Intergenerational Transmission of Health Inequities: Early Life Socioeconomic Factors, Adult Cardiometabolic and Pregnancy Outcomes, and Potential Epigenetic Mechanisms in Young Adult Women.

Thesis (Ph.D.)--University of Washington, 2014Parental socioeconomic status (SES) experienced by a woman in utero may directly affect her adult health, independent of her life course experiences. Developmental programming of gene expression through DNA methylation may be involved. However, investigations using prevailing regression methods have been impeded by complex causal structures and unmeasured confounding. Using a U.S.-national, longitudinal cohort, we investigated the effect of mother's education on (1) cardiometabolic risk and (2) pregnancy outcomes among women averaging 30 years of age. Using an Israeli birth cohort, we investigated associations between parental education and father's occupational class on (3) DNA methylation at cardiometabolic genes in 32-year old women. (1) Using marginal structural models estimated by inverse probability weighting, we found young adult women whose mothers had higher educational attainment (e.g. college versus high school) had 40% lower risk (Odds Ratio = 0.60, 95% Confidence Interval: 0.45, 0.80) of metabolic syndrome, independent of childhood maltreatment, adolescent overweight, adult SES, and behavioral risk. Additionally, there was evidence that women with more highly educated mothers were taller, thinner, and had a smaller waist, lower resting pulse rate, lower levels of inflammatory markers, and better blood sugar control. (2) Additionally, women born to more highly educated mothers who themselves bore children delivered newborns who were 90 grams heavier (95% CI: 20.8, 156.5), independent of childhood maltreatment, pre-pregnancy overweight, adult SES, and prenatal smoking. Moreover, results from (1) and (2) were robust to several sensitivity analyses including model alteration, data replacement, and quantitative bias analyses. (3) Finally, we found that lower SES at birth measured by father's occupational class was associated with reduced methylation at the ABCA1 cholesterol transporter gene and the NR3C1 glucocorticoid receptor genes in 32-year old women, after adjusting for numerous parental and offspring characteristics. Similarly, fewer years of mother's education was associated with reduced HSD11B2 glucocorticoid-inactivating enzyme gene methylation. However, such associations did not appear to mediate relationships between birth SES and young adult cardiometabolic risk. Overall, there appears to be substantial evidence that early life SES is independently related to adult women's health and DNA methylation, however the mechanisms relating them require further elucidation

Analyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach

Huang and colleagues used machine-learning estimators to analyse a broad range of parameters in a prospective cohort consisting ART and spontaneously conceived children. Small differences in stature and growth could not be explained by parental or perinatal environment factors, nor differences in fetal DNA methylation. No strong differences in metabolic parameters were seen. Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (-0.5 SD [95% CI: -0.7, -0.2]), lighter (-0.6 SD [-0.9, -0.3]) and have lower skinfold thicknesses (e.g. -14% [-24%, -3%] suprailiac), and blood pressure (-3 mmHg [-6, -0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.Peer reviewe

Parental and child genetic burden of glycaemic dysregulation and early-life cognitive development: an Asian and European prospective cohort study

Insulin resistance and glucose metabolism have been associated with neurodevelopmental disorders. However, in the metabolically more susceptible Asian populations, it is not clear whether the genetic burden of glycaemic dysregulation influences early-life neurodevelopment. In a multi-ethnic Asian prospective cohort study in Singapore (Growing Up in Singapore Towards healthy Outcomes (GUSTO)), we constructed child and parental polygenic risk scores (PRS) for glycaemic dysregulation based on the largest genome-wide association studies of type 2 diabetes and fasting glucose among Asians. We found that child PRS for HOMA-IR was associated with a lower perceptual reasoning score at ~7 years (β=-0. 141, p-value=0.024, 95%CI -0. 264 to -0. 018) and a lower WIAT-III mean score at ~9 years (β=-0.222, p-value=0.001, 95%CI -0.357 to -0.087). This association were consistent in direction among boys and girls. These inverse associations were not influenced by parental PRS and were likely mediated via insulin resistance rather than mediators such as birth weight and childhood body mass index. Higher paternal PRS for HOMA-IR was suggestively associated with lower child perceptual reasoning at ~7 years (β=-0.172, p-value=0.002, 95%CI -0.280 to -0.064). Replication analysis in a European cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, showed that higher child PRS for fasting glucose was associated with lower verbal IQ score while higher maternal PRS for insulin resistance was associated with lower performance IQ score in their children at ~8.5 years. In summary, our findings suggest that higher child PRS for HOMA-IR was associated with lower cognitive scores in both Asian and European replication cohorts. Differential findings between cohorts may be attributed to genetic and environmental factors. Further investigation of the functions of the genetic structure and ancestry-specific PRS and a more comprehensive investigation of behavioural mediators may help to understand these findings better

