility does play a role in AA and that it is necessary to investigate large numbers of genetic alterations in AA patients in order to identify this susceptibility with accuracy. The difference in incidence of AA between Europe and Asia may be related to this genetic susceptibility, and by comparing these two population we may identify new contributing genetic factors to disease. Our study aims are as follows: (1) Perform the largest and first multi-ethnic GWAS study in AA; (2) Compare our data with healthy, ethnically matched controls; (3) Pool the data from our GWAS with the data from the previous AA GWAS study in order to increase our ability to find relevant genetic associations; (4) Use the genetic alterations we discover in the GWAS to try and understand the mechanisms behind what causes immune AA and to translate our new knowledge into ways that will, in the future, directly impact patients with AA. To perform the GWAS we will be collaborating with investigators in Japan, South Korea, the UK, France, and Italy and analyzing a total of 1,740 samples (900 from Asia and 840 from America/Europe) from AA patients. This will be meta-analyzed with over 1,500 AA patient samples and with healthy matched controls in a 1:3 ratio. This project is innovative because it is the largest and first multiethnic GWAS performed in AA. It represents a novel way of approaching immune AA with the hope of offering insights into underlying disease mechanisms and possible new ways to focus our research. Any potentially discovered genes that predict risk, disease pathways, or drug targets would greatly impact patients with AA. Basic screening measures could be put in place for those found to be at high risk. Potential findings could also help us to predict AA patients who would respond to one therapy over another and aid us in our treatment decisions. Discovering gene targets or disease pathways and understanding how genetics influences the predisposition to AA may help us to develop new or personalized treatments for patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010871
Entities
People
- Neal Young
Organizations
- National Heart, Lung, and Blood Institute
- United States Army