Regulation of fasting glucose and birth weight: the impact of variation in the glucokinase gene.

Lead Research Organisation: University of Exeter
Department Name: Unlisted

Abstract

Blood sugar levels remain remarkably constant despite the considerable variation in the amount of food we eat and exercise we do. This is mainly achieved by very tight regulation of the release of a hormone into the blood called insulin which lowers blood sugar. This close regulation is vital because high blood sugars lead to diabetes and low blood sugars can lead to seizures. When we have no food (fasting) our blood sugars return to very narrow limits. However even in this limited range of normal blood sugars there is variation between individuals and studies have shown that some of the variation is inherited. Glucokinase is a key sensor of glucose levels in the blood, signalling to the pancreas to release the right amount of insulin. Rare severe genetic changes (mutations) in the glucokinase gene greatly alter blood sugar and have a big effect on birth weight. We are going to test whether there is more common milder variation which is important for regulating blood sugar when you are fasting. Our preliminary work suggests there is and that although these changes are associated with altered birth weight. Using 50,000 samples from many European countries we will define genetic changes that go with different levels of blood sugar and test whether they do alter birth weight. Finally we will test if this genetic variation is important in evolutionary selection in man. The study aims to give new insights into the regulation of the very important glucokinase gene which controls our blood sugar and look at the impact of this on the growth of babies in the womb.

The dissemination to the general public would be in the in the context of communicating important general understandings about science. One of these is how multiple common minor changes in genes contribute to the differences that exist between us all. The other general area would be an understanding of the regulation of early birth and how genetic factors both in the mother and also in the baby can be important in a baby?s intrauterine growth. The importance of screening for unknown diabetes or raised blood sugars in pregnancy would be included in such a lay public presentation. At local, regional and national lay meetings we have found that there is considerable interest in trying to understand genetics. Communicating this work to the general public would be challenging but also stimulating.

Technical Summary

The regulation of glucose is vital for human health. Variation in fasting glucose concentration (FPG) in the normal range is associated with risk of type 2 diabetes and ischaemic heart disease. In pregnancy maternal FPG concentration is an important independent determinant of offspring birth weight in non-diabetic mothers. There is evidence that the regulation of FPG has a strong genetic component. The main regulator of FPG concentration is the enzyme glucokinase; severe rare mutations in the GCK gene cause marked changes in FPG and birth weight. Our preliminary data, analysing haplotype tagging SNPs across the gene and flanking regions, shows that two common variants in the promoter region of the glucokinase gene are associated with FPG and fetal growth.

In this project we propose to test comprehensively the hypothesis that common genetic variation in GCK alters FPG and birth weight and establish if there has been evolutionary selection at this gene. To do this we will firstly continue our extensive analysis of common variation across the gene to define the optimum set of polymorphisms, based on the latest statistical techniques, to take forward to association studies. Will use DNA from over 50,000 samples inclduing 28,000 mother-child pairs. This approach will establish, if our hypothesis is true, a definitive genetic component to the normal variation in FPG and birth weight and give new insights into the regulation of a critical gene.

Publications

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Frayling TM (2016) Authors' reply to Toth. in BMJ (Clinical research ed.)

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Frayling TM (2007) A new era in finding Type 2 diabetes genes-the unusual suspects. in Diabetic medicine : a journal of the British Diabetic Association

 
Description Foundation for Genomics and Population Health
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact Prof Frayling participated in a workshop that resulted in a advisory document on genetics in public health.
 
Description Invited course teaching
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact We have been invited to teach on several courses for graduate bioscientists and clinicians as a result of our work on the genetics of birth weight and its relationship with adult diseases. We provide a counter argument to proponents that interventions targeted at changing birth weight will reduce the burden of adult chronic metabolic disease. If genetic factors link lower birth weight with an increased risk of adult metabolic disease, as we are finding, then the case for interventions targeted at fetal growth becomes weaker.
 
Description What are the practical implications of developments in genetics ?
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact Prof Frayling participated in and gave a seminar on the implications of genetics for clinical practice. This was incorporated into a consensus statement report by the Edinburgh Royal College of Physicians in 2010 entitled: "What are the practical implications of developments in genetics ?"
 
