Publications by authors named "Marie-France Hivert"

236 Publications

Impact of paternal education on epigenetic ageing in adolescence and mid-adulthood: a multi-cohort study in the USA and Mexico.

Int J Epidemiol 2021 Sep 17. Epub 2021 Sep 17.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Both parental and neighbourhood socio-economic status (SES) are linked to poorer health independently of personal SES measures, but the biological mechanisms are unclear. Our objective was to examine these influences via epigenetic age acceleration (EAA)-the discrepancy between chronological and epigenetic ages.

Methods: We examined three USA-based [Coronary Artery Risk Disease in Adults (CARDIA) study, Fragile Families and Child Wellbeing Study (FFCWS) and Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS)] and one Mexico-based (Project Viva) cohort. DNA methylation was measured using Illumina arrays, personal/parental SES by questionnaire and neighbourhood disadvantage from geocoded address. In CARDIA, we examined the most strongly associated personal, parental and neighbourhood SES measures with EAA (Hannum's method) at study years 15 and 20 separately and combined using a generalized estimating equation (GEE) and compared with other EAA measures (Horvath's EAA, PhenoAge and GrimAge calculators, and DunedinPoAm).

Results: EAA was associated with paternal education in CARDIA [GEEs: βsome college = -1.01 years (-1.91, -0.11) and β
Conclusions: These findings suggest that EAA captures epigenetic impacts of paternal education independently of personal SES later in life. Longitudinal studies should explore these associations at different life stages and link them to health outcomes. EAA could be a useful biomarker of SES-associated health and provide important insight into the pathogenesis and prevention of chronic disease.
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http://dx.doi.org/10.1093/ije/dyab196DOI Listing
September 2021

Associations of midchildhood to early adolescence central adiposity gain with cardiometabolic health in early adolescence.

Obesity (Silver Spring) 2021 Sep 16. Epub 2021 Sep 16.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

Objective: This study examined the associations of central adiposity gain from midchildhood to early adolescence with cardiometabolic health markers in early adolescence.

Methods: A total of 620 participants were studied in Project Viva. In midchildhood (mean age = 7.8 years) and early adolescence (12.9 years), waist circumference and dual-energy x-ray absorptiometry-measured visceral adipose tissue, subcutaneous abdominal adipose tissue, and trunk fat were obtained. Central adiposity gain was calculated as change per year between visits. Cardiometabolic health markers, including blood pressure, lipids, markers of insulin resistance, inflammation, and adipokines, were collected in early adolescence.

Results: Greater waist circumference gain was associated with higher log triglycerides (β 0.07 mg/dL; 95% CI: 0.02-0.13), log alanine aminotransferase (0.07 U/L; 95% CI: 0.03-0.12), log high-sensitivity C-reactive protein (0.43 mg/L; 95% CI: 0.28-0.58), and other cardiometabolic markers in early adolescence. Directly measured central adiposity gains were associated with higher systolic blood pressure z score in early adolescence (visceral adipose tissue [0.13 SD units; 95% CI: 0.04-0.23], subcutaneous abdominal adipose tissue [0.18 SD units; 95% CI: 0.04-0.31], and trunk fat [0.21 SD units; 95% CI: 0.06-0.36]). These associations were independent of baseline and change in total adiposity from midchildhood to early adolescence.

Conclusions: Monitoring central adiposity gain may enable identification and intervention in children vulnerable to developing cardiometabolic health risks.
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http://dx.doi.org/10.1002/oby.23261DOI Listing
September 2021

Sustainable food systems and nutrition in the 21st century: A report from the 22nd annual harvard nutrition obesity symposium.

Am J Clin Nutr 2021 Sep 15. Epub 2021 Sep 15.

Department of Epidemiology, Harvard T.H. Chan School of Public Health.

Food systems are at the center of a brewing storm consisting of a rapidly changing climate, rising hunger and malnutrition and significant social inequities. At the same time, there are vast opportunities to ensure that food systems produce healthy and safe food in equitable ways that promote environmental sustainability, especially if the world can come together at the UN Food Systems Summit in late 2021 and make strong and binding commitments towards food system transformation. The NIH-funded Nutrition Obesity Research Center at Harvard and the Harvard Medical School Division of Nutrition held their 22nd Annual Harvard Nutrition Obesity Symposium entitled "Global Food Systems and Sustainable Nutrition in the 21st Century" in June 2021. This paper presents a synthesis of this symposium and highlights the importance of food systems to address the burden of malnutrition and non-communicable diseases, climate change, and the economic and social inequities. Transformation of food systems is possible, and the nutrition and health communities have a significant role to play in this transformative process.
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http://dx.doi.org/10.1093/ajcn/nqab315DOI Listing
September 2021

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth.

Nat Commun 2021 08 24;12(1):5095. Epub 2021 Aug 24.

Universitat Pompeu Fabra, Barcelona, Spain.

Maternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. Here we present a meta-analysis of the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (N = 1700, 344 with MSDP). We identify 443 CpGs that are associated with MSDP, of which 142 associated with birth outcomes, 40 associated with gene expression, and 13 CpGs are associated with all three. Only two CpGs have consistent associations from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP-associated CpGs are enriched for environmental response genes, growth-factor signaling, and inflammation, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.
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http://dx.doi.org/10.1038/s41467-021-24558-yDOI Listing
August 2021

Physiological subtypes of gestational glucose intolerance and risk of adverse pregnancy outcomes.

Am J Obstet Gynecol 2021 Aug 19. Epub 2021 Aug 19.

Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Boston, MA. Electronic address:

Background: Women with gestational glucose intolerance, defined as an abnormal initial gestational diabetes mellitus screening test, are at risk of adverse pregnancy outcomes even if they do not have gestational diabetes mellitus. Previously, we defined the physiological subtypes of gestational diabetes mellitus based on the primary underlying physiology leading to hyperglycemia and found that women with different subtypes had differential risks of adverse outcomes. Physiological subclassification has not yet been applied to women with gestational glucose intolerance.

Objective: We defined the physiological subtypes of gestational glucose intolerance based on the presence of insulin resistance, insulin deficiency, or mixed pathophysiology and aimed to determine whether these subtypes are at differential risks of adverse outcomes. We hypothesized that women with the insulin-resistant subtype of gestational glucose intolerance would have the greatest risk of adverse pregnancy outcomes.

