The public health importance of vitamin D: determining causal effects of intrauterine and lifetime exposure to vitamin D

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

This aim of this grant is to determine whether low levels of vitamin D during fetal development and in childhood increase the risk for high blood pressure, high cholesterol and high glucose and insulin (markers of diabetes) in early adulthood. Vitamin D is generated by exposure of the skin to sunlight. Recent public health campaigns to reduce skin exposure to sunlight have been successful in reducing the occurrence of skin cancer, but there is some concern that they have also caused low levels of vitamin D in many people. Pregnant women and children in particular are likely to have inadequate levels. Low levels of vitamin D could have detrimental effects. There is increasing evidence that individuals who have lower levels of vitamin D have higher risk factors for diabetes and heart disease, such as higher fasting blood sugar levels and higher cholesterol and blood pressure. We will examine the association of vitamin D (measured in blood samples taken from their mothers during pregnancy and themselves when aged 7-9 years) with measures of blood cholesterol, glucose and insulin and blood pressure in a large study of individuals who are now aged 17-18 years.

Technical Summary

The success of public health campaigns to decrease UVB exposure has contributed to population level declines in vitamin D. A high proportion of pregnant women and children in developed countries have sub-optimal vitamin D levels. There is increasing evidence that lower levels of vitamin D are associated with increased risk of type 1 and 2 diabetes, insulin resistance, dyslipidaemia and cardiovascular disease. There is also some evidence that low levels of vitamin D during pregnancy could increase the risk of adverse metabolic and cardiovascular traits in the next generation. However, whether any of these associations are causal is unclear. Most studies to date have been cross-sectional, unable to control for potentially important confounders and of small sample size. There is a need to determine whether these associations are causal and also the magnitude of any causal associations. Randomised controlled trials provide the gold-standard for determining causality but are expensive and often have problems with generalisability. A better understanding of whether vitamin D is causally related to metabolic and vascular outcomes, and if so the magnitude of this causal effect, could be obtained by better designed epidemiological studies (prospective studies, with large numbers and adequate detail on important confounders), and by the use of genetic variants that are robustly associated with vitamin D levels as instrumental variables to provide causal inference. Such approaches within an established cohort would provide timely and resource efficient results. We propose to examine the association of intrauterine vitamin D (maternal pregnancy levels of 25(OH)D) and childhood vitamin D (own levels of 25(OH)D assessed at mean age 10 years) with fasting glucose, insulin and lipid levels and blood pressure at age 17 (N=7,000). Further, we propose to identify genetic variants that are robustly associated with variation in 25(OH)D (heritability 40-80%) in genome-wide association analyses of 8,200 individuals, with replication of any variants identified in the genome-wide approach in over 22,000 individuals. Identified variants will then be used in our main cohort and collaborating cohorts (numbers totalling 15,000 for continuous traits and 7,000 cases for pre-eclampsia) as instrumental variables to determine the unbiased and unconfounded association of life-time exposure to different levels of vitamin D with fasting glucose, insulin and lipid levels, blood pressure and pre-eclampsia. We will also combine maternal and offspring genotype to determine the unbiased and unconfounded association of variation in intrauterine vitamin D with later metabolic and cardiovascular risk factors.

Publications

10 25 50
 
Guideline Title Vitamin D and Health
Description Public Health England Guidance on Vitamin D in pregnancy
Geographic Reach National 
Policy Influence Type Citation in clinical guidelines
 
Description Advanced Grant
Amount € 1,800,000 (EUR)
Funding ID 669545 
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 11/2015 
End 10/2020
 
Description An examination of the association of maternal vitamin D status with abnormal glucose tolerance in pregnancy.
Amount £51,473 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Cohort Funding
Amount £2,700,000 (GBP)
Funding ID MR/N024397/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Horizon 2020
Amount € 9,957,602 (EUR)
Funding ID 733206 
Organisation European Commission 
Department Horizon 2020
Sector Public
Country European Union (EU)
Start 01/2017 
End 12/2021
 
Description Vitamin D as a (causal) determinant of insulin resistance and diabetes? An analysis of three UK based prospective studies.
Amount £195,540 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Research Training Fellowship (Tom Dudding)
Amount £187,327 (GBP)
Funding ID 201237/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 09/2019
 
