Obstetric, lifestyle and genetic determinants of vascular and metabolic traits in women in early middle-age
Lead Research Organisation:
University of Bristol
Department Name: Social Medicine
Abstract
The aim of this study is to identify the risk factors, including changes during pregnancy (such as changes in weight and blood pressure), different patterns of change in lifestyle factors such as smoking habits and physical activity, and genetic factors, that determine the variations in atherosclerosis and other vascular and metabolic traits in women in their mid-40s. Cardiovascular disease (CVD) is the commonest cause of death among women in the UK, with 113,140 women (37% of the total number of deaths in all women in the UK) dying of CVD and 11% living with either coronary heart disease or stroke in 2004. Study participants will be mothers from the Avon Longitudinal Study of Parents and Children. For these women we already have over 15 years of prospectively collected genetic, lifestyle and obstetric data collected repeatedly since their index pregnancy in the early 1990s. 7,000 women (average age 44) will be recruited to participate in a clinical examination. This will include fasting blood samples for insulin, glucose and lipid measurements, DXA determined fat mass and carotid intima media thickness (a measure of atherosclerosis). This work will provide the necessary evidence base for developing effective interventions aimed at preventing CVD in women.
Technical Summary
Aim
To identify the obstetric, lifestyle, and genetic determinants, of variations in vascular and metabolic traits in women in their mid-40s, an age at which few will have died or been on treatment for cardiovascular disease (CVD).
Objectives
1. To determine the association of obstetric factors (BMI and blood pressure at the start of pregnancy, different patterns of changes in weight, blood pressure and glycosuria throughout the antenatal period, gestational diabetes and pregnancy induced hypertension) with variations in vascular and metabolic traits (fat mass, fat distribution, fasting insulin, glucose and lipids, and blood pressure), in women in their mid-40s, and to use this information to determine whether routinely collected antenatal data can predict variations in metabolic and vascular traits in women in their mid-40s.
2. To use genetic variants with established associations with adiposity as instrumental variables to estimate the magnitude of the causal association of variations in average fat mass over the life course with metabolic and vascular traits in women.
3. To determine the different ways in which obstetric, lifestyle (different patterns of cigarette smoking, physical activity, and dietary intake including alcohol consumption) and genetic factors relate to each other to affect variations in vascular and metabolic traits in women in their 40s.
4. To contribute to determining the association of novel genetic variants (that will be identified by bioinformatics and genome wide association studies) with fat mass, fasting insulin, glucose and lipids, blood pressure and smoking, physical activity and alcohol patterns, and replicate these findings in independent studies; and to examine whether there are genetic variants that are related specifically to adverse metabolic profile in pregnancy.
Design & methodology
Study participants are mothers from the Avon Longitudinal Study of Parents And Children. For these women there is an established DNA bank, immortalised cell-lines, and data on obstetric, socio-demographic and lifestyle factors collected repeatedly, since their index pregnancy in the early 1990s. Fat mass, fat distribution and blood pressure measurements (N=5000), and fasting glucose, insulin and lipids (N=2000) will be collected for women attending their offspring‘s 15 year follow-up clinic (mean age: 44). Relevant statistical methods - generalised linear regression models, multilevel models, instrumental variables analysis - will be used as appropriate.
Medical opportunities
This study will provide the necessary evidence base for developing programmes aimed at preventing CVD in women. Identifying women at risk of future adverse metabolic and vascular risk profiles during their pregnancy is likely to be advantageous as over 85% of women experience a pregnancy and antenatal care, and they may be particularly receptive to preventive interventions at this stage in their life course.
To identify the obstetric, lifestyle, and genetic determinants, of variations in vascular and metabolic traits in women in their mid-40s, an age at which few will have died or been on treatment for cardiovascular disease (CVD).
Objectives
1. To determine the association of obstetric factors (BMI and blood pressure at the start of pregnancy, different patterns of changes in weight, blood pressure and glycosuria throughout the antenatal period, gestational diabetes and pregnancy induced hypertension) with variations in vascular and metabolic traits (fat mass, fat distribution, fasting insulin, glucose and lipids, and blood pressure), in women in their mid-40s, and to use this information to determine whether routinely collected antenatal data can predict variations in metabolic and vascular traits in women in their mid-40s.
2. To use genetic variants with established associations with adiposity as instrumental variables to estimate the magnitude of the causal association of variations in average fat mass over the life course with metabolic and vascular traits in women.
3. To determine the different ways in which obstetric, lifestyle (different patterns of cigarette smoking, physical activity, and dietary intake including alcohol consumption) and genetic factors relate to each other to affect variations in vascular and metabolic traits in women in their 40s.
4. To contribute to determining the association of novel genetic variants (that will be identified by bioinformatics and genome wide association studies) with fat mass, fasting insulin, glucose and lipids, blood pressure and smoking, physical activity and alcohol patterns, and replicate these findings in independent studies; and to examine whether there are genetic variants that are related specifically to adverse metabolic profile in pregnancy.