Study Design: In a hospital-based cohort study, we studied women with gestational glucose intolerance (glucose loading test 1-hour glucose, ≥140 mg/dL; n=236) and normal glucose tolerance (glucose loading test 1-hour glucose, <140 mg/dL; n=1472). We applied homeostasis model assessment to fasting glucose and insulin levels at 16 to 20 weeks' gestation to assess insulin resistance and deficiency and used these measures to classify women with gestational glucose intolerance into subtypes. We compared odds of adverse outcomes (large for gestational age birthweight, neonatal intensive care unit admission, pregnancy-related hypertension, and cesarean delivery) in each subtype to odds in women with normal glucose tolerance using logistic regression with adjustment for age, race and ethnicity, marital status, and body mass index.

Results: Of women with gestational glucose intolerance (12% with gestational diabetes mellitus), 115 (49%) had the insulin-resistant subtype, 70 (27%) had the insulin-deficient subtype, 40 (17%) had the mixed pathophysiology subtype, and 11 (5%) were uncategorized. We found increased odds of large for gestational age birthweight (primary outcome) in women with the insulin-resistant subtype compared with women with normal glucose tolerance (odds ratio, 2.35; 95% confidence interval, 1.43-3.88; P=.001; adjusted odds ratio, 1.74; 95% confidence interval, 1.02-3.48; P=.04). The odds of large for gestational age birthweight in women with the insulin-deficient subtype were increased only after adjustment for covariates (odds ratio, 1.69; 95% confidence interval, 0.84-3.38; P=.14; adjusted odds ratio, 2.05; 95% confidence interval, 1.01-4.19; P=.048). Among secondary outcomes, there was a trend toward increased odds of neonatal intensive care unit admission in the insulin-resistant subtype in an unadjusted model (odds ratio, 2.09; 95% confidence interval, 0.99-4.40; P=.05); this finding was driven by an increased risk of neonatal intensive care unit admission in women with the insulin-resistant subtype and a body mass index of <25 kg/m. Infants of women with other subtypes did not have increased odds of neonatal intensive care unit admission. The odds of pregnancy-related hypertension in women with the insulin-resistant subtype were increased (odds ratio, 2.09; 95% confidence interval, 1.31-3.33; P=.002; adjusted odds ratio, 1.77; 95% confidence interval, 1.07-2.92; P=.03) compared with women with normal glucose tolerance; other subtypes did not have increased odds of pregnancy-related hypertension. There was no difference in cesarean delivery rates in nulliparous women across subtypes.

Conclusion: Insulin-resistant gestational glucose intolerance is a high-risk subtype for adverse pregnancy outcomes. Delineating physiological subtypes may provide opportunities for a more personalized approach to gestational glucose intolerance.
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http://dx.doi.org/10.1016/j.ajog.2021.08.016DOI Listing
August 2021

Early-pregnancy maternal body mass index is associated with common DNA methylation markers in cord blood and placenta: a paired-tissue epigenome-wide association study.

Epigenetics 2021 Aug 12:1-11. Epub 2021 Aug 12.

Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, United States of America.

Women entering pregnancy with elevated body mass index (BMI) face greater risk of adverse outcomes during pregnancy, delivery, and for their offspring later in life, potentially via epigenetics. If epigenetic programming occurs early during development, the differential marks should be detectable in multiple tissues despite the known unique epigenetic profile in each.We used early-pregnancy BMI as reflection of maternal metabolic milieu exposure in peri-conception and early-pregnancy period. We analysed DNA methylation in paired cord blood and placenta samples among 437 newborns from Gen3G, a pre-birth prospective cohort of primarily European descent. We measured DNA methylation in both tissues across the genome in >720,000 CpG sites using the array. At each site, we used linear mixed models (LMMs) with an unstructured variance-covariance matrix to test for an association between maternal early-pregnancy BMI and DNA methylation in both tissues (modelled as -values). We adjusted for tissue-specific covariates, offspring sex, gestational age at delivery, and maternal smoking and age.Women had a mean (SD) BMI of 25.4 (5.7) kg/m measured at first trimester visit (mean=9.9 weeks). Early-pregnancy BMI was associated with differential DNA methylation levels in paired-tissue analyses at two sites: cg10593758 (β=0.0126, SE=0.0025; =4.07e-7), annotated to , and cg0762168 (β=-0.0094, SE=0.0018; =2.78e-7), annotated to .Application of LMMs in DNA methylation data from distinct fetal-origin tissues allowed us to identify CpG sites at which early-pregnancy BMI may have an epigenetic 'programming' effect on overall fetus development. One site () may play a role in hypothalamic-pituitary-adrenal axis regulation.
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http://dx.doi.org/10.1080/15592294.2021.1959975DOI Listing
August 2021

Placental miR-3940-3p is associated with maternal insulin resistance in late pregnancy.

J Clin Endocrinol Metab 2021 Aug 1. Epub 2021 Aug 1.

Mother Infant Research Institute, Tufts Medical Center, Boston, MA, USA.

Context: An increase in maternal insulin resistance (IR) during pregnancy is essential for normal fetal growth. The mechanisms underlying this metabolic adaptation to pregnancy are poorly understood. Placenta factors are believed to instigate and maintain these metabolic changes, as IR decreases shortly after delivery. Methylation of placental gene loci that are common targets for miRNAs, are associated with maternal IR.

Objective: We hypothesized that placental miRNAs targeting methylated loci are associated with maternal IR during late pregnancy.

Methods: We collected placentas from 132 elective cesarean sections and fasting blood sample at delivery to estimate maternal HOMA-IR. Placental miRNA expression was measured via whole genome small RNA-sequencing in a subset of 40 placentas selected by maternal pre-gravid BMI and neonatal adiposity. Five miRNAs that correlated with maternal HOMA-IR and were previously identified as targeting methylated genes were selected for validation in all 132 placenta samples via RT-qPCR. Multiple regression was used to adjust for relevant clinical variables.

