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1.  Prenatal Exposure to Maternal Cigarette Smoking and DNA Methylation: Epigenome-Wide Association in a Discovery Sample of Adolescents and Replication in an Independent Cohort at Birth through 17 Years of Age 
Environmental Health Perspectives  2014;123(2):193-199.
Background: Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth.
Objective: We examined whether such alterations are present from birth through adolescence.
Methods: We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447).
Results: In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 × 10–11) and CNTNAP2 (cg25949550, p = 4.0 × 10–9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study)–significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort.
Conclusions: Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years—at least until adolescence.
Citation: Lee KW, Richmond R, Hu P, French L, Shin J, Bourdon C, Reischl E, Waldenberger M, Zeilinger S, Gaunt T, McArdle W, Ring S, Woodward G, Bouchard L, Gaudet D, Davey Smith G, Relton C, Paus T, Pausova Z. 2015. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect 123:193–199;
PMCID: PMC4314251  PMID: 25325234
2.  Prenatal exposure to cigarette smoke interacts with OPRM1 to modulate dietary preference for fat 
Preference for fatty foods is a risk factor for obesity. It is a complex behaviour that involves the brain reward system and is regulated by genetic and environmental factors, such as the opioid receptor mu-1 gene (OPRM1) and prenatal exposure to maternal cigarette smoking (PEMCS). We examined whether OPRM1 and PEMCS interact in influencing fat intake and whether exposure-associated epigenetic modifications of OPRM1 may mediate this gene–environment interaction.
We studied adolescents from a French Canadian genetic founder population, half of whom were exposed prenatally to maternal cigarette smoking. Fat intake was assessed with a 24-hour food recall in the form of a structured interview conducted by a trained nutritionist. The OPRM1 variant rs2281617 was genotyped for the whole sample with the Illumina Human610-Quad and HumanOmniExpress BeadChips. Methylation of blood DNA was assessed at 21 CpGs across OPRM1 in a subset of the sample using the Illumina HumanMethylation450 BeadChip.
We included 956 adolescents in our study. In the whole sample, OPRM1 (T carrier in rs2281617) was associated with lower fat intake (−1.6%, p = 0.017), and PEMCS was associated with higher fat intake (+1.6%, p = 0.005). OPRM1 and PEMCS interacted with each other (p = 0.003); the “protective” (fat intake–lowering) allele of OPRM1 was associated with lower fat intake in nonexposed (−3.2%, p < 0.001) but not in exposed individuals (+0.8%, p = 0.42). Further, PEMCS was associated with lower DNA methylation across multiple CpGs across OPRM1 in exposed versus nonexposed individuals (p = 0.031).
A limitation of our study was its cross-sectional design.
Our study suggests that PEMCS may interact with OPRM1 in increasing fat preference. Silencing of the protective OPRM1 allele in exposed adolescents might be related to epigenetic modification of this gene.
PMCID: PMC4275330  PMID: 25266401
4.  Adaptations of placental and cord blood ABCA1 DNA methylation profile to maternal metabolic status 
Epigenetics  2013;8(12):1289-1302.
In utero environmental perturbations have been associated with epigenetic changes in the offspring and a lifelong susceptibility to cardiovascular diseases (CVD). DNA methylation at the ATP-binding cassette transporter A1 (ABCA1) gene was previously associated with CVD, but whether these epigenetic marks respond to changes in the maternal environment is unknown. This study was undertaken to assess the associations between the maternal metabolic profile and ABCA1 DNA methylation levels in placenta and cord blood. Placenta and cord blood samples were obtained at delivery from 100 women including 26 with impaired glucose tolerance (IGT) diagnosed following a 75 g-oral glucose tolerance test (OGTT) between week 24 and 28 of gestation. ABCA1 DNA methylation and mRNA levels were measured using bisulfite pyrosequencing and quantitative real-time PCR, respectively. We report that ABCA1 DNA methylation levels on the maternal side of the placenta are correlated with maternal high density lipoprotein cholesterol (HDL-C) levels (r < –0.21; P < 0.04) and glucose levels 2 h post-OGTT (r = 0.25; P = 0.02). On the fetal side of the placenta, ABCA1 DNA methylation levels are associated with cord blood triglyceride levels (r = –0.28; P = 0.01). ABCA1 DNA methylation variability on both sides of the placenta are also associated with ABCA1 mRNA levels (r < –0.35; P = 0.05). As opposed to placenta, cord blood DNA methylation levels are negatively correlated with maternal glucose 2 h post-OGTT (r = –0.26; P = 0.02). In conclusion, the epivariations observed in placenta and cord blood likely contribute to an optimal materno–fetal cholesterol transfer. These in utero epigenetics adaptations may also potentially trigger the long-term susceptibility of the newborn to dyslipidemia and CVD.
