Atrial fibrillation: understanding determinants and effects on wider disease in UK Biobank

Atrial fibrillation (AF) is a common condition in which the heart beats irregularly and affects over 33 million people worldwide. AF can increase patients' risk of having strokes or heart failure. The reasons why some individuals develop AF are unclear although evidence supports a role for high blood pressure, among other risk factors. The underlying cause for AF is particularly unexplained in cases where individuals develop AF without any comorbidities. Previous studies have suggested that those with a higher body mass index (BMI) are at increased risk of AF. However, it has not been definitively proved that increased fat tissue (adipose tissue) causes AF, nor is it clear why fat tissue leads to the development of AF. It is known that fat can be distributed differently between individuals and that this distribution can alter the likelihood of developing other medical conditions.

We hypothesize that more fat tissue is an underlying cause for the development of AF. We also propose that the effect of increased fat tissue on developing AF may depend on where in the body fat tissue predominates.

The objectives of this studentship are four-fold:
1. To establish whether increased fat tissue causes the development of AF.
2. To determine the effect that fat tissue distribution has on the development of AF through the use of MRI images of the body.
3. To examine the mechanisms by which fat tissue causes the development of AF including whether body-fat distribution alters the effect of this relationship.
4. To explore the role of fat tissue in causing AF in different groups (including those that develop AF without any other known medical conditions), and the impact fat tissue has in patient outcomes from AF.

To answer these questions, we will use information, including genetic data, individuals have previously provided to the UK Biobank (UKB). Participants (n=500,000) in the UKB have previously answered questions on their past medical history and agreed to have their hospital records linked to the study. We will use this information to establish those with AF. We will initially confirm that those with higher weights are at increased risk of developing AF once they have entered the study.

Previous research has identified genetic mutations that are associated with higher BMI. We will use this information to establish people who, in general, are likely to have more fat tissue than others. Using this information, we will then look to see if those who are genetically more likely to be overweight are at increased risk of developing AF through a process called Mendelian Randomization.

A number of participants in the UK biobank have also undergone scans including whole-body MRI. These scans provide information on fat tissue distribution. We will look at whether the areas in which individuals have fat tissue effects the development of AF.

Once the BMI-AF relationship is established, we will then examine why this relationship exists. Being overweight can be related to other health conditions (e.g. high blood pressure and diabetes), which, in turn, increase the risk of having AF. We will examine how much the role of fat tissue on AF development is due to associated conditions.

Specific groups will be identified to assess the role of fat tissue in AF development in different populations. The increased risk of stroke and heart failure associated with AF development have major implications for patients. As a result, we will examine how adiposity impacts the health outcomes of those with AF.

Key applications and benefits of this studentship, in addition to personal development, include the following. 1) Demonstration that increased fat tissue causes AF will allow patients at high risk of developing this irregular heart rhythm to be identified in clinical settings. 2) Understanding the pathway by which fat tissue leads to AF development will also help identify and treat those individuals at the highest risk.