Design & methodology
Study participants are mothers from the Avon Longitudinal Study of Parents And Children. For these women there is an established DNA bank, immortalised cell-lines, and data on obstetric, socio-demographic and lifestyle factors collected repeatedly, since their index pregnancy in the early 1990s. Fat mass, fat distribution and blood pressure measurements (N=5000), and fasting glucose, insulin and lipids (N=2000) will be collected for women attending their offspring‘s 15 year follow-up clinic (mean age: 44). Relevant statistical methods - generalised linear regression models, multilevel models, instrumental variables analysis - will be used as appropriate.
Medical opportunities
This study will provide the necessary evidence base for developing programmes aimed at preventing CVD in women. Identifying women at risk of future adverse metabolic and vascular risk profiles during their pregnancy is likely to be advantageous as over 85% of women experience a pregnancy and antenatal care, and they may be particularly receptive to preventive interventions at this stage in their life course.
Publications
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(2013)
Estimating trajectories of energy intake through childhood and adolescence using linear-spline multilevel models.
in Epidemiology (Cambridge, Mass.)
Anderson EL
(2013)
Associations of postnatal growth with asthma and atopy: the PROBIT Study.
in Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology
Anderson EL
(2014)
Weight trajectories through infancy and childhood and risk of non-alcoholic fatty liver disease in adolescence: the ALSPAC study.
in Journal of hepatology
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The Prevalence of Non-Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta-Analysis.
in PloS one
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Physical Activity Is Prospectively Associated With Adolescent Nonalcoholic Fatty Liver Disease.
in Journal of pediatric gastroenterology and nutrition
Anderson EL
(2013)
Anti-müllerian hormone is not associated with cardiometabolic risk factors in adolescent females.
in PloS one
Boyd A
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Cohort Profile: the 'children of the 90s'--the index offspring of the Avon Longitudinal Study of Parents and Children.
in International journal of epidemiology
Carslake D
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Associations of mortality with own height using son's height as an instrumental variable.
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Davey Smith G
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The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study.
in BMJ (Clinical research ed.)
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Commentary: liver enzymes and all-cause mortality.
in International journal of epidemiology
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(2014)
Maternal diabetes in pregnancy and offspring cognitive ability: sibling study with 723,775 men from 579,857 families.
in Diabetologia
Fraser A
(2012)
Associations of existing diabetes, gestational diabetes, and glycosuria with offspring IQ and educational attainment: the Avon Longitudinal Study of Parents and Children.
in Experimental diabetes research
Fraser A
(2013)
Hypertensive disorders of pregnancy and cardiometabolic health in adolescent offspring.
in Hypertension (Dallas, Tex. : 1979)
Fraser A
(2010)
Association of maternal weight gain in pregnancy with offspring obesity and metabolic and vascular traits in childhood.
in Circulation
Fraser A
(2011)
Associations of gestational weight gain with maternal body mass index, waist circumference, and blood pressure measured 16 y after pregnancy: the Avon Longitudinal Study of Parents and Children (ALSPAC).
in The American journal of clinical nutrition
Fraser A
(2013)
Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort.
in International journal of epidemiology
Fraser A
(2014)
Long-term health outcomes in offspring born to women with diabetes in pregnancy.
in Current diabetes reports
Fraser A, Lawlor DA
(2012)
Maternal Obesity
Gage SH
(2013)
Associations of maternal weight gain in pregnancy with offspring cognition in childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children.
in American journal of epidemiology
Howe LD
(2014)
Rapid increases in infant adiposity and overweight/obesity in childhood are associated with higher central and brachial blood pressure in early adulthood.
in Journal of hypertension
Knipe DW
(2014)
Is interpregnancy interval associated with cardiovascular risk factors in later life? A cohort study.
in BMJ open
Lacey RE
(2020)
The Clustering of Adverse Childhood Experiences in the Avon Longitudinal Study of Parents and Children: Are Gender and Poverty Important?
in Journal of interpersonal violence
Lawlor DA
(2011)
Does maternal weight gain in pregnancy have long-term effects on offspring adiposity? A sibling study in a prospective cohort of 146,894 men from 136,050 families.
in The American journal of clinical nutrition
Lawlor DA
(2013)
Association of maternal vitamin D status during pregnancy with bone-mineral content in offspring: a prospective cohort study.
in Lancet (London, England)
Lawlor DA
(2011)
Maternal and offspring adiposity-related genetic variants and gestational weight gain.
in The American journal of clinical nutrition
Lawlor DA
(2014)
Nonalcoholic fatty liver disease, liver fibrosis, and cardiometabolic risk factors in adolescence: a cross-sectional study of 1874 general population adolescents.
in The Journal of clinical endocrinology and metabolism
Lawlor DA
(2010)
Association between general and central adiposity in childhood, and change in these, with cardiovascular risk factors in adolescence: prospective cohort study.
in BMJ (Clinical research ed.)