PMCID: PMC3933490  PMID: 24113149
Gestational diabetes; high-density lipoprotein cholesterol; fetal programming; lipid metabolism; epigenetics
5.  Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies 
Diabetes  2013;62(9):3282-3291.
Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks’ gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.
PMCID: PMC3749326  PMID: 23903356
6.  Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases 
Epigenetics  2013;8(9):935-943.
Offspring exposed to gestational diabetes mellitus (GDM) have an increased risk for chronic diseases, and one promising mechanism for fetal metabolic programming is epigenetics. Therefore, we postulated that GDM exposure impacts the offspring’s methylome and used an epigenomic approach to explore this hypothesis. Placenta and cord blood samples were obtained from 44 newborns, including 30 exposed to GDM. Women were recruited at first trimester of pregnancy and followed until delivery. GDM was assessed after a 75-g oral glucose tolerance test at 24–28 weeks of pregnancy. DNA methylation was measured at > 485,000 CpG sites (Infinium HumanMethylation450 BeadChips). Ingenuity Pathway Analysis was conducted to identify metabolic pathways epigenetically affected by GDM. Our results showed that 3,271 and 3,758 genes in placenta and cord blood, respectively, were potentially differentially methylated between samples exposed or not to GDM (p-values down to 1 × 10−06; none reached the genome-wide significance levels), with more than 25% (n = 1,029) being common to both tissues. Mean DNA methylation differences between groups were 5.7 ± 3.2% and 3.4 ± 1.9% for placenta and cord blood, respectively. These genes were likely involved in the metabolic diseases pathway (up to 115 genes (11%), p-values for pathways = 1.9 × 10−13 < p < 4.0 × 10−03; including diabetes mellitus p = 4.3 × 10−11). Among the differentially methylated genes, 326 in placenta and 117 in cord blood were also associated with newborn weight. Our results therefore suggest that GDM has epigenetic effects on genes preferentially involved in the metabolic diseases pathway, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming.
PMCID: PMC3883770  PMID: 23975224
epigenetics; epigenome-wide; in utero; maternal hyperglycemia; DNA methylation; fetal metabolic programming
7.  Acetylsalicylic acid, aging and coronary artery disease are associated with ABCA1 DNA methylation in men 
Clinical Epigenetics  2014;6(1):14.
Previous studies have suggested that DNA methylation contributes to coronary artery disease (CAD) risk variability. DNA hypermethylation at the ATP-binding cassette transporter A1 (ABCA1) gene, an important modulator of high-density lipoprotein cholesterol and reverse cholesterol transport, has been previously associated with plasma lipid levels, aging and CAD, but the association with CAD has yet to be replicated.
ABCA1 DNA methylation levels were measured in leucocytes of 88 men using bis-pyrosequencing. We first showed that DNA methylation at the ABCA1 gene promoter locus is associated with aging and CAD occurrence in men (P < 0.05). The latter association is stronger among older men with CAD (≥61 years old; n = 19), who showed at least 4.7% higher ABCA1 DNA methylation levels as compared to younger men with CAD (<61 years old; n = 19) or men without CAD (n = 50; P < 0.001). Higher ABCA1 DNA methylation levels in older men were also associated with higher total cholesterol (r = 0.34, P = 0.03), low-density lipoprotein cholesterol (r = 0.32, P = 0.04) and triglyceride levels (r = 0.26, P = 0.09). Furthermore, we showed that acetylsalicylic acid therapy is associated with 3.6% lower ABCA1 DNA methylation levels (P = 0.006), independent of aging and CAD status of patients.
This study provides new evidence that the ABCA1 epigenetic profile is associated with CAD and aging, and highlights that epigenetic modifications might be a significant molecular mechanism involved in the pathophysiological processes associated with CAD. Acetylsalicylic acid treatment for CAD prevention might involve epigenetic mechanisms.
PMCID: PMC4120725  PMID: 25093045
ATP-binding cassette transporter A1; Epigenetics; Aging; Cardiovascular disease
8.  Epigenetics and Fetal Metabolic Programming: A Call for Integrated Research on Larger Cohorts 
Diabetes  2013;62(4):1026-1028.
PMCID: PMC3609562  PMID: 23520280
9.  The Lipid Accumulation Product for the Early Prediction of Gestational Insulin Resistance and Glucose Dysregulation 
Journal of Women's Health  2013;22(4):362-367.
Recent insights linking insulin resistance and lipid overaccumulation suggest a novel approach for the early identification of women who may soon experience glucose dysregulation. Among women without a history of gestational diabetes, we tested the association between the lipid accumulation product (LAP) obtained in early pregnancy and glucose dysregulation or insulin resistance in the second trimester.
