Community Research and Development Information Service - CORDIS



Project ID: 323195
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Mid-Term Report Summary - GLUCOSEGENES (The causes of hyperglycaemia in the face of rising obesity)

The overarching hypothesis of GLUCOSEGENES is that processes across the lifecourse influence risk of high glucose levels independently of obesity. We split these processes up into three areas:

1. in utero life: We have tested the hypothesis that the in utero environment alters offspring glucose control and metabolism. This work has proceeded in collaboration with my colleague Dr Rachel Freathy (who under my mentorship, has obtained two prestiguous fellowships from the Wellcome Trust and is building her own career as an outstanding early career female scientist). In collaboration with most if not all studies around the world with maternal and or fetal DNA samples and offspring birthweight information, we have:
a. identified 57 common genetic variants associated with birth weight when inherited by the fetus. These fall into various categories and are providing insight into the processes that influence growth through the fetal genotype. This work represents the most comprehensive assessment of the genetic components to fetal growth yet performed.
b. Paternal Diabetes is associated with reduced birth weight. We showed the influence of genetics on birth weight by showing extremely strong evidence that paternal diabetes is associated with lower birth weight in offspring.
c. used genetic variants in the maternal genome as proxies for the maternal intrauterine environment to test the hypothesis that different aspects of the maternal in utero environment alter birth weight. This work, published in JAMA (Tyrrell et al. [an early stage female researcher in our group] in 2016, showed causal relationships between maternal glucose levels and BMI with higer offspring birthweight and higher blood pressure and lower birth weight. The blood pressure finding was showed that the association between higher SBP in mothers and higher birthweight is likely to be confounded by BMI.
2. In the second part of "GLUCOSEGENES" we are testing the effects of exposure to “long-term” risk factors: We are testing the hypothesis that long-term exposure to altered metabolic and circulating factors influences diabetes risk. To do this we are using genetic variants associated primarily with circulating factors such as adiponectin. This work can be summarized as follows:
a. We have shown that higher circulating adiponectin levels are unlikely to result in increased insulin sensitivity.
b. One of the most exciting outcomes from "GLUCOSEGENES" is the characterisation of common human alleles (versions of genes) that are associated with higher adiposity but lower risk of disease, including type 2 diabetes. This work has been led by Dr Yaghootkar and shows that alleles in some genes can increase adiposity but lower risk of type 2 diabetes, hypertension and heart disease.
3. In the third part of "GLUCOSEGENES", we are studying the "prediabetes" life using a recruit be genotype approach. The aim was to use our local cohort of 10,000 research volunteers as a "pool" of "animal models" - and as human beings they provide us with an opportunity to perform in vivo experiments in the most relevant species.

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United Kingdom
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