Proposal summaries
B159 - Factor V Leiden and adverse pregnancy outcome - 01/03/2004
The aetiology of adverse pregnancy outcomes such as pre-eclampsia and fetal growth retardation is likely to be multifactorial and influenced by a complex interplay between maternal, fetal and placental factors. Given that a successful pregnancy outcome is highly dependent on the establishment and maintenance of an adequate placental circulation, it is possible that abnormalities of placental vasculature, leading to inadequate fetomaternal circulation, may be responsible for at least some poor pregnancy outcomes. This has led to an interest in the thrombophilias as risk factors for adverse pregnancy outcome. The factor V Leiden mutation is the most common form of inherited thrombophilia.1 A point mutation in the factor V gene at nucleotide position 1691, resulting in an arginine to glutamine substitution, reduces the sensitivity of the factor V protein to inactivation by activated protein C (activated protein C resistance) resulting in a pro-coagulant state and an increased risk of thrombosis.2 The trait is inherited in an autosomal dominant manner with the risk of thrombosis increased seven times in heterozygotes and 80 times in homozygotes. 3 Studies have shown that the distribution of the factor V Leiden mutation varies in different populations, being present in about 5% of Caucasian individuals (Europeans, Jews, Arabs and Indians) and virtually absent in Africans and Asians.
Rey et al 2003 published a meta-analysis confirming the association between recurrent fetal loss and the factor V Leiden mutation.4 Rai et al 2002 aimed to tease out the isolated contribution of factor V Leiden by comparing FVL+ women with recurrent fetal loss to FVL- women with the same history of fetal loss. The live birth rate was significantly lower among the women who carried the mutation confirming that factor V Leiden independently increases the risk of fetal loss.5 Data from our recently published meta-analysis concludes that factor V Leiden is also associated with a 2.9 fold (95%CI 2.0-4.3) increased risk of severe pre-eclampsia and a 4.8 fold (95% CI 2.4-9.4) increased risk of fetal growth retardation6.
A function enhancing mutation in the Prothrombin gene (Prothrombin G20210A) results in higher circulating levels of prothrombin, the precursor of thrombin. This mutation is present in 2.3 % of the general population is associated with a 3-4 fold increased risk of thromboembolism. The Leiden thrombophilia study reported a relative risk of 2.8 with the 20210A Prothrombin gene variant in 2.3% of healthy carriers and 6.2% of consecutive controls.
A meta-analysis with pooled data from nine studies (n=2087) indicated a significant association between the prothrombin G20210A mutation with late non-recurrent fetal loss (2.30,1.09-4.87) 4 A number of small case-control studies have conflicting results with respect to a possible association between prothrombin and the risk of pre-eclampsia and intrauterine growth restriction; and larger prospective studies are needed to clarify a possible relationship. There have been no studies evaluating a possible risk of adverse pregnancy outcome associated with the fetal Prothrombin G20210A mutation.
Most of the research in this area has been in the form of case-control studies which are notoriously subject to bias. We are therefore proposing a nested case-control study, which is methodologically more vigorous.
Placental thrombi resulting in placental infarction may occur on either side of the maternal-fetal interface, and theoretically the fetal as well as the maternal factor V Leiden genotype may influence the risk of adverse pregnancy outcome. Therefore, we aim to address the effect, not only of maternal factor V Leiden and prothrombin G20210A mutation, but also of fetal factor V Leiden and prothrombin G20210A mutation on pre-eclampsia, intrauterine growth retardation and late fetal death.
1 Rosendaal F. Thrombosis Series: Venous thrombosis: a multi causal disease. Lancet 1993;353:1167-73.
2 Bertina R, Koelenan B, Koster T, Rosendall FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:65-67.
3 Spina V, Aleandri V, Morini F. The impact of Factor V Leiden on pregnacy. Hum Reprod Update 2000;6: 301-306.
4 Rey E, Kahn S, David M, Shier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361:901-908.
5 Rai R, Backos M, Elgaddal S, Shlebak A, Regan L. Factor V leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Human Reproduction 2002;17:442-445.
6 Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V ledien genotype: a meta-analysis. Thromb Haemost 2004;91:700-11.
B154 - Selective assessment of colour motion and contrast acuity in the ALSPAC study - 01/03/2004
(No outline received).
B152 - Childhood viral infections - 01/02/2004
(No outline received).
B151 - Are higher levels of physical activity in pregnant women associated with better mental health before and after children - 01/02/2004
(No outline received).
B144 - Investigation of the role of calcium homeostasis in the programming of bone development by early life factors - 01/01/2004
(No outline received).
B143 - A life course study on the cause of obesity and its co-morbidities OBESGEN - 01/01/2004
(No outline received).
B141 - A large scale study of the impact of speech language abilities on psychological development in adolescence - 01/12/2003
(No outline received).
B140 - EARNEST - 01/12/2003
The idea that nutrition in early life (foetal and infant) influences or 'programmes' long term health outcomes
has major implications for human biology, public health practice, inequalities in health and policy
development as well as for product development and wealth creation.
The scientific objectives of EARNEST with an indication of which THEMES will contribute to their
achievement are listed below.