A total of 180 white pregnant women of French-Canadian origin were included in this study. At 11–14 weeks' gestation, fasting insulin, glucose, C-peptide concentrations, and estimated insulin resistance (HOMA-IR) were obtained. The waist circumference (WC) and fasting triglycerides (TG) were measured to calculate LAP as (WC[cm] − 58)×TG[mmol/L]. At 24–28 weeks' gestation, glucose was measured 2 hours after a 75-g oral glucose challenge and other fasting variables were repeated.
Among the nulliparous women tested at the end of the second trimester, fasting insulin, C-peptide, insulin resistance (HOMA-IR index), fasting glucose, and 2-hour glucose progressively increased (p≤0.002) according to their first-trimester LAP tertiles. Similar results were observed in parous women except for the glucose variables. The first-trimester LAP tended to show a stronger correlation to the second-trimester HOMA-IR index (r=0.56) than fasting triglyceride levels alone (r=0.40) or waist circumference alone (r=0.44) among nulliparous women. Similar associations were observed for parous women. Adjustment for body mass index weakened these associations, especially among parous women.
An increased value of LAP at the beginning of a pregnancy could be associated with an increased risk of insulin resistance or hyperglycemia later in gestation.
PMCID: PMC3627434  PMID: 23717842
10.  IGF2 DNA methylation is a modulator of newborn’s fetal growth and development 
Epigenetics  2012;7(10):1125-1132.
The insulin-like growth factor 2 (IGF2) gene, located within a cluster of imprinted genes on chromosome 11p15, encodes a fetal and placental growth factor affecting birth weight. DNA methylation variability at the IGF2 gene locus has been previously reported but its consequences on fetal growth and development are still mostly unknown in normal pediatric population. We collected one hundred placenta biopsies from 50 women with corresponding maternal and cord blood samples and measured anthropometric indices, blood pressure and metabolic phenotypes using standardized procedures. IGF2/H19 DNA methylation and IGF2 circulating levels were assessed using sodium bisulfite pyrosequencing and ELISA, respectively. Placental IGF2 (DMR0 and DMR2) DNA methylation levels were correlated with newborn’s fetal growth indices, such as weight, and with maternal IGF2 circulating concentration at the third trimester of pregnancy, whereas H19 (DMR) DNA methylation levels were correlated with IGF2 levels in cord blood. The maternal genotype of a known IGF2/H19 polymorphism (rs2107425) was associated with birth weight. Taken together, we showed that IGF2/H19 epigenotype and genotypes independently account for 31% of the newborn’s weight variance. No association was observed with maternal diabetic status, glucose concentrations or prenatal maternal body mass index. This is the first study showing that DNA methylation at the IGF2/H19 genes locus may act as a modulator of IGF2 newborn’s fetal growth and development within normal range. IGF2/H19 DNA methylation could represent a cornerstone in linking birth weight and fetal metabolic programming of late onset obesity.
PMCID: PMC3469454  PMID: 22907587
birth weight; epigenetics; fetal programming; imprinting; somatomedin A; IGF2 and H19
11.  Placental Adiponectin Gene DNA Methylation Levels Are Associated With Mothers’ Blood Glucose Concentration 
Diabetes  2012;61(5):1272-1280.
Growing evidence suggests that epigenetic profile changes occurring during fetal development in response to in utero environment variations could be one of the mechanisms involved in the early determinants of adult chronic diseases. In this study, we tested whether maternal glycemic status is associated with the adiponectin gene (ADIPOQ) DNA methylation profile in placenta tissue, in maternal circulating blood cells, and in cord blood cells. We found that lower DNA methylation levels in the promoter of ADIPOQ on the fetal side of the placenta were correlated with higher maternal glucose levels during the second trimester of pregnancy (2-h glucose after the oral glucose tolerance test; rs ≤ −0.21, P < 0.05). Lower DNA methylation levels on the maternal side of the placenta were associated with higher insulin resistance index (homeostasis model assessment of insulin resistance) during the second and third trimesters of pregnancy (rs ≤ −0.27, P < 0.05). Finally, lower DNA methylation levels were associated with higher maternal circulating adiponectin levels throughout pregnancy (rs ≤ −0.26, P < 0.05). In conclusion, the ADIPOQ DNA methylation profile was associated with maternal glucose status and with maternal circulating adiponectin concentration. Because adiponectin is suspected to have insulin-sensitizing proprieties, these epigenetic adaptations have the potential to induce sustained glucose metabolism changes in the mother and offspring later in life.
