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

Tobias Frischmuth; Kristian Hindberg; Maiken E. Gabrielsen; Ben Brumpton; Kristian Hveem; Sigrid K. Brækkan; John-Bjarne Hansen; Vânia M. Morelli

doi:10.1055/a-1497-9777

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

¹Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway

,

Kristian Hindberg

¹Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway

,

Maiken E. Gabrielsen

²Department of Public Health, K. G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway

,

Ben Brumpton

²Department of Public Health, K. G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway

,

Kristian Hveem

²Department of Public Health, K. G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway

³Department of Public Health, HUNT Research Center, Norwegian University of Science and Technology, Levanger, Norway

,

Sigrid K. Brækkan

¹Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway

⁴Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway

,

John-Bjarne Hansen

¹Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway

⁴Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway

,

Vânia M. Morelli

¹Department of Clinical Medicine, K.G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT - The Arctic University of Norway, Tromsø, Norway

› Institutsangaben

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

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References
1 Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5 (04) 692-699
2 Arshad N, Isaksen T, Hansen JB, Brækkan SK. Time trends in incidence rates of venous thromboembolism in a large cohort recruited from the general population. Eur J Epidemiol 2017; 32 (04) 299-305
3 World Health Organization (WHO). Fact sheet: obesity and overweight. 2018 . Accessed February 24, 2020 at: https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight
4 Braekkan SK, Siegerink B, Lijfering WM, Hansen JB, Cannegieter SC, Rosendaal FR. Role of obesity in the etiology of deep vein thrombosis and pulmonary embolism: current epidemiological insights. Semin Thromb Hemost 2013; 39 (05) 533-540
5 Rahmani J, Haghighian Roudsari A, Bawadi H. et al. Relationship between body mass index, risk of venous thromboembolism and pulmonary embolism: a systematic review and dose-response meta-analysis of cohort studies among four million participants. Thromb Res 2020; 192: 64-72
6 Horvei LD, Brækkan SK, Hansen JB. Weight change and risk of venous thromboembolism: the Tromsø Study. PLoS One 2016; 11 (12) e0168878
7 Heit JA, Ashrani A, Crusan DJ, McBane RD, Petterson TM, Bailey KR. Reasons for the persistent incidence of venous thromboembolism. Thromb Haemost 2017; 117 (02) 390-400
8 Klovaite J, Benn M, Nordestgaard BG. Obesity as a causal risk factor for deep venous thrombosis: a Mendelian randomization study. J Intern Med 2015; 277 (05) 573-584
9 Klarin D, Emdin CA, Natarajan P, Conrad MF, Kathiresan S. INVENT Consortium. Genetic analysis of venous thromboembolism in UK Biobank identifies the ZFPM2 locus and implicates obesity as a causal risk factor. Circ Cardiovasc Genet 2017; 10 (02) e001643
10 Lindström S, Germain M, Crous-Bou M. et al; INVENT Consortium. Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian randomization study. Hum Genet 2017; 136 (07) 897-902
11 Larsson SC, Bäck M, Rees JMB, Mason AM, Burgess S. Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a Mendelian randomization study. Eur Heart J 2020; 41 (02) 221-226
12 de Haan HG, Bezemer ID, Doggen CJ. et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012; 120 (03) 656-663
13 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353 (9159): 1167-1173
14 Pomp ER, le Cessie S, Rosendaal FR, Doggen CJ. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007; 139 (02) 289-296
15 Severinsen MT, Overvad K, Johnsen SP. et al. Genetic susceptibility, smoking, obesity and risk of venous thromboembolism. Br J Haematol 2010; 149 (02) 273-279