Results: Median maternal age was 27.5 years, with a median pre-pregnancy BMI of 24.7 kg/m 2, and median HOMA-IR of 2.9. Among the five selected miRNA, maternal HOMA-IR correlated with the placental expression of miRNA-371b-3p (r=0.25; p=0.008) and miRNA-3940-3p (r=0.32; p=0.0004) across the 132 individuals. After adjustment for confounding variables, placental miRNA-3940-3p expression remained significantly associated with HOMA-IR (β=0.16; p=0.03).

Conclusion: Placental miRNA-3940-3p was associated with maternal IR at delivery. This placental miRNA may have an autocrine or paracrine effect - regulating placental genes which play a role in modulating maternal IR.
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http://dx.doi.org/10.1210/clinem/dgab571DOI Listing
August 2021

Temporal trends of concentrations of per- and polyfluoroalkyl substances among adults with overweight and obesity in the United States: Results from the Diabetes Prevention Program and NHANES.

Environ Int 2021 Jul 29;157:106789. Epub 2021 Jul 29.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA. Electronic address:

Background: Understanding the temporal trends and change of concentrations of per- and polyfluoroalkyl substances (PFAS) is important to evaluate the health impact of PFAS at both the individual- and population-level, however, limited information is available for pre-diabetic adults in the U.S.

Objectives: Determine trends and rate of change of plasma PFAS concentrations in overweight or obese U.S. adults and evaluate variation by sex, race/ethnicity, and age.

Methods: We described temporal trends of plasma PFAS concentrations using samples collected in 1996-1998, 1999-2001, and 2011-2012 from 957 pre-diabetic adults enrolled in the Diabetes Prevention Program (DPP) trial and Outcomes Study (DPPOS) and compared to serum concentrations from the National Health and Nutrition Examination Survey (NHANES 1999-2000, 2003-2016, adults with BMI ≥ 24 kg/m). We examined associations between participants' characteristics and PFAS concentrations and estimated the rate of change using repeated measures in DPP/DPPOS assuming a first-order elimination model.

Results: Longitudinal measures of PFAS concentrations in DPP/DPPOS individuals were comparable to NHANES cross-sectional populational means. Plasma concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid, perfluorohexanesulfonic acid (PFHxS), N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), and N-methylperfluorooctane sulfonamido acetic acid (MeFOSAA) started to decline after the year 2000 and concentrations of perfluorononanoic acid (PFNA) increased after 2000 and, for NHANES, decreased after 2012. We consistently observed higher PFOS, PFHxS and PFNA among male, compared to female, and higher PFOS and PFNA among Black, compared to white, participants. The estimated time for concentrations to decrease by half ranged from 3.39 years for EtFOSAA to 17.56 years for PFHxS.

Discussion: We observed a downward temporal trend in plasma PFOS concentrations that was consistent with the timing for U.S. manufacturers' phaseout. Male and Black participants consistently showed higher PFOS and PFNA than female and white participants, likely due to differences in exposure patterns, metabolism or elimination kinetics.
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http://dx.doi.org/10.1016/j.envint.2021.106789DOI Listing
July 2021

Early Life Exposure to Green Space and Mid-childhood Cognition in the Project Viva Cohort (Massachusetts, USA).

Am J Epidemiol 2021 Jul 23. Epub 2021 Jul 23.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

The association between early life greenness and child cognition is not well understood. Using prospective data from Project Viva (n=857) from 1999 to 2010, we examined associations of early life greenness exposure with mid-childhood cognition. We estimated residential greenness at birth, early childhood (median age 3.1y), and mid-childhood (7.8y) using 30m resolution Landsat satellite imagery [Normalized Difference Vegetation Index]. In early childhood and mid-childhood, we administered standardized assessments of verbal and nonverbal intelligence, visual-motor abilities, and visual memory. We used natural splines to examine associations of early life-course greenness with mid-childhood cognition, adjusting for age, sex, race, income, neighborhood socioeconomic status, maternal intelligence, and parental education. At lower levels of greenness (greenness<0.6), greenness exposure at early childhood was associated with a 0.48% increase in non-verbal intelligence and 2.64% increase in visual memory in mid-childhood. The association between early childhood greenness and mid-childhood visual memory was observed after further adjusting for early childhood cognition and across different methodologies, while the association with non-verbal intelligence was not. No other associations between early life-course greenness and mid-childhood cognition were found. Early childhood greenness was nonlinearly associated with higher mid-childhood visual memory. Our findings highlight the importance of nonlinear associations between greenness and cognition.
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http://dx.doi.org/10.1093/aje/kwab209DOI Listing
July 2021

Dietary fat intake during early pregnancy is associated with cord blood DNA methylation at IGF2 and H19 genes in newborns.

Environ Mol Mutagen 2021 Aug 31;62(7):388-398. Epub 2021 Jul 31.

Division of Environmental Health Sciences, University of California, Berkeley School of Public Health, Berkeley, Berkeley, California, USA.

Maternal fat intake during pregnancy affects fetal growth, but mechanisms underlying this relationship are unclear. We performed an exploratory study of the associations of fat consumption during pregnancy with cord blood DNA methylation of the insulin-like growth factor 2 (IGF2) and H19 genes. We used data from 96 uncomplicated full-term pregnancies of mothers of whom majority had normal body mass index (BMI) (66%) in Project Viva, a prospective pre-birth cohort. We assessed maternal diet with validated food frequency questionnaires during the first and second trimesters and measured DNA methylation in segments of the IGF2- and H19-differentially methylated regions (DMRs) by pyrosequencing DNA extracted from umbilical cord blood samples. Mean (SD) age was 32.8 (4.1) years and prepregnancy BMI was 24.0 (4.4) kg/m . Mean DNA methylation was 56.3% (3.9%) for IGF2-DMR and 44.6% (1.9%) for H19-DMR. Greater first trimester intake of omega-6 polyunsaturated fat (effect per 1% of calories at the expense of carbohydrates) was associated with lower DNA methylation of IGF2-DMR (-1.2%; 95% confidence interval [CI]: -2.2%, -0.2%) and higher DNA methylation at H19-DMR (0.8%; 95% CI: 0.3%, 1.3%). On the other hand, greater first trimester intake of omega-3 polyunsaturated fat was associated with lower DNA methylation of the H19-DMR (-4.3%; 95% CI: -7.9%, -0.8%). We did not find significant associations of IGF2 and H19 methylation with IGF2 cord blood levels. Our findings suggest that early prenatal fat intake (omega-3, omega-6, and saturated fatty acids) may influence DNA methylation at the IGF2 and H19 locus, which could impact fetal development and long-term health.
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http://dx.doi.org/10.1002/em.22452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364885PMC
August 2021

Associations of maternal insulin resistance during pregnancy and offspring inflammation at birth and at 5 years of age: A prospective study in the Gen3G cohort.