PMCID: PMC3331769  PMID: 22396200
12.  Fetal epigenetic programming of adipokines 
Adipocyte  2013;2(1):41-46.
Epigenetics generates a considerable interest in the field of research on complex traits, including obesity and diabetes. Recently, we reported a number of epipolymorphisms in the placental leptin and adiponectin genes associated with maternal hyperglycemia during pregnancy. Our results suggest that DNA methylation could partly explain the link between early exposure to a detrimental fetal environment and an increased risk to develop obesity and diabetes later in life. This brief report discusses the potential importance of adipokine epigenetic changes in fetal metabolic programming. Additionally, preliminary data showing similarities between methylation variations of different tissues and cell types will be presented along with the challenges and future perspectives of this emerging field of research.
PMCID: PMC3661130  PMID: 23700551
leptin; adiponectin; fetal programming; Barker hypothesis; gestational diabetes; placenta; DNA methylation; gene expression
13.  A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population 
BMC Medical Genetics  2012;13:72.
Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved.
We identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990–2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation.
A homozygous mutation (c.802_815del, p.[Val207_Gln294del, Val76_Gln294del]) in PEX6 was identified and then shown in 4 other patients. Parental heterozygosity was confirmed in all. Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55. In addition, we present data suggesting that this mutation abolishes a SF2/ASF splice enhancer binding site, resulting in the use of two alternative cryptic donor splice sites and predicted to encode an internally deleted in-frame protein.
We report increased incidence of ZS in French-Canadians of SLSJ caused by a PEX6 founder mutation. To our knowledge, this is the highest reported incidence of ZS worldwide. These findings have implications for carrier screening and support the utility of NGS for molecular confirmation of peroxisomal disorders.
PMCID: PMC3483250  PMID: 22894767
Zellweger syndrome; Founder effect; Peroxisome biogenesis disorders; Next generation sequencing
14.  Leptin Gene Epigenetic Adaptation to Impaired Glucose Metabolism During Pregnancy 
Diabetes Care  2010;33(11):2436-2441.
To verify whether the leptin gene epigenetic (DNA methylation) profile is altered in the offspring of mothers with gestational impaired glucose tolerance (IGT).
Placental tissues and maternal and cord blood samples were obtained from 48 women at term including 23 subjects with gestational IGT. Leptin DNA methylation, gene expression levels, and circulating concentration were measured using the Sequenom EpiTYPER system, quantitative real-time RT-PCR, and enzyme-linked immunosorbent assay, respectively. IGT was assessed after a 75-g oral glucose tolerance test (OGTT) at 24–28 weeks of gestation.
We have shown that placental leptin gene DNA methylation levels were correlated with glucose levels (2-h post-OGTT) in women with IGT (fetal side: ρ = −0.44, P ≤ 0.05; maternal side: ρ = 0.53, P ≤ 0.01) and with decreased leptin gene expression (n = 48; ρ ≥ −0.30, P ≤ 0.05) in the whole cohort. Placental leptin mRNA levels accounted for 16% of the variance in maternal circulating leptin concentration (P < 0.05).
IGT during pregnancy was associated with leptin gene DNA methylation adaptations with potential functional impacts. These epigenetic changes provide novel mechanisms that could contribute to explaining the detrimental health effects associated with fetal programming, such as long-term increased risk of developing obesity and type 2 diabetes.
PMCID: PMC2963508  PMID: 20724651
15.  The “hypertriglyceridemic waist” phenotype and glucose intolerance in pregnancy 
Abdominal visceral adiposity in early pregnancy has been associated with impaired glucose tolerance in later pregnancy. The “hypertriglyceridemic waist” phenotype (i.e., abdominal obesity in combination with hyper-triglyceridemia) is a clinical marker of visceral obesity. Our study aimed to assess the association between the hyper-triglyceridemic-waist phenotype in early pregnancy and glucose intolerance in later pregnancy.
Plasma triglycerides and waist girth were measured at 11–14 weeks of gestation among 144 white pregnant women. Glycemia was measured following a 75-g oral glucose tolerance test performed at 24–28 weeks of gestation.
A waist girth greater than 85 cm in combination with a triglyceride level ≥ 1.7 mmol/L in the first trimester was associated with an increased risk of two-hour glucose ≥ 7.8 mmol/L following the 75-g oral glucose tolerance test (odds ratio [OR] 6.1, p = 0.002). This risk remained significant even after we controlled for maternal age, fasting glucose at first trimester and previous history of gestational diabetes (OR 4.7, p = 0.02).
Measurement of waist girth in combination with measurement of triglyceride concentrations in the first trimester of pregnancy could improve early screening for gestational glucose intolerance.
PMCID: PMC2952030  PMID: 20855478

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