IFNA17, DOK3 genetic variants associated with increased incidence, severity of pediatric ITP

Issue: December 25, 2015

ORLANDO, Fla. — Damaging gene variants associated with cellular immunity appeared to increase risk for chronic immune thrombocytopenia in children, according to findings from a multi-institutional study conducted through the ITP Consortium of North America presented at the 2015 ASH Annual Meeting and Exposition.

Chronic immune thrombocytopenia (ITP) is characterized by abnormalities — such as an altered T-cell balance with a shift toward immune activation, as well as a decreased number and impaired function of regulatory T cells — the cause of which has not been fully elucidated.

Jenny M. Despotovic

Jenny M. Despotovic, DO, MS, director of the immune hematology program at Texas Children’s Cancer Center and assistant professor in the department of pediatrics at Baylor College of Medicine in Houston, and colleagues sought to identify genetic variants that could be involved in ITP pathogenesis and impact the susceptibility and severity of chronic ITP in children.

“This is the first study of its kind in chronic ITP,” Despotovic told HemOnc Today. “Improved understanding of genetic factors impacting ITP susceptibility, evolution to chronic disease and treatment response could help predict high risk patients, optimize therapy and minimize exposure to potentially toxic therapies that may be less likely to be effective.”

Researchers performed whole exome sequencing on 262 samples with robust phenotype data from two databases: the North American Chronic ITP Registry (n = 173) and the Platelet Disorders Center at Weill-Cornell Medicine (n = 89).

All but three patients were 19 years or younger at the time of diagnosis. Eighty-three percent had a primary ITP, 10% had Evans syndrome and the remaining 7% had other autoimmune disorders.

Researchers compared the gene sequencing results of patients with ITP of European-American descent with gene sequencing of 5,664 European-American controls with platelets greater than 150 x 10⁹/L from the Atherosclerosis Risk in Communities study.

Results of this analysis revealed several damaging genetic variants involving cellular immunity that occurred significantly more frequently in the ITP cohort, including IFNA17, DGCR14, SMAD2 and CD83.

The IFNA17 gene is associated with TGF-beta secretion and may affect the number and function of regulatory T cells. The IFNA17 rs9298814 variant was identified in 26% of the cases compared with 5.6% of the controls. Other low-frequency but dangerous variants were also identified in this gene, and these variants remained significant in the most severely affected patients, such as those requiring second-line therapy.

Researchers noted DGCR14, SMAD2 and CD83 variants also impact T-cell count and function.

In an analysis of data from patients who needed second-line therapy (n = 139), DOK3 (P = 1.26 x 10^–6) and REL (P = 1.39 x 10^–14) appeared significantly associated with the need for additional therapy.

These data did not validate any of the more than 20 variants that were previously published as candidates for ITP susceptibility or evolution to chronic ITP.

“We will continue to investigate genetic changes in patients with ITP, including looking to identify genetic factors affecting treatment response, as well as looking at the functional significance of the variants identified,” Despotovic said. “We also intend to enroll a cohort of children with newly diagnosed ITP, in order to compare the prevalence of these variants in children with ITP that resolves quickly.” – by Anthony SanFilippo

Reference:

Despotovic JM, et al. Abstract 73. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Disclosure: Despotovic reports no relevant financial disclosures. The other researchers report research funding and honoraria from and consultant/advisory roles with Amgen; Baxalta; Cangene; GlaxoSmithKline; Hardin, Kundla, McKeon, & Poletto; Kedrion; Novartis; Novo Nordisk; Protalex and Rigel.