Cytokine 2021 Oct 13;146:155636. Epub 2021 Jul 13.

Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA; Department of Medicine, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada; Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address:

Background: Maternal insulin resistance is associated with greater maternal inflammation during pregnancy, but its relation to inflammation in offspring remains unclear. The goal of this study was to assess the relationship of gestational insulin resistance and other glycemic markers with offspring inflammation at birth and at 5 years of age.

Methods: We included 653 mother-child pairs from the prospective pre-birth Gen3G cohort. We examined maternal insulin and glucose levels measured during the second trimester of pregnancy, from which we derived the homeostatic model of assessment of insulin resistance (HOMA-IR) and the Matsuda index. We assessed offspring inflammation at birth and at 5 years of age by measuring plasma tumor necrosis factor-α (TNFα) concentrations. We conducted multivariable regression models to evaluate associations of each insulin and glucose marker with offspring inflammation adjusting for confounding variables.

Results: Higher levels of fasting insulin were associated with lower TNFα levels at birth (-0.78, 95% CI [-1.45, -0.11]), in the fully adjusted model. We observed similar associations with the HOMA-IR and opposite direction with the Matsuda index. We did not find persistence of the association between maternal fasting insulin and offspring TNFα at 5 years of age.

Conclusions: Greater maternal insulin resistance during pregnancy was associated with lower cord blood TNFα levels in newborns. The mechanisms by which maternal insulin resistance may promote lower inflammatory levels in newborns are not fully understood and more research is needed to deepen our understanding of these mechanisms.
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http://dx.doi.org/10.1016/j.cyto.2021.155636DOI Listing
October 2021

Genetic Interactions with Intrauterine Diabetes Exposure in Relation to Obesity: The EPOCH and Project Viva Studies.

Pediatr Rep 2021 Jun 1;13(2):279-288. Epub 2021 Jun 1.

Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.

To examine whether BMI-associated genetic risk variants modify the association of intrauterine diabetes exposure with childhood BMI z-scores, we assessed the interaction between 95 BMI-associated genetic variants and in utero exposure to maternal diabetes among 459 children in the Exploring Perinatal Outcomes among Children historical prospective cohort study (n = 86 exposed; 373 unexposed) in relation to age- and sex-standardized childhood BMI z-scores (mean age = 10.3 years, standard deviation = 1.5 years). For the genetic variants showing a nominally significant interaction, we assessed the relationship in an additional 621 children in Project Viva, which is an independent longitudinal cohort study, and used meta-analysis to combine the results for the two studies. Seven of the ninety-five genetic variants tested exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to the offspring BMI z-score in EPOCH. Five of the seven variants exhibited a consistent direction of interaction effect across both EPOCH and Project Viva. While none achieved statistical significance in the meta-analysis after accounting for multiple testing, three variants exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to offspring BMI z-score: rs10733682 near (interaction β = 0.39; standard error (SE) = 0.17), rs17001654 near (β = 0.53; SE = 0.22), and rs16951275 near (β = 0.37; SE = 0.17). BMI-associated genetic variants may enhance the association between exposure to in utero diabetes and higher childhood BMI, but larger studies of in utero exposures are necessary to confirm the observed nominally significant relationships.
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http://dx.doi.org/10.3390/pediatric13020036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293453PMC
June 2021

Detecting cord blood cell type-specific epigenetic associations with gestational diabetes mellitus and early childhood growth.

Clin Epigenetics 2021 Jun 26;13(1):131. Epub 2021 Jun 26.

Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de La Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada.

Background: Epigenome-wide association studies (EWAS) have provided opportunities to understand the role of epigenetic mechanisms in development and pathophysiology of many chronic diseases. However, an important limitation of conventional EWAS is that profiles of epigenetic variability are often obtained in samples of mixed cell types. Here, we aim to assess whether changes in cord blood DNA methylation (DNAm) associated with gestational diabetes mellitus (GDM) exposure and early childhood growth markers occur in a cell type-specific manner.

Results: We analyzed 275 cord blood samples collected at delivery from a prospective pre-birth cohort with genome-wide DNAm profiled by the Illumina MethylationEPIC array. We estimated proportions of seven common cell types in each sample using a cord blood-specific DNAm reference panel. Leveraging a recently developed approach named CellDMC, we performed cell type-specific EWAS to identify CpG loci significantly associated with GDM, or 3-year-old body mass index (BMI) z-score. A total of 1410 CpG loci displayed significant cell type-specific differences in methylation level between 23 GDM cases and 252 controls with a false discovery rate < 0.05. Gene Ontology enrichment analysis indicated that LDL transportation emerged from CpG specifically identified from B-cells DNAm analyses and the mitogen-activated protein kinase pathway emerged from CpG specifically identified from natural killer cells DNAm analyses. In addition, we identified four and six loci associated with 3-year-old BMI z-score that were specific to CD8+ T-cells and monocytes, respectively. By performing genome-wide permutation tests, we validated that most of our detected signals had low false positive rates.

Conclusion: Compared to conventional EWAS adjusting for the effects of cell type heterogeneity, the proposed approach based on cell type-specific EWAS could provide additional biologically meaningful associations between CpG methylation, prenatal maternal GDM or 3-year-old BMI. With careful validation, these findings may provide new insights into the pathogenesis, programming, and consequences of related childhood metabolic dysregulation. Therefore, we propose that cell type-specific analyses are worth cautious explorations.
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http://dx.doi.org/10.1186/s13148-021-01114-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236204PMC
June 2021

Early pregnancy exposure to metal mixture and birth outcomes - A prospective study in Project Viva.

Environ Int 2021 11 17;156:106714. Epub 2021 Jun 17.