16 Christiansen SC, Lijfering WM, Naess IA. et al. The relationship between body mass index, activated protein C resistance and risk of venous thrombosis. J Thromb Haemost 2012; 10 (09) 1761-1767
17 Ribeiro DD, Lijfering WM, Rosendaal FR, Cannegieter SC. Risk of venous thrombosis in persons with increased body mass index and interactions with other genetic and acquired risk factors. J Thromb Haemost 2016; 14 (08) 1572-1578
18 Kim J, Kraft P, Hagan KA, Harrington LB, Lindstroem S, Kabrhel C. Interaction of a genetic risk score with physical activity, physical inactivity, and body mass index in relation to venous thromboembolism risk. Genet Epidemiol 2018; 42 (04) 354-365
19 van Langevelde K, Flinterman LE, van Hylckama Vlieg A, Rosendaal FR, Cannegieter SC. Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum. Blood 2012; 120 (05) 933-946
20 Weingarz L, Schwonberg J, Schindewolf M. et al. Prevalence of thrombophilia according to age at the first manifestation of venous thromboembolism: results from the MAISTHRO registry. Br J Haematol 2013; 163 (05) 655-665
21 Jacobsen BK, Eggen AE, Mathiesen EB, Wilsgaard T, Njølstad I. Cohort profile: the Tromso Study. Int J Epidemiol 2012; 41 (04) 961-967
22 Holmen J, Midthjell K, Krüger Ø. et al. The Nord-Trøndelag Health Study 1995–97 (HUNT2). Nor Epidemiol 2011; 13 (01) 19-32
23 Braekkan SK, Borch KH, Mathiesen EB, Njølstad I, Wilsgaard T, Hansen JB. Body height and risk of venous thromboembolism: the Tromsø Study. Am J Epidemiol 2010; 171 (10) 1109-1115
24 Småbrekke B, Rinde LB, Evensen LH. et al. Impact of prothrombotic genotypes on the association between family history of myocardial infarction and venous thromboembolism. J Thromb Haemost 2019; 17 (08) 1363-1371
25 Horvei LD, Braekkan SK, Smith EN. et al. Joint effects of prothrombotic genotypes and body height on the risk of venous thromboembolism: the Tromsø Study. J Thromb Haemost 2018; 16 (01) 83-89
26 Li Y, Bezemer ID, Rowland CM. et al. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost 2009; 7 (11) 1802-1808
27 Rothman KJ. Measuring interactions. In: Epidemiology: An Introduction. New York, NY: Oxford University Press; 2002: 168-180
28 Andersson T, Alfredsson L, Källberg H, Zdravkovic S, Ahlbom A. Calculating measures of biological interaction. Eur J Epidemiol 2005; 20 (07) 575-579
29 Vandenbroucke JP, von Elm E, Altman DG. et al; STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Epidemiology 2007; 18 (06) 805-835
30 Crous-Bou M, De Vivo I, Camargo Jr CA. et al. Interactions of established risk factors and a GWAS-based genetic risk score on the risk of venous thromboembolism. Thromb Haemost 2016; 116 (04) 705-713
31 Shaya SA, Westrick RJ, Gross PL. Thrombus stability explains the factor V Leiden paradox: a mouse model. Blood Adv 2019; 3 (21) 3375-3378
32 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369 (6475): 64-67
33 Lowe GD, Rumley A, Woodward M, Reid E, Rumley J. Activated protein C resistance and the FV:R506Q mutation in a random population sample--associations with cardiovascular risk factors and coagulation variables. Thromb Haemost 1999; 81 (06) 918-924
34 Morelli VM, de Visser MC, van Tilburg NH. et al. ABO blood group genotypes, plasma von Willebrand factor levels and loading of von Willebrand factor with A and B antigens. Thromb Haemost 2007; 97 (04) 534-541
35 Kaye SM, Pietiläinen KH, Kotronen A. et al. Obesity-related derangements of coagulation and fibrinolysis: a study of obesity-discordant monozygotic twin pairs. Obesity (Silver Spring) 2012; 20 (01) 88-94
36 Clarke R, Shipley M, Lewington S. et al. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 1999; 150 (04) 341-353
37 Småbrekke B, Rinde LB, Hindberg K. et al. Atherosclerotic risk factors and risk of myocardial infarction and venous thromboembolism; time-fixed versus time-varying analyses. the Tromsø Study. PLoS One 2016; 11 (09) e0163242

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