UNDERSTANDING THE RELATIONSHIP BETWEEN ATHEROSCLEROSIS AND FATTY LIVER DISEASE

Bakgrund:

Cardiovascular disease (CVD) is the major cause of mortality and morbidity worldwide, with more than 17.9 million deaths annually. Fatty liver disease (FLD) is an emerging disease in internal medicine with prevalence of 20-40% in Europe. It is characterized by hepatic fat accumulation and it represents an independent risk factor for CVD.

However, the mechanism underlying the association between FLD and CVD is poorly understood. We hypothesize that FLD may lead to CVD through an overproduction of VLDL which in the circulation are catabolized in LDL-C, the main risk factor for CVD. Målsättning:

The main objective of this grant is to understand the relationship between LDL-C and FLD in determining CVD. This will be achieved by the following specific aims: AIM 1: To identify novel variants increasing the risk for FLD and CVD.

AIM 2: To understand why carriers of a novel variant protecting against FLD have lower LDL-C levels and this results in lower CVD. AIM 3: To test if increased LDL-C levels are driven by FLD. Arbetsplan:

1) To identify novel variants increasing the risk for FLD and CVD, we will screen variants in genes previously found associated with APOB-containing lipoproteins (triglycerides, LDL-C) for association with FLD and CVD in 4 independent cohorts.

2) To understand why carriers of a novel variant protecting against FLD have lower LDL-C levels we will firstly confirm the genetic association between the novel variant, lower FLD and lower LDL-C in 2 independent cohorts and test the variant for association with protection against CVD. Then, we will perform in vitro and in vivo studies to identify the molecular mechanism behind this phenomenon.

3) To test if increased LDL-C levels are driven by FLD, we will examine liver fat content of individuals with familial hypercholesterolemia (FH) in two independent cohorts. FH is a disorder characterized by elevated LDL-C and subsequent premature CVD development. Liver fat content in these individuals will be measured by non-invasive transient elastography (Fibroscan) using controlled attenuation parameter (CAP).

Betydelse:

Understanding the relationship between LDL-C and FLD in determining CVD will allow to refine the individual risk of cardiovascular disease and will lead to the identification of novel therapeutic targets to tackle both CVD and FLD.