Abstract
Background Immune thrombocytopenic purpura (ITP) is a rare though well recognized adverse event following measles, mumps, and rubella (MMR) vaccine. Identification of individuals at high risk for these and other vaccine adverse events might inform pre-vaccination screening options for the future. Working in close collaboration with the FDA, we seek to identify genetic differences underlying the susceptibility to ITP following MMR or MMR and varicella (MMRV) vaccination. We will compare the genetic make-up of these cases to ITP occurring after medication exposure and to idiopathic cases of ITP.
Methods We plan to recruit 450 persons with ITP. These will include 150 cases with ITP following vaccination from the FDA’s Vaccine Adverse Events Reporting System (VAERS) and the Intercontinental Cooperative ITP Study Group (ICIS) and 300 cases (150 with ITP related to prescribed medications, and 150 cases of idiopathic ITP) recruited from ICIS, Kaiser Permanente Georgia, and Kaiser Permanente Southern California. To identify novel candidate genes or pathways, we will perform whole exome resequencing for (at least) six unrelated individuals with a Mendelian form of ITP. Polymorphism frequencies within these candidate genes will be examined and their proportions compared with control data available from the 1000 Genomes Project. The identified polymorphisms will inform the genome-wide association study (GWAS) phase, which will also include a copy number variation (CNV) component.
Results To date, we have identified 232 potential cases of ITP following MMR/MMRV vaccination reported to VAERS during 2000–2009. Of these potential cases, 214 have been abstracted and 156 (73%) have been confirmed. Recruitment is set to begin in November 2010. In addition, we have identified six participants from families with congenital thrombocytopenia for exome resequencing. Supplemental funding was obtained to support recruitment efforts and additional sequencing.
Conclusions This study involves a unique collaboration between the FDA and the HMORN, leveraging HMORN experience in pharmacogenomics and vaccine adverse event research. The ultimate goal of this project will be to use new resequencing strategies, combined with GWAS and CNV, to identify variants which may enable the prediction of risk, at the individual level, of developing ITP after vaccination.
