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Polygenic Risk Score-Analysis of Thromboembolism in Patients with Acute Lymphoblastic Leukemia

1Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 2Technical University of Denmark, Kgs Lyngby, Denmark, 3Rigshospitalet, Copenhagen, Denmark, 4University of Copenhagen, Copenhagen, Denmark

Abstract Number: PB1279

Meeting: ISTH 2020 Congress

Theme: Pediatrics » Thrombosis in Neonates and Children

Background: Thromboembolism (TE) is a severe toxicity of acute lymphoblastic leukemia (ALL) treatment; but genetic studies on TE in patients with ALL are often underpowered. Attempts to extrapolate from the genetics of TE in adults have been many and the results conflicting.

Aims: We investigated whether there is common genetic etiology between TE in the general adult population and TE in patients with ALL, using polygenic risk scores (PRS).

Methods: We prospectively registered TE events and collected germline DNA in patients 1.0-45.9 years with ALL treated according to the NOPHO ALL2008 study (2008-2016). The study was approved by national ethical review boards and required signed informed consents. Based on summary statistics from two large genome-wide association studies from the INVENT consortium and the UK Biobank on TE in adults, we performed PRS analysis on individual level data in NOPHO. We gradually expanded the PRS by increasing the p-value threshold to capture polygenicity, with power >80% for PRS including up to 40,000 SNPs.

Results: Eighty-nine of 1252 patients with ALL developed TE, cumulative incidence 7.2%, at a median 12.7 weeks from diagnosis. PRS of genome-wide significant SNPs from INVENT and the UK Biobank were not significantly associated with TE in ALL, HR 1.16 (p 0.14) and 1.02 (p 0.86) respectively. Expanding the PRS to include more SNPs did not reveal polygenic overlap. In subgroup analysis of children < 18 years (n=1125), there was evidence of significant polygenic overlap with the INVENT data, though effect sizes were small, HR 1.60 (p < 0.001) for the best fit PRS (18,964 SNPs, p-value threshold 0.02).

Conclusions: Thus, genetic factors known to affect risk of TE in the general adult population may influence risk of TE in children with ALL, but we consider this effect to be small in the context of cancer, chemotherapy and a coagulation system under development.


[HRs of PRS from UK Biobank and INVENT summary statistics on TE in the NOPHO cohort (top), with subgroup analysis of children 1.0-17.9 years (bottom)]

To cite this abstract in AMA style:

Jarvis KB, Gupta R, Hede FD, Nielsen R, Ruud E, Schmiegelow K, Leblanc M. Polygenic Risk Score-Analysis of Thromboembolism in Patients with Acute Lymphoblastic Leukemia [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/polygenic-risk-score-analysis-of-thromboembolism-in-patients-with-acute-lymphoblastic-leukemia/. Accessed September 24, 2023.

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