Understanding the role of fatty acids in the aetiology of cardiovascular disease using novel causal inference methods

Despite efforts on prevention and treatment, cardiovascular disease is still a leading cause of death globally and in the UK. The World Health Organization emphasizes promoting healthy diets as a key factor to stem the alarming social and economic burden of cardiovascular disease. Since 1950s there is a widespread belief that the quantity and quality of dietary fat (fatty acids) are major triggers of cardiovascular disease, known as the 'diet-heart hypothesis'. However over the past few decades new research has challenged this prevailing idea. The current controversy surrounding health effects of fatty acids is partly driven by limitations of current studies. Studies of observational nature look for associations between people's diet and risk of cardiovascular disease, but cannot distinguish whether dietary fat is causally related to the disease or is just a bystander. Intervention studies usually have short duration and target very specific populations, and therefore also have limitations when interpreting long term effects of dietary fatty acids on the risk of developing cardiovascular disease in the general population.

I aim to embark on a four-year Medical Research Council funded programme at the University of Bristol to address the controversy surrounding fatty acids and cardiovascular health using innovative methods.

Blood levels of fatty acids are influenced by our genetic makeup. Individuals genetically predisposed to higher blood levels of certain fatty acids will have higher exposure to these nutrients throughout life. I will compare individuals with different genetic makeups related to blood levels of fatty acids using a technique named Mendelian randomisation to assess whether fatty acids directly cause cardiovascular disease (heart disease and stroke). In addition, I will use highly-detailed information on the biochemical constituents of blood (known as high throughput metabolomics) to understand precisely which mechanism could link fatty acids to cardiovascular disease. Finally, I will synthesise the available evidence on cardiovascular health effects of fatty acids in order to provide an overview of research findings and seek explanations for the potential inconsistencies regarding the 'diet-heart hypothesis'.
This type of research is only just becoming possible, due to a range of complementary factors. Firstly, advances in technology allowed scientists to measure millions of common between-individual differences in DNA sequence and to perform detailed biochemical measurement in the blood. Secondly, the proliferation of open access summary data from genetic studies and other initiatives, such as the UK Biobank, have yielded large-scale information on the relation between genetics and disease. Thirdly, the development of sophisticated statistical methods has allowed researchers to combine complex information on genetics, metabolism and health status. This fellowship takes advantage of all of these factors.

In summary, this project aims to produce world-leading research on the role of diet in health, particularly with regard to health effects of fatty acids, in order to better inform policy and care dedicated to cardiovascular disease prevention. Also, this research is likely to provide insights into cardiovascular disease mechanisms that may be useful to inform the design of new preventative drugs that would be helpful to the whole population, irrespective of their genetic makeup.

Aim: To assess whether fatty acids are involved in the aetiology of cardiovascular disease (CVD) and to identify potential underlying mechanisms.

Objectives:
1) To examine whether circulating fatty acids are causally related to CVD risk
2) To explore potential underlying mechanisms by which circulating fatty acids could be linked to CVD
3) To synthesize the literature on the relation between dietary fatty acids and CVD and extensively explore the presence and potential explanations of biases

Methodology: I will use data on genetic variants, fatty acids, other metabolites, and CVD (coronary artery disease and stroke) from UK Biobank and four study consortia (UCLEB, METASTROKE, CARDIoGRAMplusC4D, Metabolomics GWAS). The exposures of interest are fatty acids (saturated, monounsaturated, omega-3 and omega-6 fatty acids). To assess the potential causal effect of circulating fatty acids on CVD risk (Objective 1), genetic variants strongly associated with circulating free fatty acids will be used as instrumental variables in a Mendelian randomisation framework (n = 540,00-750,000 individuals). Causal mediation analysis will be used to better understand pathways by which fatty acids might be linked to CVD through a broad interrogation of various lipoproteins, lipids, and low molecular weight molecules that collectively constitute the metabolome (high throughput metabolomics profiling) (Objective 2). The literature on the association between dietary fatty acids and CVD will be appraised using novel techniques in meta-analytical research (overview of reviews and triangulation) aimed at providing an overview of the evidence and exploring the presence and reasons for potential biases (Objective 3).
Scientific and medical opportunities: My findings will provide important causal evidence regarding health effects of fatty acids that can be used to inform research, clinical practice and make appropriate public health policy.

This work will appeal to a wide academic audience in the UK and internationally. The discussion on the role of dietary fat in cardiovascular disease ('diet-heart hypothesis') has divided academics for decades. Researchers within fields of nutrition, cardiovascular health, epidemiology, genetics, and public health will benefit from contributions this work will make to evidence base. Statisticians and epidemiologists may also benefit from the methodological insights which will be gained by the application of multiple techniques involving causal inference and evidence synthesis.
Research funding agencies from the UK and abroad are also potential beneficiaries. Despite the massive amount of resources invested in the field, the evidence base for the 'diet-heart hypothesis' is still a matter of heated debate. I propose to address this long-running scientific controversy using innovative approaches with data that have already been collected in order to greatly advance in our understanding of the health effects of fatty acids while maximising the resources currently available.
The findings of the proposed research will benefit a number of public sector organisations from UK and internationally. The findings will be directly relevant to the NHS and the Department of Health. Other national bodies such as Public Health England (PHE) would be able to use research outputs from this proposal. Part of their remit is to set the agenda for priorities in public health policy, and robust evidence on the health effects of fatty acids could be fed into policy at this level. The 2016 UK's national food guide, the Eatwell Guide, led by PHE, has eight core messages, three of which involve recommendations on dietary fat either directly (by promoting lower fat products, replacement of saturated by unsaturated fats or consumption of fish rich in omega-3 fatty acids) or indirectly (by recommending meals should be based on starchy foods). The promotion of dietary fat recommendations as a core component of food guides is a common feature among organization across the globe and, therefore, findings will be of widespread interest to international and global organizations. The Department of Chronic Disease and Health Promotion from World Health Organization (WHO) has as a top priority the implementation of the WHO Global Strategy on Diet, Physical Activity and Health and will also benefit from strengthening evidence base for dietary fatty acids recommendations.
My work is directly relevant to informing research agendas and work of charities, such as British Heart Foundation (BHF) and British Nutrition Foundation (BNF). For example, prevention of heart disease is a key feature of BHF research strategy and work in the wider community. In addition, translating and communicating complex scientific information on nutrition to the general public is a core purpose of BNF.
Advisory committees, such as the Scientific Advisory Committee in Nutrition (SACN), are also potential beneficiaries, particularly the SACN Saturated fats Working Group dedicated to review the evidence for the relationship between saturated fats and health and make recommendations.
My findings will also be of interest to health professionals providing dietary advice to patients and for the wider public which frequently faces difficulties when interpreting controversial findings from nutrition research.
Finally, there is likely to be a commercial interest in the research findings. Given that drug target validation has been identified as a key obstacle underlying the unsustainably high rate of drug development failure, the findings are likely to be of particular interest to the pharmaceutical industry.
The timescale for these benefits could be both within the lifetime of the fellowship, e.g. providing important aetiological insights for cardiovascular disease, or outside of the lifetime of the project, e.g. potential improvements in health policy and care influenced by these findings.