Tobias Frischmuth

The doctoral thesis!

Prøveforelesningen starter kl. 09.15

Prøveforelesningen har følgende tittel:  “Venous thromboembolism in men and women”

Prøveforelesning kan strømmes her / The trial lecture will be streamed!

Disputasen starter 11.15

Disputasen kan strømmes her / The defence will be streamed!

Auditoriet er åpent for publikum. Disputasen vil strømmes og et opptak vil være tilgjengelig i et døgn.

The auditorium is open to the public. The defense will still be streamed, and a recording of the disputation will be available for 24 hours.

Populærvitenskapelig sammendrag av avhandlingen:

Venous thromboembolism (VTE), a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common and multicausal disease. Obesity is a major and likely causal risk factor for VTE. However, to what extent obesity contributes to VTE risk in the general population and the mechanism of obesity-related VTE remain poorly understood.

The overall aim of this thesis was (i) to determine the risk of VTE attributed to obesity at population level and (ii) to reveal biomarkers of obesity-related VTE.

The study population in all papers was recruited from the 4th-7th surveys of the Tromsø Study (enrolment: 1994-2016), a population-based cohort study. Paper II also included participants from the Trøndelag Health Study (HUNT 2). Exposure information was obtained at survey inclusion through self-administered questionnaires, physical examination, and blood samples. Incident VTE events during follow-up were registered and objectively validated.

In paper I, to assess the VTE risk attributed to overweight and obesity, we calculated the population attributable fraction (PAF) using a cohort design and repeated measurements of body mass index (BMI). The PAF of incident VTE due to overweight (BMI 25-30 kg/m2) and obesity (BMI ≥30 kg/m2) was 24.6% (12.9% was attributed to overweight and 11.7% to obesity). In paper II, the joint effect of obesity and established prothrombotic genotypes

(rs8176719 in ABO, rs6025 in F5, rs1799963 in F2, rs2066865 in FGG, and rs2036914 in

F11) on VTE risk was investigated. Using a case-cohort design, it was observed that the combination of obesity and prothrombotic genotypes, assessed either individually or as a genetic risk score, had an additive effect on VTE risk (i.e., no biological interaction).

However, the combination of obesity and some prothrombotic genotypes appeared to have a supra-additive effect on the risk of DVT and unprovoked VTE. In papers III and IV, a nested case-control design was used to investigate whether plasma leptin and plasminogen activator

inhibitor-1 (PAI-1) were associated with VTE risk and their potential to mediate the VTE risk in obesity. The VTE risk increased with increasing levels of leptin, and particularly of PAI-1.

Additional adjustment for BMI markedly attenuated risk estimates for leptin, while PAI-1 remained associated with VTE. In a mediation analysis, PAI-1 mediated almost 15% of the VTE risk in obesity, while no apparent mediation was observed for leptin.

In conclusion, the main findings of this thesis indicate that obesity is a major risk factor for VTE at population level and that PAI-1 levels mediate part of the VTE risk in obesity.

Hovedveileder

Forsker Vania Maris Morelli, Institutt for klinisk medisin, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet

Biveiledere

Professor John Bjarne Hansen, Institutt for klinisk medisin, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet

Professor Sigrid Brækkan, Institutt for klinisk medisin, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet

Bedømmelseskomité

1. opponent er Pierre Morange, Hematology Laboratory, La Timone University Hospital of Marseille, Aix-Marseille University, Marseille, France.

2. opponent er Marcus Lind, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
3. opponent og leder av komité er Ph.d. Anja Davis Norbye. Institutt for helse og omsorgsfag, UiT Norges arktiske universitet

Disputasleder: Førsteamanuensis Jorunn Pauline Cavanagh, Institutt for klinisk medisin, Det helsevitenskapelige fakultet, UiT Norges arktiske universitet