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA. Electronic address:

Background: Prenatal exposure to metals has been individually associated with birth outcomes. However, little is known about the effect of metal mixture, particularly at low exposure levels.

Objectives: To estimate individual and joint effects of metal mixture components on birth outcomes.

Methods: We used data from 1,391 mother-infant pairs in Project Viva (1999-2002). We measured 11 metals in maternal 1st trimester erythrocyte; abstracted birth weight from medical records; calculated gestational age from last menstrual period or ultrasound; and obtained birth length (n = 729) and head circumference (n = 791) from research measurements. We estimated individual and joint effects of metals using multivariable linear and Bayesian kernel machine regressions.

Results: In both single metal and metal mixture analyses, exposure to higher concentrations of arsenic was associated with lower birth weight in males, zinc with higher head circumference in females, and manganese with higher birth length in sex-combined analysis. We also observed sex-specific metal interactions with birth outcomes. Arsenic and manganese showed a synergistic association with birth weight in males, in whom an interquartile range (IQR) increase in arsenic was associated with 25.3 g (95% CI: -79.9, 29.3), 47.9 g (95% CI: -98.0, 2.1), and 72.2 g (95% CI: -129.8, -14.7) lower birth weight when manganese concentrations were at 25th, 50th, and 75th percentiles, respectively. Lead and zinc showed an antagonistic association with head circumference in males, where an IQR increase in lead was associated with 0.18 cm (95% CI: -0.35, -0.02), 0.10 cm (95% CI: -0.25, 0.04), 0.03 cm (95% CI: -0.2, 0.14) smaller head circumference when zinc concentrations were at 25th, 50th, and 75th percentiles, respectively. Exposure to higher concentrations of arsenic was also associated with lower gestational age in males when concentrations of manganese and lead were higher.

Discussion: Maternal erythrocyte concentrations of arsenic, manganese, lead, and zinc were individually and interactively associated with birth outcomes. The associations varied by infant sex and exposure level of other mixture components.
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http://dx.doi.org/10.1016/j.envint.2021.106714DOI Listing
November 2021

Early pregnancy essential and non-essential metal mixtures and gestational glucose concentrations in the 2nd trimester: Results from project viva.

Environ Int 2021 10 10;155:106690. Epub 2021 Jun 10.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Metals are involved in glucose metabolism, and some may alter glycemic regulation. However, joint effects of essential and non-essential metals on glucose concentrations during pregnancy are unclear. This study explored the joint associations of pregnancy exposures to essential (copper, magnesium, manganese, selenium, zinc) and non-essential (arsenic, barium, cadmium, cesium, lead, mercury) metals with gestational glucose concentrations using 1,311 women enrolled 1999-2002 in Project Viva, a Boston, MA-area pregnancy cohort. The study measured erythrocyte metal concentrations from 1 trimester blood samples and used glucose concentrations measured 1 h after non-fasting 50-gram glucose challenge tests (GCT) from clinical gestational diabetes screening at 26-28 weeks gestation. Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation were applied to model the associations of metal mixtures-including their interactions-with glucose concentrations post-GCT. We tested for reproducibility of BKMR results using generalized additive models. The BKMR model showed an inverse U-shaped association for barium and a linear inverse association for mercury. Specifically, estimated mean glucose concentrations were highest around 75th percentile of barium concentrations [2.1 (95% confidence interval: -0.2, 4.4) mg/dL higher comparing to the 25th percentile], and each interquartile range increase of erythrocyte mercury was associated with 1.9 mg/dL lower mean glucose concentrations (95% credible interval: -4.2, 0.4). Quantile g-computation showed joint associations of all metals, essential-metals, and non-essential metals on gestational glucose concentrations were all null, however, we observed evidences of interaction for barium and lead. Overall, we found early pregnancy barium and mercury erythrocytic concentrations were associated with altered post-load glucose concentrations in later pregnancy, with potential interactions between barium and lead.
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http://dx.doi.org/10.1016/j.envint.2021.106690DOI Listing
October 2021

Physical Activity as a Critical Component of First-Line Treatment for Elevated Blood Pressure or Cholesterol: Who, What, and How?: A Scientific Statement From the American Heart Association.

Hypertension 2021 Aug 2;78(2):e26-e37. Epub 2021 Jun 2.

Current guidelines published by the American Heart Association and the American College of Cardiology broadly recommend lifestyle approaches to prevent and treat elevated blood pressure and cholesterol. For patients with mildly or moderately elevated blood pressure and blood cholesterol, lifestyle-only approaches are the first line of therapy. The purpose of this scientific statement is to: (1) highlight the mild-moderate-risk patient groups indicated for lifestyle-only treatment for elevated blood pressure or cholesterol; (2) describe recommendations, average effects, and additional considerations when prescribing lifestyle treatment with physical activity; and (3) provide guidance and resources for clinicians to assess, prescribe, counsel, and refer to support increased physical activity in their patients. An estimated 21% and 28% to 37% of US adults, respectively, have mild-moderate-risk blood pressure and cholesterol and should receive lifestyle-only as first-line treatment. Of the recommended lifestyle changes, increasing physical activity has extensive benefits, including improving both blood pressure and blood cholesterol, that are comparable, superior, or complementary to other healthy lifestyle changes. Physical activity assessment and prescription are an excellent lifestyle behavior treatment option for all patients, including for the large population of mild-moderate-risk patients with elevated blood pressure and blood cholesterol.
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http://dx.doi.org/10.1161/HYP.0000000000000196DOI Listing
August 2021

Diet and erythrocyte metal concentrations in early pregnancy-cross-sectional analysis in Project Viva.

Am J Clin Nutr 2021 08;114(2):540-549

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: Dietary sources of metals are not well established among pregnant women in the United States.

Objective: We aimed to perform a diet-wide association study (DWAS) of metals during the first trimester of pregnancy.

Methods: In early pregnancy (11.3 ± 2.8 weeks of gestation), 1196 women from Project Viva (recruited 1999-2002 in eastern Massachusetts) completed a validated FFQ (135 food items) and underwent measurements of erythrocyte metals [arsenic (As), barium, cadmium, cesium (Cs), copper, mercury (Hg), magnesium, manganese, lead (Pb), selenium (Se), zinc]. The DWAS involved a systematic evaluation and visualization of all bivariate relations for each food-metal combination. For dietary items with strong associations with erythrocyte metals, we applied targeted maximum likelihood estimations and substitution models to evaluate how hypothetical dietary interventions would influence metals' concentrations.