Parental and child genetic burden of glycaemic dysregulation and early-life cognitive development : an Asian and European prospective cohort study

Insulin resistance and glucose metabolism have been associated with neurodevelopmental disorders. However, in the metabolically more susceptible Asian populations, it is not clear whether the genetic burden of glycaemic dysregulation influences early-life neurodevelopment. In a multi-ethnic Asian prospective cohort study in Singapore (Growing Up in Singapore Towards healthy Outcomes (GUSTO)), we constructed child and parental polygenic risk scores (PRS) for glycaemic dysregulation based on the largest genome-wide association studies of type 2 diabetes and fasting glucose among Asians. We found that child PRS for HOMA-IR was associated with a lower perceptual reasoning score at similar to 7 years (beta = -0. 141, p-value = 0.024, 95% CI -0. 264 to -0. 018) and a lower WIAT-III mean score at similar to 9 years (beta = -0.222, p-value = 0.001, 95% CI -0.357 to -0.087). This association were consistent in direction among boys and girls. These inverse associations were not influenced by parental PRS and were likely mediated via insulin resistance rather than mediators such as birth weight and childhood body mass index. Higher paternal PRS for HOMA-IR was suggestively associated with lower child perceptual reasoning at similar to 7 years (beta = -0.172, p-value = 0.002, 95% CI -0.280 to -0.064). Replication analysis in a European cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, showed that higher child PRS for fasting glucose was associated with lower verbal IQ score while higher maternal PRS for insulin resistance was associated with lower performance IQ score in their children at similar to 8.5 years. In summary, our findings suggest that higher child PRS for HOMA-IR was associated with lower cognitive scores in both Asian and European replication cohorts. Differential findings between cohorts may be attributed to genetic and environmental factors. Further investigation of the functions of the genetic structure and ancestry-specific PRS and a more comprehensive investigation of behavioural mediators may help to understand these findings better.Peer reviewe

Brown Adipose Tissue, Adiposity, and Metabolic Profile in Preschool Children

Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.Context: An inverse relationship between brown adipose tissue (BAT) and obesity has previously been reported in older children and adults but is unknown in young children. Objective: We investigated the influence of BAT in thermoneutral condition on adiposity and metabolic profile in Asian preschool children. Design, Setting, and Participants: A total of 198 children aged 4.5 years from a prospective birth cohort study, Growing Up in Singapore Towards Healthy Outcomes (GUSTO) were successfully studied with water-fat magnetic resonance imaging of the supraclavicular and axillary fat depot (FDSA). Regions within FDSA with fat-signal-fraction between 20% and 80% were considered BAT, and percentage BAT (%BAT; 100∗BAT volume/ FDSA volume) was calculated. Main Outcome Measures: Abdominal adipose tissue compartment volumes, ectopic fat in the soleus muscle and liver, fatty liver index, metabolic syndrome scores, and markers of insulin sensitivity. Results: A 1% unit increase in %BAT was associated with lower body mass index, difference (95% CI), -0.08 (-0.10, -0.06) kg/m2 and smaller abdominal adipose tissue compartment volumes. Ethnicity and sex modified these associations. In addition, each unit increase in %BAT was associated with lower ectopic fat at 4.5 years in the liver, -0.008% (-0.013%, -0.003%); soleus muscle, -0.003% (-0.006%, -0.001%) of water content and lower fatty liver index at 6 years. Conclusions: Higher %BAT is associated with a more favorable metabolic profile. BAT may thus play a role in the pathophysiology of obesity and related metabolic disorders. The observed ethnic and sex differences imply that the protective effect of BAT may vary among different groups.Peer reviewe

Cohort profile: Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO)

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18 to 45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N=557 censored). Women who successfully conceived (N=475) were characterised at gestational weeks 6-8, 11-13, 18-21, 24-26, 27-28 and 34-36. Follow up of their index offspring (N=373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated phenotypic data collected which include genetic and epigenetic sampling from preconception which is unique in mother-offspring epidemiological cohorts This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition the S-PRESTO study, draws from the three major Asian ethnic groups that represent 50% of the global population, increasing the relevance of its findings to global efforts to address non-communicable diseases

Cohort profile : Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO)

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18–45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N = 557 censored). Women who successfully conceived (N = 475) were characterised at gestational weeks 6–8, 11–13, 18–21, 24–26, 27–28 and 34–36. Follow up of their index offspring (N = 373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated data collected which include genetic and epigenetic sampling from preconception which is unique in mother–offspring epidemiological cohorts. This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition, the S-PRESTO study draws from the three major Asian ethnic groups that represent 50% of the global population, increasing the relevance of its findings to global efforts to address non-communicable diseases