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Thromb Haemost 2022; 122(02): 267-276
DOI: 10.1055/a-1497-9777
Stroke, Systemic or Venous Thromboembolism

Joint Effect of Multiple Prothrombotic Genotypes and Obesity on the Risk of Incident Venous Thromboembolism

Tobias Frischmuth 
1   Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway
,
Kristian Hindberg
1   Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway
,
Maiken E. Gabrielsen
2   Department of Public Health, K. G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway
,
Ben Brumpton
2   Department of Public Health, K. G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway
,
Kristian Hveem
2   Department of Public Health, K. G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway
3   Department of Public Health, HUNT Research Center, Norwegian University of Science and Technology, Levanger, Norway
,
Sigrid K. Brækkan
1   Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway
4   Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
,
John-Bjarne Hansen
1   Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway
4   Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
,
Vânia M. Morelli
1   Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway
› Author Affiliations Funding K.G. Jebsen TREC and K.G. Jebsen Center for Genetic Epidemiology are supported by independent grants from Stiftelsen Kristian Gerhard Jebsen. The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St Olav's Hospital and the Faculty of Medicine and Health Sciences, NTNU. T. Frischmuth is supported by the Northern Norway Regional Health Authority.
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Abstract

Background The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear.

Objective To investigate the joint effect of obesity and a genetic risk score (GRS) composed of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case–cohort.

Methods Cases with incident VTE (n = 1,470) and a subcohort (n = 12,826) were derived from the Tromsø Study (1994–2012) and the Trøndelag Health Study (HUNT) (1995–2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914) SNPs. Age- and sex-adjusted hazard ratios (HRs) were estimated according to body mass index (BMI) categories and number of risk alleles for individual SNPs and the GRS (0–1, 2, 3, ≥4 alleles).

Results The combination of obesity (BMI ≥ 30kg/m2) and risk alleles, either as individual SNPs or as a GRS, had an additive effect on VTE risk (i.e., no biological interaction). Obese subjects who were carriers of ≥4 risk alleles had a 2.85-fold (95% confidence interval [CI]: 2.05–3.96) increased risk of overall VTE compared with those with BMI <25 kg/m2 and 0 to 1 risk allele. However, in subgroups, the combination of obesity and ≥4 risk alleles was more pronounced for deep vein thrombosis (DVT) (HR: 3.20; 95% CI: 2.09–4.90) and unprovoked VTE (HR: 3.82; 95% CI: 2.25–6.47), suggesting a supra-additive effect.

Conclusion Our findings indicate that the combination of obesity and GRS has an additive effect on the risk of overall VTE. However, it may have a supra-additive effect on the risk of DVT and unprovoked VTE.

Keywords

deep vein thrombosis - interaction - obesity - single nucleotide polymorphisms - venous thromboembolism

Author Contributions

T.F. analyzed data, interpreted the results, and drafted the manuscript. K.H. provided statistical support, interpreted the results, and revised the manuscript. M.E.G., B.B., and K.H. organized data collection and revised the manuscript. S.K.B. designed the study, organized data collection, interpreted the results, contributed to the manuscript draft, and revised the manuscript. J-.B. H. designed the study, organized data collection, interpreted the results, and revised the manuscript. V.M.M. designed the study, interpreted the results, contributed to the manuscript draft, and revised the manuscript. All authors reviewed and approved the final version of the manuscript.


Supplementary Material



Publication History

Received: 12 January 2021

Accepted: 30 April 2021

Accepted Manuscript online:
03 May 2021

Article published online:
25 June 2021

© 2021. Thieme. All rights reserved.

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