Lawlor DA, Brion M-J A, Howe LD, Fraser A
(2013)
Lifestyle Medicine
Macdonald-Wallis C
(2013)
Gestational weight gain as a risk factor for hypertensive disorders of pregnancy.
in American journal of obstetrics and gynecology
Macdonald-Wallis C
(2011)
Established preeclampsia risk factors are related to patterns of blood pressure change in normal term pregnancy: findings from the Avon Longitudinal Study of Parents and Children.
in Journal of hypertension
Macdonald-Wallis C
(2015)
Antenatal blood pressure for prediction of pre-eclampsia, preterm birth, and small for gestational age babies: development and validation in two general population cohorts.
in BMJ (Clinical research ed.)
Macdonald-Wallis C
(2015)
Gestational-age-specific reference ranges for blood pressure in pregnancy: findings from a prospective cohort.
in Journal of hypertension
Macdonald-Wallis C
(2014)
Associations of blood pressure change in pregnancy with fetal growth and gestational age at delivery: findings from a prospective cohort.
in Hypertension (Dallas, Tex. : 1979)
Macdonald-Wallis C
(2012)
Blood pressure change in normotensive, gestational hypertensive, preeclamptic, and essential hypertensive pregnancies.
in Hypertension (Dallas, Tex. : 1979)
Macdonald-Wallis C
(2011)
Relationships of risk factors for pre-eclampsia with patterns of occurrence of isolated gestational proteinuria during normal term pregnancy.
in PloS one
Millard LA
(2013)
Physical activity during pregnancy and offspring cardiovascular risk factors: findings from a prospective cohort study.
in BMJ open
Patel S
(2015)
The association of nonalcoholic fatty liver disease with central and peripheral blood pressure in adolescence: findings from a cross-sectional study.
in Journal of hypertension
Patel S
(2012)
Associations of gestational diabetes, existing diabetes, and glycosuria with offspring obesity and cardiometabolic outcomes.
in Diabetes care
Rich-Edwards JW
(2014)
Pregnancy characteristics and women's future cardiovascular health: an underused opportunity to improve women's health?
in Epidemiologic reviews
Richmond RC
(2016)
DNA Methylation and BMI: Investigating Identified Methylation Sites at HIF3A in a Causal Framework.
in Diabetes
Sharp GC
(2015)
Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: findings from the Avon Longitudinal Study of Parents and Children.
in International journal of epidemiology
Tolppanen AM
(2012)
Risk factors for variation in 25-hydroxyvitamin D3 and D2 concentrations and vitamin D deficiency in children.
in The Journal of clinical endocrinology and metabolism
Williams DM
(2011)
Associations of vitamin D, parathyroid hormone and calcium with cardiovascular risk factors in US adolescents.
in Heart (British Cardiac Society)
Williams DM
(2012)
Associations of 25-hydroxyvitamin D2 and D3 with cardiovascular risk factors in childhood: cross-sectional findings from the Avon Longitudinal Study of Parents and Children.
in The Journal of clinical endocrinology and metabolism
Williams DM
(2013)
Associations of maternal 25-hydroxyvitamin D in pregnancy with offspring cardiovascular risk factors in childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children.
in Heart (British Cardiac Society)
| Description | MRC Career Development Award |
| Amount | £852,812 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 12/2014 |
| End | 11/2019 |
| Description | MRC Centenary Award |
| Amount | £100,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2013 |
| End | 08/2014 |
| Description | Wellcome Trust PhD Molecular, Genetic and Lifecourse Epidemiology |
| Amount | £150,161 (GBP) |
| Funding ID | 105503/z/14/z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2014 |
| End | 09/2018 |
| Description | Maternal and Child Health Life Course Research Network |
| Organisation | Brigham and Women's Hospital |
| Country | United States |
| Sector | Hospitals |
| PI Contribution | Joint position paper presented at the Network meeting in Washington DC in February 2013. Subsequently published in Epidemiological Reviews |
| Collaborator Contribution | As above. |
| Impact | Paper published in Epidemiological Reviews. |
| Start Year | 2012 |
| Description | Maternal and Child Health Life Course Research Network |
| Organisation | University of Pittsburgh |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Joint position paper presented at the Network meeting in Washington DC in February 2013. Subsequently published in Epidemiological Reviews |
| Collaborator Contribution | As above. |
| Impact | Paper published in Epidemiological Reviews. |
| Start Year | 2012 |
| Description | Invited internet based commentary |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Health professionals |
| Results and Impact | I was invited to provide a commentary on a publication for Healio a media outlet for health professionals. N/A |
| Year(s) Of Engagement Activity | 2012 |
| Description | Press coverage of several scientific publications |
| 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 | Media coverage of several publications resulting from my Fellowship work. This included radiocoverage and written media coverage. N/A |
| Year(s) Of Engagement Activity | 2010,2011,2012 |
| Description | Public talk as part of the ALSPAC Summer School series |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Participants in your research and patient groups |
| Results and Impact | Some 60 people, mostly ALSPAC mothers participated. Following this activity, I have been invited by Bristol Women's Voice to give a similar presentation. |
| Year(s) Of Engagement Activity | 2014 |