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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - INTERPLAY (Interplay between genetic determinants of glycaemia, type 2 diabetes and cardiovascular disease in interaction with dietary and lifestyle factors)

Teaser

Summary

Type 2 diabetes (T2D), a disease characterised by persistent hyperglycaemia, is a global public health crisis comprising a major, growing cause of morbidity and premature death. Efforts to prevent worldwide diabetes and its disabling and life-threatening complications, such as coronary artery diseases (CAD), blindness, kidney failure or traumatic lower-limb amputations, are now at the forefront of global public health concerns. The disease is a consequence of obesogenic lifestyles, acting upon the backdrop of genetic predisposition, and the scaling number of individuals affected by T2D over the past few decades is more likely linked to rapid lifestyle transition rather than inherited changes. However, adverse lifestyles do not always cause diabetes, and healthy lifestyles are not ubiquitously protective. Why people develop T2D? Why individuals with T2D experience different clinical complications? What is the role of glycaemia on T2D and related complications? Can we use the mounting troves of data generated by high-throughput technologies during the last decade to understand T2D biological variability to ultimately better prevent or treat T2D?

Our research proposal consisted of five Aims. The objectives of each Aim were as follows. Aim 1 was to to assess if genetically driven hyperglycaemia increases risk of CHD. This objective pursued to answer, 1) whether chronic exposure to hyperglycaemia, driven by genetic background results in higher CVD risk, and 2) to elucidate which component of glycaemic physiology [increased insulin resistance (fasting insulin and HOMA-IR) or increased glycaemia (2h glucose or HbA1c)] raise this risk. Aim 2 was to examine the association between genetic determinants of CHD and intermediate cardiometabolic phenotypes in the context of dysglycaemia. This objective is aimed to identify whether a genetic risk score (GRS) composed of variants that increase risk of CHD is associated with other cardiometabolic traits including lipids, blood pressure, anthropometrics and inflammation in participants from multiple ethnic groups at high risk of T2D. The objective of Aim 3 was to evaluate whether dietary components and lifestyle changes influence the association of a CHD GRS with cardiometabolic traits. This objective is aimed to test the interaction between GRS and environmental factors on cardiometabolic traits. The environmental factors to be examined include 1) the global lifestyle intervention administered in the Diabetes Prevention Program (DPP), focused on body weight loss by physical activity (150 minutes/week) and energy restricted low-fat diet, and 2) specific dietary components (macronutrients composition and food groupsâ€™consumption). Aim 4 was to replicate previous results in a large case-cohort database (EPIC-InterAct) and in a randomized clinical trial (PREDIMED). Finally, Aim 5 was to evaluate whether the associated variants that emerge from the above studies coalesce into integrated mechanistic pathways. This objective seeks to shed light on mechanisms and uncovering the functional role of non-coding genetic variants and depict potential targets and avenues for intervention.

Work performed

In the past six months, Dr. Merino have started the work addressing objectives from Aim 1 to empirically test the hypothesis that genetically raised hyperglycemia increases CAD risk separately from the risk conferred by T2D as a whole. To test this hypothesis we take advantage of the crucial observation that some genetic variants raise FG without affecting T2D risk. We used public available genetic data from MAGIC (the Meta-Analyses of Glucose and Insulin-related traits Consortium), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) and CARDIOGRAM (Coronary ARtery DIsease Genome wide Replication and Meta-analysis) Consortia to conduct a Mendelian Randomisation analysis. Mendelian Randomisation is a novel statistical method that uses genetic variants to investigate the causal relationship of a biomarker on risk of disease. The fundamental principle of this statistical approach is that if genetic variants that either alter the level of a modifiable biomarker that is causal in disease, then these genetic variants should also be associated with disease risk to the extent predicted by the effect of the genetic variant with the biomarker. To validate the approach we used data from the Framingham Heart Study. The working group Dr. Merino established has accomplished his goal of publishing the results of their work.

The objective of Aim 2 was to examine the association between genetic determinants of CHD and intermediate cardiometabolic risk factors in the context of dysglycaemia and whether dietary components and lifestyle changes influence the association of a CHD GRS with cardiometabolic traits (Aim 3). To address these linked objectives we took advantage of the Diabetes Prevention Program, a multicenter randomized controlled trial that tested the effects of intensive lifestyle intervention (ILS) and metformin (MET) interventions on the incidence of diabetes in ~3,000 glucose-intolerant individuals. In the Diabetes prevention program we built a 45-variant GRS weighted by published effect sizes for CAD and tested for association to baseline and one-year changes in cardiovascular risk factors including glycaemia, lipids, blood pressure, anthropometrics and inflammation in 2,634 participants.
Results from these combined objectives have been recently presented as a poster presentation in the last American Diabetes Association Annual scientific sessions

Final results

\"The impact of the results of this project rises on the generation of new knowledge for T2D and CVD prevention and management. Fully understanding of the genetic and molecular impact of diverse dietary components and lifestyle behaviours in different genetic backgrounds may facilitate the development of nutritional remedies for T2D and CVD, as well as preventive strategies for curbing the T2D epidemic.
Regarding Aim 1, we have demonstrated that genetically raised isolated glycaemia indeed increases CAD risk by ~30% per each 1 mmol/L increment in fasting glucose, independently of T2D. This effect persists after we exclude genetic variants that affect other CAD risk factors. Our findings lend credence to the notion that modulating glycaemia may confer cardiovascular benefits, and definitively answers the main clinical question. Overall, these results provide strong support for the role of hyperglycemia as a CAD risk factor, even in the absence of diabetes. Possibly, over the years, this genetically determined \"\"mild\"\" hyperglycemia could have significant direct or indirect vascular effects and interactions with other determinants of atherosclerotic cardiovascular disease pathobiology. The identification of a causal biomarker improves understanding of disease pathophysiology and suggests an actionable intervention for clinical translation.

Results of the present project will inform a call for action in group-specific CVD testing genetic campaigns and improved treatment strategies at the EU level, allowing for precision medicine implementation.

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