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Novel Approach to Systematically Characterize Exercise- and Nutrient- responsive genes in Type 2 diabetes and cardiovascular disease

Periodic Reporting for period 2 - NASCENT (Novel Approach to Systematically Characterize Exercise- and Nutrient- responsive genes in Type 2 diabetes and cardiovascular disease)

Reporting period: 2018-08-01 to 2020-01-31

• What is the problem/issue being addressed?
Genetically susceptible individuals often suffer disproportionately and unnecessarily from cardiometabolic disease, yet they can benefit dramatically from targeted programmes of lifestyle modification. Nevertheless, one size does not fit all, and the optimization of preventive interventions is necessary to make these sufficiently effective in all at risk persons. Identifying the factors that determine success or failure of a given lifestyle intervention may prove useful, as this would help better understand the aetiology of disease and may help optimize interventions focusing on the aspects that are most likely to succeed. This concept is broadly terms precision medicine.

• Why is it important for society?
Identifying the factors that can be intervened upon and characterizing the factors that can help optimize these interventions may lead to more effective prevention strategies and reduce costs and unnecessary side-effects for those at high risk of disease.

• What are the overall objectives?
The overarching objective of NASCENT is to discover genotypes and other biomarkers that functionally impact the effectiveness of lifestyle therapies in the prevention of type 2 diabetes and cardiovascular disease, and to show that stratifying lifestyle interventions by genotype beneficially impacts the cardiometabolic response of the participant.
The first phase of the project used epidemiological methods to i) identify modifiable environmental risk factors for cardiometabolic disease traits (Koivula et al. Diabetologia, in review), ii) determine the heritability of gene-environment interactions (Poveda et al. Diabetologia, 2016); iii) identify SNP candidates for gene-environment interactions (Shungin et al. PLOS Genet. 2017; Poveda et al. J Am Heart Assoc. in resubmission); iv) test explicit examples of gene-environment interactions and functionally annotate these using in silico bioinformatics methods (Chen et al. Int J Obes. 2019). Building on this work, my team has also developed new approaches to assess genetic susceptibility to environmental risk factors, where we are identifying subgroups of the population that appear either very susceptible to the adverse cardiometabolic effects of adverse lifestyle exposures or those who appear protected from these effects. This work will continue through the remainder of the project period. A more comprehensive breakdown of the work undertaken and the related output is given below (under the section on ‘project achievements’).
The second and current phase of the project is focused on functional studies using gene editing technologies and other cutting-edge cell biology methods to study the basis of gene-environment interactions in vitro. Several subprojects have been running in parallel. These include:

• MATE1: Analysis of interactions between metformin and MATE1 variants in glucose metabolism. In summary, this suggests a functional role of a genetic variant in MATE1 expression, and thus in metformin retention in hepatocytes, which might explain and predict an improved metformin response in individuals with certain genotypes.
• RAB3GAP2: Through a GWAS of muscle fibre phenotypes, we identified variants in RAB3GAP2 that appear to affect capillary density and coagulation. The study is of high relevance for the exercise-induced effect in muscle capillary formation and risk of thrombosis.

The third and final phase of NASCENT is focused on clinical trials. I am using existing trials (such as the Diabetes Prevention Program [DPP] and PREDICT) and will conduct one or more new studies. We have already published one paper reporting analyses of existing trial data from the DPP (Apolzan et al, Annals Intern Med. 2019), where we identified a subgroup of the DPP population that responds adversely to the intensive lifestyle intervention. This subgroup comprises participants who failed to meet the 12-month >5% weight loss goal went on to gain and retain a clinically meaningful amount of excess weight over the ensuing decade. This contrasts the experience of participants who failed to achieve the 5% weight loss goal in the metformin and control arms of the trial, whose weight remained roughly the same as weight at enrollment during the next decade. In part three of NASCENT, we will i) seek to identify factors at enrollment that predict failure with lifestyle intervention and ii) determine if the excess weight exposure this subgroup endures predisposes high risk of type 2 diabetes and cardiovascular disease.

The second major trial of relevance to NASCENT is PREDICT. Through a collaboration initiated in 2017 with colleagues at Kings College London, I was one of four principal investigators who designed and implemented the PREDICT diet intervention trial (see Fig). Throughout 2018 and early 2019, we administered set meals to 1,100 adults and monitored glucose, lipid and insulin (or c-peptide) postprandial responses during a one-day clinical visit followed by a two week at-home assessment period. The primary purpose of the study is to identify molecular and non-molecular predictors of postprandial metabolism, with a view to developing personalized diet recommendations. Although the trial maps tightly to the specific aims of NASCENT, the high costs of this trial required additional funding, which we did primarily through a public-private partnership (with Zoe Global Ltd).
Timeline protocol for the PREDICT trial