Description Diabetes UK, Project Grant Using human genetics to understand the role of adiponectin in type 2 diabetes and insulin resistance.
Amount £214,000 (GBP)
Funding ID 12/0004470 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description Diabetes and Wellness Foundation fellowship for Jessica Tyrrell
Amount £172,389 (GBP)
Organisation The Diabetes Research & Wellness Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2017
 
Description Henry Wellcome Fellowships
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2008 
End 06/2012
 
Description MRC CASE
Amount £98,000 (GBP)
Funding ID MR/P016065/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 08/2021
 
Description MRC Clinical Infrastructure
Amount £2,137,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2015 
End 01/2017
 
Description MRC Experimental Medicine
Amount £583,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 08/2018
 
Description MRC Using genetics to understand sleep and chronotype and their relationship to obesity and type 2 diabetes.
Amount £401,000 (GBP)
Funding ID MR/P012167/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2017 
End 01/2019
 
Description The causes of hyperglycaemia in the face of rising obesity
Amount € 2,000,000 (EUR)
Funding ID 323195 
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 10/2013 
End 09/2018
 
Description Using human genetics to understand the role of adiponectin in diabetes and insulin resistance
Amount £134,000 (GBP)
Funding ID 12/0004470 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 09/2015
 
Description Wellcome Trust Henry Dale award to Rachel Freathy
Amount £800,000 (GBP)
Funding ID 104150/Z/14/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 01/2021
 
Description Association of maternal diabetes genes with offspring adiposity as a test of the developmental overnutrition hypothesis 
Organisation Danish Ministry of Health
Department Danish National Birth Cohort
Country Denmark 
Sector Public 
PI Contribution Analyses completed in ALSPAC. Key aims of the project are to examine independent (of offspring genotype) associations of maternal type 2 diabetes related genetic variants with offspring weight, BMI, waist and fat mass in infancy and childhood
Impact Paper due for submission imminently.
Start Year 2008
 
Description Association of maternal diabetes genes with offspring adiposity as a test of the developmental overnutrition hypothesis 
Organisation Erasmus University Rotterdam
Country Netherlands 
Sector Academic/University 
PI Contribution Analyses completed in ALSPAC. Key aims of the project are to examine independent (of offspring genotype) associations of maternal type 2 diabetes related genetic variants with offspring weight, BMI, waist and fat mass in infancy and childhood
Impact Paper due for submission imminently.
Start Year 2008
 
Description Association of maternal diabetes genes with offspring adiposity as a test of the developmental overnutrition hypothesis 
Organisation Norwegian National Birth Cohort
Country Norway 
Sector Public 
PI Contribution Analyses completed in ALSPAC. Key aims of the project are to examine independent (of offspring genotype) associations of maternal type 2 diabetes related genetic variants with offspring weight, BMI, waist and fat mass in infancy and childhood
Impact Paper due for submission imminently.
Start Year 2008
 
Description Association of maternal diabetes genes with offspring adiposity as a test of the developmental overnutrition hypothesis 
Organisation University of Exeter
Department College of Social Sciences and International Studies
Country United Kingdom 
Sector Academic/University 
PI Contribution Analyses completed in ALSPAC. Key aims of the project are to examine independent (of offspring genotype) associations of maternal type 2 diabetes related genetic variants with offspring weight, BMI, waist and fat mass in infancy and childhood
Impact Paper due for submission imminently.
Start Year 2008
 
Description Association of maternal diabetes genes with offspring adiposity as a test of the developmental overnutrition hypothesis 
Organisation University of Western Australia
Department Raine Medical Research Foundation
Country Australia 
Sector Academic/University 
PI Contribution Analyses completed in ALSPAC. Key aims of the project are to examine independent (of offspring genotype) associations of maternal type 2 diabetes related genetic variants with offspring weight, BMI, waist and fat mass in infancy and childhood
Impact Paper due for submission imminently.
Start Year 2008
 
Description Genetics of birth weight in the 1958 cohort 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution We have funded and led efforts to identify common genetic variants that influence birth weight. Together with the ALSPAC and NCCGP studies, the 1958 study has been key to providing adequate power to achieve the stringent levels of statistical power required for genetic association studies.
Collaborator Contribution We have formed a succesful collaboration with Prof Chris Power, Dr Elina Hyponen, and Prof David Strachan, leads of the 1958 birth cohort. They have been extremely helpful in contributing DNA and phenotype data to increase power in our efforts to identify common gene variants that influence birth weight.
Impact 17503332 19228808
Start Year 2007
 
Description Genetics of birth weight in the ALSPAC cohort study 
Organisation University of Bristol
Department School of Social and Community Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution The Exeter genetics group has been the team that has funded and led the most extensive genotyping efforts in the ALSPAC cohort. In addition to common variants in glucokinase, we have established roles for other type 2 diabetes variants in birth weight, including those in the TCF7L2 and CDKAL1 loci. This work was largely possible through working with ALSPAC
Collaborator Contribution The detailed longitudinal phenotyping of nearly 10,000 children and their mothers in the ALSPAC cohort, together with the excellent DNA resources and the flexibility of use has been extremely important to our research on the genetic component to fetal growth and its links with diabetes. With the ALSPAC resource and expertise, our genetics group in Exeter has established itself as one of the the leading groups investigating the genetics of birth outcomes. Our successful collaboration allowed us to assay, analyse and write up key type 2 diabetes genetic variants that emerged from the GWAS studies funded by the Wellcome Trust in 2007. The best example of this was our ability to analyse the FTO variant in the ALSPAC children very quickly and so establish the role of FTO in fat mass, rather than another aspect of body mass (because ALSPAC children have DXA measures of fat mass available.)
Impact 15677518 17186458 17503332 19228808
Start Year 2006
 
