Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia

Kirsten Brunsvig Jarvis; Rikke Linnemann Nielsen; Ramneek Gupta; Freja Dahl Hede; Pasi Huttunen; Ólafur Gisli Jónsson; Cecilie Utke Rank; Susanna Ranta; Kadri Saks; Sonata Saulyte Trakymiene; Ruta Tuckuviene; Morten Tulstrup; INVENT consortium; Ellen Ruud; Kjeld Schmiegelow; Marissa LeBlanc

doi:10.1016/j.thromres.2020.08.015

Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia

Thromb Res. 2020 Dec:196:15-20. doi: 10.1016/j.thromres.2020.08.015. Epub 2020 Aug 12.

Authors

Kirsten Brunsvig Jarvis¹, Rikke Linnemann Nielsen², Ramneek Gupta³, Freja Dahl Hede³, Pasi Huttunen⁴, Ólafur Gisli Jónsson⁵, Cecilie Utke Rank⁶, Susanna Ranta⁷, Kadri Saks⁸, Sonata Saulyte Trakymiene⁹, Ruta Tuckuviene¹⁰, Morten Tulstrup¹¹; INVENT consortium; Ellen Ruud¹², Kjeld Schmiegelow¹³, Marissa LeBlanc¹⁴

Affiliations

¹ Department of Pediatric Hematology and Oncology, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway; Department of Pediatric Research, Oslo University Hospital, Postbok 4950 Nydalen, 0424 Oslo, Norway; The Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Postboks 1072 Blindern, 0316 Oslo, Norway. Electronic address: kirjar@ous-hf.no.
² Department of Health technology, Technical University of Denmark, 2800 Kgs Lyngby, Denmark; Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
³ Department of Health technology, Technical University of Denmark, 2800 Kgs Lyngby, Denmark.
⁴ Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, New Children's Hospital, Helsinki University Hospital, Stenbäckinkatu 9, 00290 Helsinki, Finland.
⁵ Children's Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Hringbraut 101, 101 Reykjavik, Iceland.
⁶ Department of hematology, Rigshospitalet, University of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark; Pediatric Oncology Research Laboratory, Rigshospitalet, University of Copenhagen, Belgdamsvej 9, 2100 Copenhagen, Denmark.
⁷ Astrid Lindgren Children's Hospital, Karolinska University Hospital, Eugeniavägen 3, 171 76 Solna, Sweden; Childhood Cancer Research Unit, Women's and Children's Health, Karolinska Insitutet, Tomtebodavägen 18, 171 77 Solna, Sweden.
⁸ Department of Hematology and Oncology, Tallinn Children's Hospital, 13419 Tallinn, Estonia.
⁹ Clinic of Children's Diseases, Faculty of Medicine, Vilnius University, Vilnius 08410, Lithuania.
¹⁰ Department of Pediatrics, Aalborg University Hospital, Hobrovej 18-22, 9100 Aalborg, Denmark.
¹¹ Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark.
¹² Department of Pediatric Hematology and Oncology, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway; The Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Postboks 1072 Blindern, 0316 Oslo, Norway.
¹³ Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Nørregade 10, 1165 Copenhagen, Denmark.
¹⁴ Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway.

PMID: 32818716
DOI: 10.1016/j.thromres.2020.08.015

Abstract

Introduction: Thromboembolism (TE) is a common and serious toxicity of acute lymphoblastic leukemia (ALL) treatment, but studies of genetic predisposition have been underpowered with conflicting results. We tested whether TE in ALL and TE in the general adult population have a shared genetic etiology.

Materials and methods: We prospectively registered TE events and collected germline DNA in patients 1.0-45.9 years in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 study (7/2008-7/2016). Based on summary statistics from two large genome-wide association studies (GWAS) on venous TE in adults (the International Network of VENous Thromboembolism Clinical Research Networks (INVENT) consortium and the UK Biobank), we performed polygenic risk score (PRS) analysis on TE development in the NOPHO cohort, progressively expanding the PRS by increasing the p-value threshold of single nucleotide polymorphism (SNP) inclusion.

Results and conclusion: Eighty-nine of 1252 patients with ALL developed TE, 2.5 year cumulative incidence 7.2%. PRS of genome-wide significant SNPs from the INVENT and UK Biobank data were not significantly associated with TE, HR 1.16 (p 0.14) and 1.02 (p 0.86), respectively. Expanding PRS by increasing p-value threshold did not reveal polygenic overlap. However, subgroup analysis of adolescents 10.0-17.9 years (n = 231), revealed significant polygenic overlap with the INVENT GWAS. The best fit PRS, including 16,144 SNPs, was associated with TE with HR 1.76 (95% CI 1.23-2.52, empirical p-value 0.02). Our results support an underlying genetic predisposition for TE in adolescents with ALL and should be explored further in future TE risk prediction models.

Keywords: Acute lymphoblastic leukemia; Polygenic risk score; Thromboembolism.

MeSH terms

Adolescent
Adult
Child
Genome-Wide Association Study
Humans
Multifactorial Inheritance
Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
Risk Factors
Venous Thromboembolism* / genetics