Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia
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Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia. / Jarvis, Kirsten Brunsvig; Nielsen, Rikke Linnemann; Gupta, Ramneek; Hede, Freja Dahl; Huttunen, Pasi; Jónsson, Ólafur Gisli; Rank, Cecilie Utke; Ranta, Susanna; Saks, Kadri; Trakymiene, Sonata Saulyte; Tuckuviene, Ruta; Tulstrup, Morten; Ruud, Ellen; Schmiegelow, Kjeld; LeBlanc, Marissa; the INVENT consortium.
In: Thrombosis Research, Vol. 196, 2020, p. 15-20.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Polygenic risk score-analysis of thromboembolism in patients with acute lymphoblastic leukemia
AU - Jarvis, Kirsten Brunsvig
AU - Nielsen, Rikke Linnemann
AU - Gupta, Ramneek
AU - Hede, Freja Dahl
AU - Huttunen, Pasi
AU - Jónsson, Ólafur Gisli
AU - Rank, Cecilie Utke
AU - Ranta, Susanna
AU - Saks, Kadri
AU - Trakymiene, Sonata Saulyte
AU - Tuckuviene, Ruta
AU - Tulstrup, Morten
AU - Ruud, Ellen
AU - Schmiegelow, Kjeld
AU - LeBlanc, Marissa
AU - the INVENT consortium
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Acute lymphoblastic leukemia
KW - Polygenic risk score
KW - Thromboembolism
U2 - 10.1016/j.thromres.2020.08.015
DO - 10.1016/j.thromres.2020.08.015
M3 - Journal article
C2 - 32818716
AN - SCOPUS:85089437495
VL - 196
SP - 15
EP - 20
JO - Thrombosis Research
JF - Thrombosis Research
SN - 0049-3848
ER -
ID: 250255880