Description Genetics of birth weight in the North Cumbria Community Genetics Project 
Organisation Royal Victoria Infirmary
Country United Kingdom 
Sector Hospitals 
PI Contribution We have used the NCCGP as an important additional resource to increase power for detecting birth weight effects of common gene variants in the Glucokinase and TCF7L2 loci.
Collaborator Contribution The North Cumbria Community Genetics Project, led by Dr Caroline Relton, is an important resource for investigating the role of genetics in birth weight and other fetal outcomes.
Impact 17503332
Start Year 2006
 
Description Longitudinal effects of gene variants in the Busselton (Western Australia) study 
Organisation University of Western Australia
Country Australia 
Sector Academic/University 
PI Contribution We have tested the role of several robustly associated common genetic variants in longitudinal measures of glucose and lipid levels. These include the APOAV and LPL variants that alter triglyceride levels, as well as the GLucokinase variants we confirmed as associated with Fasting glucose.
Collaborator Contribution The Busselton study is one of the best longitudinal studies in the world, having an average of 20 years follow up data from over 6000 participants across adult age ranges. We have collaborated with the Genetic Epidemology group headed by Lyle Palmer to investigate the longitudinal effects of common gene variants such as those in Glucokinase on diabetes and glycaemic traits.
Impact 19018513
Start Year 2008
 
Description Mendelian Randomisation to help identify potential adverse effects of drug treatments 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution We are working with GSK to perform genetic tests to understand potential adverse effects of cardio vascular drug treatments. These include those affecting the HIF pathway and anaemia in Chronic kidney disease such as EPO stimulating agents.
Collaborator Contribution GSK are providing the expertise in cardio vascular endpoints and contributing financially to staff in Exeter. This collaboration stimulated an MRC CASE studentship award which will begin in September 2017.
Impact Too early
Start Year 2016
 
Description Population genetics of the Glucokinase gene 
Organisation University of Chicago
Country United States 
Sector Academic/University 
PI Contribution We informed the Di Rienzo group of the polymorphisms robustly associated with glucose levels, whilst they informed us of the variants most likely to have been sujected to selection. Each group tested the variants highlighted by the other.
Collaborator Contribution Anna Di Rienzo, a co-applicant on the grant, has investigated the Glucokinase gene in depth for molecular signals of selection. This work was published in AJHG (Weedon et al.)
Impact 17186458
 
Description Cafe Scientifique - Exeter 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A 40-45 minute presentation to a lay audience followed by 45 minutes of questions and answers. This was mainly around the "fat gene" story, but all aspects of human genetics were discussed.

There was lots of interest from the audience who asked plenty of searching questions! A member of the audience interviewed me for a piece in Devon Country Life magazine, which increased the impact of the research.
Year(s) Of Engagement Activity 2009
 
Description DNA testing: "Science or Swindle?" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact This was a public seminar hosted by the DANA centre at the Science Museum, London. I was one of four scientists giving a brief presentation followed by four question and answer sessions. The topic was direct to consumer DNA tests that companies such as DecodeMe and 23andMe are offering.

Lots of questions and comments from a lay audience. For myself, an improved understanding of the public's perceptions of human genetics. For the public, hopefully an improved understanding of human genetics.
Year(s) Of Engagement Activity 2009
 
Description Diabetes UK patient and volunteer conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact A presentation followed by question and answer session to >300 Diabetic patients and fundraisers at their annual conference in Manchester, October 2009. I was the only presenter invited to talk about type 2 diabetes related research, along with one presenter invited to talk about type 1 diabetes.

Considerable interest in the question and answer session. Hopefully an improved understanding by the patients of what we learn from their DNA samples.
Year(s) Of Engagement Activity 2009
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A talk on obesity genetics at a local pub. "Pint of Science" was sponsored by the Wellcome Trust and eLIFE
Year(s) Of Engagement Activity 2016
 
Description Short article in study participants' newsletter. 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Short articles describing our research on diabetes and birth weight genes aimed at patients and research volunteers who had contributed DNA and phenotype information from themselves and in some cases, their offspring.

A greater understanding of genetic research by the study participants - in Exeter we have successfully recruited a large number of individuals to genetic studies. Virtually no-one declines to take part in a study on the grounds that they are suspicious of genetic research. Although hard to prove we hope that our "user-friendly" dissemination is part of the reason for this success.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description TV programme to explain obesity genetics 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Many 1000s of people who watch the Channel Four show "Embarrasing bodies" will have heard about and understood a little more about the partial role of genetics in obesity

Hard to measure but many people have mentioned the programme to me suggesting it made some general impression on the public understanding of obesity biology. The episode has been repeated several times.
Year(s) Of Engagement Activity 2011
URL http://www.channel4.com/programmes/embarrassing-fat-bodies