Results: Participants' mean ± SD age was 32.5 ± 4.5 y and prepregnancy BMI was 24.8 ± 5.4 kg/m2; they were mostly white (75.9%), college graduates (72.4%), married or cohabitating (94.6%), had a household income >$70,000/y (63.5%), and had never smoked (67.1%). Compared with other US-based cohorts, the overall diet quality of participants was above average, and concentrations of erythrocyte metals were lower. The DWAS identified significant associations of several food items with As, Hg, Pb, Cs, and Se; for example, As was higher for each SD increment in fresh fruit (11.5%; 95% CI: 4.9%, 18.4%), white rice (17.9%; 95% CI: 9.4%, 26.9%), and seafood (50.9%; 95% CI: 42.8%, 59.3%). Following the guidelines for pregnant women to consume ≤3 servings/wk of seafood was associated with lower As (-0.55 ng/g; 95% CI: -0.82, -0.28 ng/g) and lower Hg (-2.67 ng/g; 95% CI: -3.55, -1.80 ng/g). Substituting white rice with bread, pasta, tortilla, and potato was also associated with lower As (35%-50%) and Hg (35%-70%).

Conclusions: Our DWAS provides a systematic evaluation of diet-metals relations. Prenatal diet may be an important source of exposures to metals.
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http://dx.doi.org/10.1093/ajcn/nqab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326032PMC
August 2021

Residential PM exposure and the nasal methylome in children.

Environ Int 2021 08 16;153:106505. Epub 2021 Apr 16.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Rationale: PMinduced adverse effects on respiratory health may be driven by epigenetic modifications in airway cells. The potential impact of exposure duration on epigenetic alterations in the airways is not yet known.

Objectives: We aimed to study associations of fine particulate matter PM exposure with DNA methylation in nasal cells.

Methods: We conducted nasal epigenome-wide association analyses within 503 children from Project Viva (mean age 12.9 y), and examined various exposure durations (1-day, 1-week, 1-month, 3-months and 1-year) prior to nasal sampling. We used residential addresses to estimate average daily PM at 1 km resolution. We collected nasal swabs from the anterior nares and measured DNA methylation (DNAm) using the Illumina MethylationEPIC BeadChip. We tested 719,075 high quality autosomal CpGs using CpG-by-CpG and regional DNAm analyses controlling for multiple comparisons, and adjusted for maternal education, household smokers, child sex, race/ethnicity, BMI z-score, age, season at sample collection and cell-type heterogeneity. We further corrected for bias and genomic inflation. We tested for replication in a cohort from the Netherlands (PIAMA).

Results: In adjusted analyses, we found 362 CpGs associated with 1-year PM (FDR < 0.05), 20 CpGs passing Bonferroni correction (P < 7.0x10) and 10 Differentially Methylated Regions (DMRs). In 445 PIAMA participants (mean age 16.3 years) 11 of 203 available CpGs replicated at P < 0.05. We observed differential DNAm at/near genes implicated in cell cycle, immune and inflammatory responses. There were no CpGs or regions associated with PM levels at 1-day, 1-week, or 1-month prior to sample collection, although 2 CpGs were associated with past 3-month PM.

Conclusion: We observed wide-spread DNAm variability associated with average past year PM exposure but we did not detect associations with shorter-term exposure. Our results suggest that nasal DNAm marks reflect chronic air pollution exposure.
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http://dx.doi.org/10.1016/j.envint.2021.106505DOI Listing
August 2021

Longitudinal associations of fruit juice intake in infancy with DXA-measured abdominal adiposity in mid-childhood and early adolescence.

Am J Clin Nutr 2021 07;114(1):117-123

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: Excessive abdominal adiposity is associated with health risks in children and adults. Higher consumption of fruit juice and other sources of fructose has been shown to promote weight gain and specifically visceral adiposity in adulthood.

Objectives: We aimed to examine the longitudinal associations of fruit juice intake in infancy with visceral adiposity in mid-childhood and early adolescence.

Methods: We analyzed data from 783 participants in Project Viva, a US prebirth cohort. Our exposure was fruit juice intake at 1 y old. We measured visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAAT), and total abdominal adipose tissue (TAAT) in mid-childhood (mean age 7.8 ± 0.7 y) and early adolescence (13 ± 0.8 y) using DXA. We examined longitudinal associations of fruit juice intake at 1 y with VAT, SAAT, and TAAT area sex-specific standard deviation scores (SDSs) in mid-childhood and early adolescence using linear mixed models. We adjusted for child age at outcome, sex, race/ethnicity, age and BMI z-score at 1 y-questionnaire, maternal prepregnancy BMI, level of education, and prenatal sugar-sweetened beverage intake, paternal BMI, and median household income at birth.

Results: After adjusting for child and parental covariates, each serving (120 mL) per day of fruit juice intake at 1 y was associated with persistently greater VAT area SDS (β = 0.08; 95% CI: 0.03, 0.13) at both timepoints in boys and girls. The association of fruit juice intake with VAT appeared stronger than that with SAAT (β = 0.05; 95% CI: 0.00, 0.09) and TAAT (β = 0.05; 95% CI: 0.01, 0.10).

Conclusions: Higher fruit juice intake in infancy was associated with greater abdominal adiposity, particularly VAT, in mid-childhood and early adolescence. Our findings support limiting fruit juice intake in infancy, which can have later impact on visceral adiposity in childhood and adolescence.Clinical Trial Registry number: NCT02820402 (https://clinicaltrials.gov/ct2/show/NCT02820402).
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http://dx.doi.org/10.1093/ajcn/nqab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246602PMC
July 2021

Cesarean delivery and metabolic health and inflammation biomarkers during mid-childhood and early adolescence.

Pediatr Res 2021 Apr 6. Epub 2021 Apr 6.

Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.

Background: We assessed differences in plasma levels of metabolic health and inflammation biomarkers during mid-childhood and early adolescence between children born by cesarean section vs. vaginal delivery.