Description Wellcome Trust call for Genome Wide Association Studies (Genome-wide association study of maternal pregnancy phenotypes and later-life maternal and offspring vascular and metabolic phenotypes)
Amount £2,028,579 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Title Development of Triangulation method for causal inference 
Description Study design and analytical method for improving causal inference Paper published in IJE and work presented at (a) Causal inference workshop in Harvard Boston USA November 2016 and (b) at the London School of Hygiene & Tropical Medicine to MSc, PhD students and staff March 2017 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2016 
Provided To Others? Yes  
Impact To date too early to tell 
 
Description 25(OH)D GWAS in children 
Organisation University of Queensland
Department Genetic Epidemiology Laboratory
Country Australia 
Sector Public 
PI Contribution We are leading this collaboration which includes teams from Australia (QIMR and Perth) and the US (NHANES) who are working with us to identify genetic variants associated with 25(OH)D, calcuim, phosphate and PTH in children.
Collaborator Contribution Replication sample for our GWAS, which will be published Replication of our GWAS analysis, which will be published
Impact Draft first publication currently being circulated amongst co-authors. The collaboration is multidisciplinary including epidemiologists, statisticians, geneticists and bioinformaticians.
Start Year 2010
 
Description 25(OH)D GWAS in children 
Organisation University of Western Australia
Department School of Population Health
Country Australia 
Sector Academic/University 
PI Contribution We are leading this collaboration which includes teams from Australia (QIMR and Perth) and the US (NHANES) who are working with us to identify genetic variants associated with 25(OH)D, calcuim, phosphate and PTH in children.
Collaborator Contribution Replication sample for our GWAS, which will be published Replication of our GWAS analysis, which will be published
Impact Draft first publication currently being circulated amongst co-authors. The collaboration is multidisciplinary including epidemiologists, statisticians, geneticists and bioinformaticians.
Start Year 2010
 
Description Born in Bradford 
Organisation Bradford Institute for Health Research (BIHR)
Country United Kingdom 
Sector Academic/University 
PI Contribution We are collaborating with the Born in Bradford cohort to examine the association of maternal 25(OH)D in pregnancy with pregnancy complications.
Collaborator Contribution Advances understanding of the relationship of 25(OH)D to pregnancy complications. Output includes research journal publications.
Impact Two papers are currently at advanced darft status. One examines associations with results from oral glucose tolerance tests in pregnancy and the second with hypertensive disorders of pregnancy.
Start Year 2010
 
Description CHICOS 
Organisation CHICOS: Developing a Child Cohort Research Strategy for Europe
Country European Union (EU) 
Sector Academic/University 
PI Contribution Overall aim is to improve child health across Europe by developing an integrated strategy for mother-child cohort research in Europe. Methodologically we are working on ways of harmonising data and comparing results between and, where appropriate, pooling data from all European mother-child cohorts. I lead the work on child obesity and cardiometabolic health. I contribute data and/or analyses results for reserach that other partners lead in other research areas.
Collaborator Contribution Partners contribute data or results from analyses for research that I lead on child obesity and cariometabolic health.
Impact Publications currently being drafted
Start Year 2010
 
Description Cancer Research UK - Integrative Cancer Epidemiology Programme 
Organisation University of Bristol
Department Department of Computer Science
Country United Kingdom 
Sector Academic/University 
PI Contribution The Cancer Research UK - Integrative Cancer Epidemiology Programme (ICEP) is recently formed (2015) and provides a much needed link between epidemiology, causal analyses (using Mendelian randomisation and other approaches) and basic science/mechanistic analyses for the study of cancer risk, progression and potential intervention. Key to this is the study of potentially modifiable, environmental, risk factors which may be important for either cancer cancer risk or progression. Vitamin D is one of these factors and through the application of Mendelian randomisation (facilitated by a greater understanding of the genetics of vitamin D levels which is directly aided by research here), this factor is being analyse within causal frameworks.
Collaborator Contribution The key contribution from ICEP here is in the provision of access to data sets (with health outcomes and genetics) with cancer outcomes and relevant measures. This is allowing the causal analysis of vitamin D in data sets representing different cancers types and sites.
Impact Please see website for pertinent outputs.
Start Year 2015
 
Description The SUNLIGHT consortium - Brent Richards 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution The SUNLIGHT consortium is concerned with the genetic analysis of vitamin D levels. I am currently contributing to this through the analysis of vitamin D levels within the ALSPAC study and also through the coordination of access to the biomarker panel of the UK Biobank (expected at the end of 2016). This work was initiated in 2014, but is ongoing.
Collaborator Contribution SUNLIGHT is coordinated by my collaborator and ultimately responsible for scientific output. The work is balanced across centres, however, and two Bristol ACF analysts are undertaking this work in Bristol.
Impact Data analyses being undertaken.
Start Year 2015
 
