Understanding gender differences in cardiometabolic risk across the life course

Heart disease and diabetes are leading causes of death in men and women globally and in the UK. Gender differences in diabetes exist in adults. For example, diabetes is more common in men than in women. On average, overweight or obese men also develop diabetes at a lower level of fatness than overweight or obese women. However, once a woman becomes diabetic she is much more likely to develop heart disease than a diabetic man. We know that a person's risk of diabetes and heart disease begins to take shape in childhood. Even in young children the level of sugar and other substances in the blood can tell us about the risk of them developing diabetes as adults.

The aim of this project is to find out if differences between men and women in terms of their diabetes and heart disease risk later in life are already evident in young boys and girls from birth all the way through childhood and into early adulthood. I will do this by comparing the amount of sugar and other substances in the blood of boys and girls from when they are born to when they are young adults. I will investigate if young boys who are overweight or obese have the same levels of sugar in their blood as young girls who are overweight or obese. This will tell us if overweight or obese boys already show a higher chance of getting diabetes compared to overweight or obese girls. I will also investigate if girls with high levels of sugar and other substances in their blood have problems with their hearts compared to boys with high level of sugars and other substances in their blood. This will tell us if the higher level of heart disease in diabetic women later in life is already detectable in the hearts of young girls with high levels of sugar and other substances in their blood, that are linked to diabetes. I will then investigate the reasons behind any differences; whether different behaviour patterns such as smoking or physical activity, biological factors such as hormones or differences in body shape which reflect different patterns of fat storage explain the differences. I will use data from two different studies that followed participants from birth across childhood into adulthood. The Avon Longitudinal Study of Parents and Children started with over 14,000 pregnant women in Bristol in 1991/1992 and their children have been followed ever since, now aged 25. The Andhra Pradesh Children and Parents Study started with over 2,500 children born in India between 1987 and 1990 and has followed them up three times up to the age of 25. I will examine each study separately and then compare the findings to see if they are alike or different. This will help me to find out if my findings are consistent in these two very different populations.

By identifying when in life the gender differences we see in older adults actually start, we can identify times when programs to prevent them might be effective. By identifying the reasons behind any gender differences, effective gender-specific programs and interventions can be delivered early in life to prevent gender differences later in life.

Aim
To study gender differences in measures of cardiometabolic risk from birth through to adulthood and to identify potential underlying mechanisms

Objectives
1)To describe gender differences in measures of cardiometabolic risk across childhood and adolescence
2)To examine whether the stronger relationship between adiposity and measures of cardiometabolic risk seen in adult males is observed in contemporary children and adolescents
3)To examine whether the stronger association between measures of metabolic risk and measures of cardiovascular risk in females is already present in adolescence
4)To examine whether gender differences are explained by adiposity, lifestyle factors (smoking, diet, physical activity) and pubertal development
5)To identify biological mechanisms underlying gender differences by examining the role of metabalomics, DNA methylation, hormones and hepatic fat

Methods: I will use data from two contemporary longitudinal cohort studies from very different settings; ALSPAC, a birth cohort of over 14,000 children which began in 1991/1992 in the south west of England and APCAPS, a prospective cohort study of 2,601 babies born in India between 1987 and 1990. I will examine gender differences in cardiometabolic risk across the life course in each cohort separately using multilevel models and structural equation models. I will examine the role of potential lifestyle mediators of associations in each cohort and biological mechanisms in ALSPAC including differential DNA methylation and metabolomics. I will draw on causal analysis methods developed at the MRC IEU and conduct cross cohort comparisons to improve causal inference.

Scientific Opportunities
My findings will increase understanding in the aetiology of gender differences in cardiometabolic health by identifying the origin of gender differences in cardiometabolic risk, how they change with age, and the intermediate processes that drive the gender differences.

Academia will benefit from this research by receiving new scientific knowledge. The primary benefit to academia will be in the provision of new, in-depth understandings of the emergence and development of gender differences in cardiometabolic health across the life course and what factors might explain them. The outputs of my research will have a wide and diverse academic appeal, since they might be used to generate new hypotheses and further research in a range of areas including further epidemiological studies and investigation of policies and interventions.

Academia will also benefit through the development of new methods and skills. As my work involves examining many trajectories simultaneously and multiple mediators, I will develop an advanced epidemiological skill set. I can directly re-invest these skills back into the UK research base and to colleagues in other institutions through dissemination in methodological journals, conferences, teaching, seminars and talks. Academics wishing to use either the ALSPAC or APCAPS resources will also benefit, since I will deposit data on fasting insulin to ALSPAC (funding is requested here) and make the methods and modelled trajectories available to other researchers wishing to examine them in relation to other exposures and outcomes.

Health policy makers and authorities involved in setting clinical guidance will benefit from this research by receiving new knowledge about the origins and drivers of gender differences in cardiometabolic health. My research will investigate whether gender differences which arise in mid-life are already present in early life thereby shedding light on potential early life prevention opportunities which may be more effective than prevention efforts later in life. My findings will raise awareness and discussion about the value of gender-specific interventions and screening for cardiometabolic risk. I will also use appropriate study design and statistical approaches to strengthen causal inference wherever possible, and my findings on processes which drive gender differences may also be of use to policy.

Health service planners and health economists will benefit from this research. This research could also be included in modelling exercises to predict future burden of disease, healthcare needs and gender differences in this. The results could be used to map the future likely benefit of prevention and therapeutic efforts in each gender, since I will investigate gender-specific lifestyle determinants and biological mechanisms.

Charities such as Diabetes UK will benefit from this research. For example, one of the key priorities of Diabetes UK is 'Healthy Lifestyles', and prevention and early diagnosis of diabetes is a key feature of the Diabetes UK research strategy and work in the wider community. Thus, my work is directly relevant to informing the research agendas and prevention work of charities.

The wider public will benefit from this research. Any improvements in policy, services or guidance which could emanate from this research will have a direct impact on enhancing health downstream through reducing gender inequalities in cardiometabolic risk. Indirectly, this research may stimulate further research which results in policy, service and treatment changes that improve health. Increases in the effectiveness of public services and policy may result in reduced direct and indirect healthcare costs and lower economic impacts of cardiometabolic disease which will benefit society as a whole.

The timescale for these benefits could be both within the lifetime of the fellowship, e.g., providing new aetiological insights and stimulating new skills or outside of the lifetime of the project, e.g., potential health care savings following changes to healthcare planning after a modelling exercise that included some of my findings.

Details of the actions I will take to achieve these benefits are detailed in 'Pathways to Impact'.