Methods: Mother-child pairs (N = 942) enrolled during pregnancy in obstetric practices and child follow-up started at birth. Risk biomarkers were assessed in blood samples collected at the mild-childhood (median = 7 years) and early adolescence (median = 13 years) in-person visits.

Results: Two hundred and six children (22%) were born by cesarean section. There were no significant differences in biomarker levels between children born by cesarean and children born vaginally in mid-childhood. However, adolescents born by cesarean section had significantly lower adiponectin [% difference (95% confidence interval (CI)) = -11.3 (-18.1, -4.0) µg/mL] compared to vaginal delivery. We also found some suggestion of higher insulin resistance [insulin levels % difference (95% CI) = 11.5 (-0.40, 25.0) µU/mL and HOMA-IR (homeostatic model assessment of insulin resistance) % difference (95% CI) = 9.1 (-2.30, 21.8) U] in adolescents born by cesarean section compared to those born vaginally.

Conclusions: We found suggestive evidence that adolescents born by cesarean section show differences in certain metabolic health biomarkers relative to adolescents born by vaginal delivery. Further studies are needed to reevaluate these associations since the clinical significance of these differences is unclear.

Impact: Multiple studies show that children born by cesarean section are at higher risk of obesity compared to those born vaginally. It is unclear yet to what extent this elevated risk may extend to a more adverse profile of biomarkers of metabolic health and inflammation. Adolescents born by cesarean section show small differences in adiponectin and insulin relative to adolescents born by vaginal delivery. Adolescents born by cesarean section may be at higher risk to a more adverse profile of biomarkers of metabolic health and inflammation, but the clinical significance of these differences is uncertain.
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http://dx.doi.org/10.1038/s41390-021-01503-9DOI Listing
April 2021

DNA methylation architecture of the ACE2 gene in nasal cells of children.

Sci Rep 2021 03 29;11(1):7107. Epub 2021 Mar 29.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converting Enzyme 2 (ACE2) receptors, highly expressed in nasal epithelium with parallel high infectivity. The nasal epigenome is in direct contact with the environment and could explain COVID-19 disparities by reflecting social and environmental influences on ACE2 regulation. We collected nasal swabs from anterior nares of 547 children, measured DNA methylation (DNAm), and tested differences at 15 ACE2 CpGs by sex, age, race/ethnicity and epigenetic age. ACE2 CpGs were differentially methylated by sex with 12 sites having lower DNAm (mean = 12.71%) and 3 sites greater DNAm (mean = 1.45%) among females relative to males. We observed differential DNAm at 5 CpGs for Hispanic females (mean absolute difference = 3.22%) and lower DNAm at 8 CpGs for Black males (mean absolute difference = 1.33%), relative to white participants. Longer DNAm telomere length was associated with greater ACE2 DNAm at 11 and 13 CpGs among males (mean absolute difference = 7.86%) and females (mean absolute difference = 8.21%), respectively. Nasal ACE2 DNAm differences could contribute to our understanding COVID-19 severity and disparities reflecting upstream environmental and social influences. Findings need to be confirmed among adults and patients with risk factors for COVID-19 severity.
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http://dx.doi.org/10.1038/s41598-021-86494-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007733PMC
March 2021

Childhood patterns of overweight and wheeze and subsequent risk of current asthma and obesity in adolescence.

Paediatr Perinat Epidemiol 2021 Sep 22;35(5):569-577. Epub 2021 Mar 22.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: Obesity and asthma in childhood often co-occur. Few studies have examined this relationship using repeated measures of body mass index (BMI) or asthma symptoms (such as wheeze).

Objective: We compared two analytic approaches for repeated measures data to investigate this relationship.

Methods: Our baseline sample consisted of 1277 children enrolled in a Boston-area cohort with BMI or wheeze at age 1 year and no missing covariates. We used latent class growth models (LCGM) and inverse probability weighting (IPW) of marginal structural models to examine the extent to which presence of overweight across childhood was associated with early adolescent current asthma, and conversely of repeated measures of wheeze across childhood with early adolescent obesity.

Results: Using LCGM, a "persistent" childhood overweight class (vs "never") was associated with higher risk of asthma in early adolescence (RR 1.9; 95% CI 1.1, 3.0), while "persistent" childhood wheeze (vs "never") was associated with higher risk of obesity in early adolescence (RR 2.7; 95% CI 1.0, 6.4) after adjusting for baseline covariates. An IPW analysis treating childhood overweight and wheeze as time-varying exposures and adjusting for baseline and time-varying covariates resulted in weaker and less precise associations of "persistent" (vs "never") overweight with adolescent asthma (RR 1.3; 95% CI 0.3, 3.0), and of "persistent" (vs "never") wheeze with adolescent obesity (RR 2.3; 95% CI 0.4, 5.3).

Conclusion: Our point estimates from both approaches suggest an association between "persistent" childhood overweight and adolescent asthma, and between "persistent" childhood wheeze and adolescent obesity. LCGM results were stronger and more precise, whereas IPW results were less conclusive with wider 95% confidence intervals containing the null. The precision gained from LCGM may be at the expense of bias, and the use of both approaches helps to shed some light on this tradeoff.
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http://dx.doi.org/10.1111/ppe.12760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380670PMC
September 2021

Maternal glucose in pregnancy is associated with child's adiposity and leptin at 5 years of age.

Pediatr Obes 2021 Sep 16;16(9):e12788. Epub 2021 Mar 16.

Faculty of Medicine and Health Sciences, Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.

Background: Exposure to maternal hyperglycaemia in pregnancy has been associated with childhood obesity. Leptin regulation might be involved in this 'adiposity programming' and may depend on timing of exposure.

Objectives: To investigate associations of maternal glycaemia at different periods in pregnancy with childhood adiposity and leptin levels at 5 years of age.

Methods: In a prospective pre-birth cohort, we measured maternal glucose levels after a 50 g oral glucose challenge test at first trimester (9.8 ± 2.3 weeks) and during a 75 g oral glucose tolerance test at second trimester (26.5 ± 0.9 weeks). We followed up children at 5 years; we measured anthropometry and body composition using dual-energy X-ray absorptiometry (DXA). We measured fasting leptin levels using immunoassays (Luminex) in 328 children. We conducted linear regression analyses, adjusting for potential confounders.