Description Vitamin D and IGFBP-3 Mendelian Randomization 
Organisation Albert Einstein College of Medicine
Department Department of Epidemiology & Population Health
Country United States 
Sector Academic/University 
PI Contribution Two sample Mendelian Randomization analyses using summary level data (and circulating vitamin D measurements when available) will be led by myself and Dr Nicholas Timpson, but working cooperatively with others involved in the collaboration.
Collaborator Contribution Partners in this collaboration had contributed summary level data from their GWAS to this project.
Impact -A paper is currently in draft form.
Start Year 2015
 
Description Vitamin D and IGFBP-3 Mendelian Randomization 
Organisation University of Greifswald
Country Germany 
Sector Academic/University 
PI Contribution Two sample Mendelian Randomization analyses using summary level data (and circulating vitamin D measurements when available) will be led by myself and Dr Nicholas Timpson, but working cooperatively with others involved in the collaboration.
Collaborator Contribution Partners in this collaboration had contributed summary level data from their GWAS to this project.
Impact -A paper is currently in draft form.
Start Year 2015
 
Description Vitamin D and insulin resistance and diabetes in adults 
Organisation University of Glasgow
Department BHF Glasgow Cardiovascular Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution I am co-applicant (and University of Bristol lead) on a successfully funded grant (Diabetes UK) to examine the causal associations of vitamin D with insulin resistance and diabetes in adults. We will compare associations of vitamin D with fasting glucose and markers of insulin resistance in adults (determined as part of that Diabetes UK grant) with equivalent associations in children that are being examined as part of this MRC funded grant.
Collaborator Contribution We will compare associations of vitamin D with fasting glucose and insulin and other cardiovascular risk factors in children assessed as part of this MRC grant with the same with equivalent associations in adults assessed as part of the Diabetes UK grant. NB: the financial contribution is for work on the adult cohorts and will not directly contribute or overlap with the MRC funded work.
Impact Successful Diabetes UK grant awarded. The collaboration is multidisciplinary, bringing together expertise in clinical biochemistry (N Sattar & P Welsh, University of Glasgow), epidemiology and public health (DA Lawlor, University of Bristol, and G Wannamethee, P Whincup and S Ebrahim, University of London) and biostatistics (R Morris, University of London and DA Lawlor, University of Bristol).
Start Year 2010
 
Description Vitamin D and pregnancy outcomes 
Organisation University of Bradford
Department Bradford Research Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution I am a co-applicant on a successful grant (Diabetes UK) which funds completion of vitamin D assays with pregnancy glucose tolerance test outcomes (fasting and postload glucose, fasting insulin and gestational diabetes) in the Born in Bradford cohort. The focus of that grant was on gestational diabetes, which is poorly measured in ALSPAC, but nonetheless we will use the assays completed on stored samples in the ALSPAC mothers (funded by this MRC grant) to further explore this question using glycosuria and a medical record review diagnosis of gestational diabetes. We have excellent repeat measurements of blood pressure and proteinuria during pregnancy and hence hypertensive disorders of pregnancy in ALSPAC mothers and reasonable measurements in the Born in Bradford study and so both studies will be used to explore the relationship of vitamin D to these outcomes.
Collaborator Contribution We will share, and where appropriate pool, results from the ALSPAC cohort (funded by this MRC grant) and the Born in Bradford cohort (funded by the Diabetes UK grant)
Impact Grant from Diabetes UK to examine the relationship of Vitamin D with gestational diabetes and fasting and postload glucose in the Born in Bradford Cohort. The collaboration is multidisciplinary, bringing together expertise in epidemiology (DA Lawlor, University of Bristol), clinical endocrinology (D Whitelaw, University of Bradford), obstetrics (S Nelson, University of Glasgow), clinical biochemistry (N Sattar, University of Glasgow), vitamin D/bone health expertise (W Fraser, University of Liverpool) and health services research (J Wright, University of Bradford).
Start Year 2009
 
Description Radio 4 Inside Science 
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 Participated in Inside Science radio 4 programme - discussing the value of population cohort studies for understanding causes of disease and how to prevent these
Year(s) Of Engagement Activity 2016