* Quantification of the effects of early programming on later cardiovascular diseases, obesity, diabetes,
cognitive and mental disorders, bone health and some cancers (Themes 1-3)
* Definition of the relative importance of critical periods in foetal and early life on later disease (1-3)
Exploration of the impact of genetic determinants on early programming effects and on subsequent
outcome (3)
* Understanding the role of specific nutrients and their interactions in the maternal and infant diet on
programming effects on disease and their risk factors (1-3)
* Understanding mechanisms for early programming on later disease and their risk factors (3)
* Development of appropriate strategies for treating and especially for preventing the amplification of
adverse programming effects of early nutrition (1)
* Exploration of the public health impact of how knowledge about early programming affects consumer
behaviour (4)
* Quantification of the impact of early nutrition on the economic burden of adult ill-health (5)
* Improvement of training and enhancement of training opportunities for all including accession countries
(8)
Objectives are given in a broad sense for the themes, more specifically for the included workpackages and
for the individual activitiesm wherever possible and meaningful.
B149 - ESRC - Centre for Public Organisation - 01/12/2003
(No outline received).
B138 - The Avon Secondary Schools Project - 01/11/2003
(No outline received).
B137 - The role of nutrition and paracetamol exposure in the aetiology of asthma - 01/11/2003
As part of our analyses of prenatal nutrition we plan to analyse the effects of prenatal alcohol exposure on childhood atopic outcomes. We propose, in addition to analysing the maternal questionnaire data on alcohol intake, to utilise a Mendelian randomisation approach in order to remove potential bias and confounding and add rigour. We would like to analyse the maternal ADH1B variant (data requested) which has been shown to predict alcohol intake in pregnancy in ALSPAC. A DTA covering analysis of genetic data is already in place with QMUL. We have all other variables (maternal exposure, confounders and childhood atopic outcomes) needed to carry out these analyses.
B163 - The influence of environmental factors on hip structure in childhood - 01/11/2003
This project aims to identify major environmental influences on hip structure in childhood, by testing hypotheses for how expansion of the inner and outer surfaces of the hip bone is controlled during growth. This will be achieved by exploiting the unique Avon and Longitudinal Study of Parents and Children (ALSPAC) birth cohort, in which children born in Avon between 1991-2 have been followed up in detail since before birth. We will investigate the relationship between environmental factors recorded in ALSPAC, and hip structure as assessed at age 13 using a low energy x-ray technique. By improving our understanding of the deterimants of hip structure in this way, the present proposal is intended to shed light on the childhood origins of hip fracture in later life, and provide a basis for population-based strategies aimed at reducing the prevalence of this common condition.
B135 - NAC Fellowship - 01/11/2003
(No outline received).
B162 - The prevalence and co-morbidity of autism spectrum disorders - 01/11/2003
(No outline received).
B134 - Cognitive behavioural educational outcomes of children who have been bereaved - 01/11/2003
(No outline received).
B132 - Improved learning in the mentally handicapped - 01/10/2003
(No outline received).
B131 - Replication of the gene-environment interaction of Moffit and Caspi in the children - looking at the onset of depression - 01/10/2003
(No outline received).
B130 - The aetiology of traits contributing to autism and the autistic spectrum disorders - 01/09/2003
This research project is focused within the Avon Longitudinal Study of Parents and Children (ALSPAC) which was specifically designed to identify features in the environment which influence health and development and ways that the effect of such features may be modified by the genotype of the individual. The proposal is to address a number of questions concerning the aetiology of autism and the autistic spectrum disorders by concentrating on the different traits that are an integral part of these disorders. This will involve determination of associations with immunisations (and mercury exposures), obstetric factors, maternal and infant infections, fetal exposure to toxins and dietary features as well as a study of co-morbidity such as digestive symptoms and the presence of coeliac disease. This baseline study will then be available for specific add on projects which may concern analysis of DNA for specific candidate genes, serum for signs of infection or autoimmune disorderes, or umbilical cord for toxins.
B129 - Diet IGF and cancer risk an inter-generational investigation - 01/09/2003
A westernised diet increases the risk of breast, prostate and colorectal cancers. Prospective studies
suggest a common mediator: high circulating IGF-I concentrations. Recent data suggested IGF-I is also
associated with cervical cancer. The large inter-individual differences in IGF-I concentrations are thought to
be partly heritable, but also strongly dependent upon nutrition. We suggest that interactions between
heritable factors and nutrition determine an individual's IGF-I concentration and subsequent cancer risk.
We propose a nested case-control study within ALSPAC. To date there have been 400 incident cases of
cancer in the ALSPAC mothers. Dietary information and blood samples have been collected from mothers
(in pregnancy) prior to the cancer presentation and from their children at age 7-8 years. We will measure
circulating concentrations of IGF-I, IGF-II and IGFBP-3 in (a) mothers who have developed breast or
cervical cancer (b) control mothers without cancer and (c) their children. We will examine whether
IGF-measures were prospectively associated with the development of cancer. Furthermore we will use
the disease-free mother-child pairs to examine associations between IGF-measures in mothers and their offspring
and the extent to which these may be due to common patterns of diet, other shared environmental exposures
or may be inherited.
B126 - Dietary influences on insulin resistance at 8 years of age - 01/09/2003
(No outline received).