Results: Maternal glycaemia at first trimester was associated with childhood leptin levels at 5 years, independently of maternal pre-pregnancy BMI and other confounders (β = .09 ± .04; P = .03). Higher post-load glucose levels at second trimester were associated with greater total body fat percentage measured by DXA (1 hour-glucose: β = .010 ± .004; P = .03 and 2 hours-glucose: β = .016 ± .005; P = .002), but not with leptin levels.

Conclusions: Our results suggest that programming of leptin regulation may be sensitive to maternal hyperglycaemia specifically in early pregnancy.
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http://dx.doi.org/10.1111/ijpo.12788DOI Listing
September 2021

Comparative epigenome-wide analysis highlights placenta-specific differentially methylated regions.

Epigenomics 2021 Mar 4;13(5):357-368. Epub 2021 Mar 4.

Département de Biologie, Université de Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada.

The placenta undergoes DNA methylation (DNAm) programming that is unique compared with all other fetal tissues. We aim to decipher some of the physiologic roles of the placenta by comparing its DNAm profile with that of another fetal tissue. We performed a comparative analysis of genome-wide DNAm of 444 placentas paired with cord blood samples collected at birth. Gene ontology term analyses were conducted on the resulting differentially methylated regions. Genomic regions upstream of transcription start sites showing lower DNAm in the placenta were enriched with terms related to miRNA functions and genes encoding G-protein-coupled receptors. These results highlight genomic regions that are differentially methylated in the placenta in contrast to fetal blood.
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http://dx.doi.org/10.2217/epi-2020-0271DOI Listing
March 2021

Detecting differentially methylated regions with multiple distinct associations.

Epigenomics 2021 Mar 1;13(6):451-464. Epub 2021 Mar 1.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.

We evaluated five methods for detecting differentially methylated regions (DMRs): DMRcate, comb-p, seqlm, GlobalP and dmrff. We used a simulation study and real data analysis to evaluate performance. Additionally, we evaluated the use of an ancestry-matched reference cohort to estimate correlations between CpG sites in cord blood. Several methods had inflated Type I error, which increased at more stringent significant levels. In power simulations with 1-2 causal CpG sites with the same direction of effect, dmrff was consistently among the most powerful methods. This study illustrates the need for more thorough simulation studies when evaluating novel methods. More work must be done to develop methods with well-controlled Type I error that do not require individual-level data.
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http://dx.doi.org/10.2217/epi-2020-0344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023344PMC
March 2021

Per- and polyfluoroalkyl substances and calcifications of the coronary and aortic arteries in adults with prediabetes: Results from the diabetes prevention program outcomes study.

Environ Int 2021 06 22;151:106446. Epub 2021 Feb 22.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals that have been associated with cardiovascular risk factors including elevated body weight and hypercholesterolemia. Therefore, PFAS may contribute to the development of atherosclerosis and cardiovascular disease (CVD). However, no previous study has evaluated associations between PFAS exposure and arterial calcification.

Methods And Results: This study used data from 666 prediabetic adults enrolled in the Diabetes Prevention Program trial who had six PFAS quantified in plasma at baseline and two years after randomization, as well as measurements of coronary artery calcium (CAC) and ascending (AsAC) and descending (DAC) thoracic aortic calcification 13-14 years after baseline. We performed multinomial regression to test associations between PFAS and CAC categorized according to Agatston score [low (<10), moderate (11-400) and severe (>400)]. We used logistic regression to assess associations between PFAS and presence of AsAC and DAC. We adjusted models for baseline sex, age, BMI, race/ethnicity, cigarette smoking, education, treatment assignment (placebo or lifestyle intervention), and statin use. PFAS concentrations were similar to national means; 53.9% of participants had CAC > 11, 7.7% had AsAC, and 42.6% had DAC. Each doubling of the mean sum of plasma concentrations of linear and branched isomers of perfluorooctane sulfonic acid (PFOS) was associated with 1.49-fold greater odds (95% CI: 1.01, 2.21) of severe versus low CAC. This association was driven mainly by the linear (n-PFOS) isomer [1.54 (95% CI: 1.05, 2.25) greater odds of severe versus low CAC]. Each doubling of mean plasma N-ethyl-perfluorooctane sulfonamido acetic acid concentration was associated with greater odds of CAC in a dose-dependent manner [OR = 1.26 (95% CI:1.08, 1.47) for moderate CAC and OR = 1.37 (95% CI:1.07, 1.74) for severe CAC, compared to low CAC)]. Mean plasma PFOS and n-PFOS were also associated with greater odds of AsAC [OR = 1.67 (95% CI:1.10, 2.54) and OR = 1.70 (95% CI:1.13, 2.56), respectively], but not DAC. Other PFAS were not associated with outcomes.

Conclusions: Prediabetic adults with higher plasma concentrations of select PFAS had higher risk of coronary and thoracic aorta calcification. PFAS exposure may be a risk factor for adverse cardiovascular health among high-risk populations.
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http://dx.doi.org/10.1016/j.envint.2021.106446DOI Listing
June 2021

DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts.

Clin Epigenetics 2021 02 23;13(1):40. Epub 2021 Feb 23.

MRC Integrative Epidemiology, Bristol Medical School, Bristol, BS8 2BN, UK.

Background: Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones.

Results: We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R = 10.6%).

Conclusions: This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.
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http://dx.doi.org/10.1186/s13148-021-01027-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903628PMC
February 2021

Separating Algorithms From Questions and Causal Inference With Unmeasured Exposures: An Application to Birth Cohort Studies of Early Body Mass Index Rebound.

Am J Epidemiol 2021 07;190(7):1414-1423

Observational studies reporting on adjusted associations between childhood body mass index (BMI; weight (kg)/height (m)2) rebound and subsequent cardiometabolic outcomes have often not paid explicit attention to causal inference, including definition of a target causal effect and assumptions for unbiased estimation of that effect. Using data from 649 children in a Boston, Massachusetts-area cohort recruited in 1999-2002, we considered effects of stochastic interventions on a chosen subset of modifiable yet unmeasured exposures expected to be associated with early (
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http://dx.doi.org/10.1093/aje/kwab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245877PMC
July 2021
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