Deciphering the genetic basis of immune thrombocytopenia: current evidence for genetic predisposition in adult ITP.

Immune thrombocytopenia (ITP) is the consequence of a complex, still not completely understood immunological dysregulation. Proposed mechanisms include autoantibody-induced platelet destruction, impaired platelet production as well as abnormalities in T-cell immunity, such as Th1 polarization, a high proportion of Th17 cells and a reduced number of regulatory T cells. Although the etiology of ITP is incompletely understood and considered multifactorial in most cases, genetic variants are thought to play a key role in susceptibility to ITP, especially in persistent or chronic ITP. Efforts are currently underway to uncover possible predisposing genetic factors for the development of ITP. Single nucleotide polymorphisms and copy number variations have been identified in several immune-related genes, such as cytokine genes, Fc gamma receptor genes or T-cell co-stimulation genes, and have been associated with patients' susceptibility to ITP. However, due to the clinical heterogeneity and low incidence of ITP it remains challenging to perform genetic analyses with sufficiently large sample size within informative patient populations, highlighting the need for collection of well annotated biomaterials in clinical trials or registry projects. Another significant challenge is to go beyond performing association studies alone and to establish genotype-phenotype associations, thus proving causality between a genetic alteration and ITP pathogenesis. This review summarizes our current knowledge on genetic alterations identified as potential predisposing factors for the development of ITP in adults, thereby addressing signaling pathways considered critical for ITP pathogenesis.