Person:

Hivert, Marie-France

The mechanisms that predispose to hypertension, coronary artery disease (CAD), and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy—a reduction in subcutaneous adipose tissue—it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, CAD, and T2D. We aimed to test the hypothesis that common alleles associated with IR also influence the wider clinical and biochemical profile of monogenic IR. We selected 19 common genetic variants associated with fasting insulin–based measures of IR. We used hierarchical clustering and results from genome-wide association studies of eight nondisease outcomes of monogenic IR to group these variants. We analyzed genetic risk scores against disease outcomes, including 12,171 T2D cases, 40,365 CAD cases, and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (β = 0.018; P = 4 × 10−29), lower HDL cholesterol (β = −0.020; P = 7 × 10−37), greater hepatic steatosis (β = 0.021; P = 3 × 10−4), higher alanine transaminase (β = 0.002; P = 3 × 10−5), lower sex-hormone-binding globulin (β = −0.010; P = 9 × 10−13), and lower adiponectin (β = −0.015; P = 2 × 10−26). The same risk alleles were associated with lower BMI (per-allele β = −0.008; P = 7 × 10−8) and increased visceral-to-subcutaneous adipose tissue ratio (β = −0.015; P = 6 × 10−7). Individuals carrying ≥17 fasting insulin–raising alleles (5.5% population) were slimmer (0.30 kg/m2) but at increased risk of T2D (odds ratio [OR] 1.46; per-allele P = 5 × 10−13), CAD (OR 1.12; per-allele P = 1 × 10−5), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg [per-allele P = 2 × 10−5] and 0.67 mmHg [per-allele P = 2 × 10−4], respectively) compared with individuals carrying ≤9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the “metabolic syndrome” and point to reduced subcutaneous adiposity as a central mechanism.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Background: Both higher and lower fetal growth are associated with cardio-metabolic health later in life, suggesting that prenatal developmental programming determines long-term cardiovascular disease risk. Epigenetic mechanisms, which orchestrate fetal growth and development, may offer insight on the early programming of health and disease. We investigated whether birth weight-for-gestational is associated with DNA methylation at birth and mid-childhood, measured via the Infinium 450K array. Methods/results Participants were from Project Viva, a pre-birth cohort of pregnant women and their children in Eastern Massachusetts. After exclusion of participants with maternal type 1 or 2 diabetes and gestational age <34 weeks, we used DNA methylation assays from 476 venous umbilical cord blood samples and a subset of 235 who additionally had peripheral blood samples available in mid-childhood (age 7–10 years). Among 392,918 CpG sites analyzed, birth weight-for-gestational age z-score was associated with cord blood DNA methylation at 34 CpGs (false discovery rate P < 0.05), after adjusting for maternal age, race/ethnicity, education, smoking, parity, delivery mode, pre-pregnancy BMI, gestational diabetes status, child sex, and estimated cord blood cell proportions based on a cord blood reference panel. Two of these CpGs were previously reported in epigenome-wide analyses of birth weight, and several other CpGs map to genes relevant to fetal growth and development. Namely, higher birth weight-for-gestational age was associated with higher methylation at four CpGs at the PBX1 locus (e.g., β (95% CI) for lead signal at cg06750897 = 1.9 (1.2, 2.6)), which encodes a transcription factor that regulates embryonic development. Birth weight-for-gestational age was also associated with mid-childhood blood DNA methylation at four of the 34 CpGs identified in cord blood analyses, including sites at the PBX1 locus described. Conclusions: We identified CpG sites where birth weight-for-gestational age was associated with DNA methylation at birth, and for a subset of these sites, birth weight-for-gestational age was also associated with DNA methylation at mid-childhood. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0285-3) contains supplementary material, which is available to authorized users.

Background: Excessive gestational weight gain (GWG) is associated with adverse pregnancy outcomes. In non-pregnant populations, low leptin levels stimulate positive energy balance. In pregnancy, both the placenta and adipose tissue contribute to circulating leptin levels. We tested whether maternal leptin levels are associated with subsequent GWG and whether this association varies depending on stage of pregnancy and on maternal body mass index (BMI). Methods: This prospective cohort study included 675 pregnant women followed from 1st trimester until delivery. We collected anthropometric measurements, blood samples at 1st and 2nd trimester, and clinical data until delivery. Maternal leptin was measured by ELISA (Luminex technology). We classified women by BMI measured at 1st trimester: BMI < 25 kg/m2 = normal weight; 25 ≤ BMI < 30 kg/m2 = overweight; and BMI ≥ 30 kg/m2 = obese. Results: Women gained a mean of 6.7 ± 3.0 kg between 1st and 2nd trimester (mid pregnancy GWG) and 5.6 ± 2.5 kg between 2nd and the end of 3rd trimester (late pregnancy GWG). Higher 1st trimester leptin levels were associated with lower mid pregnancy GWG, but the association was no longer significant after adjusting for % body fat (%BF; β = 0.38 kg per log-leptin; SE = 0.52; P = 0.46). Higher 2nd trimester leptin levels were associated with greater late pregnancy GWG and this association remained significant after adjustment for BMI (β = 2.35; SE = 0.41; P < 0.0001) or %BF (β = 2.01; SE = 0.42; P < 0.0001). In BMI stratified analyses, higher 2nd trimester leptin levels were associated with greater late pregnancy GWG in normal weight women (β = 1.33; SE = 0.42; P = 0.002), and this association was stronger in overweight women (β = 2.85; SE = 0.94; P = 0.003 – P for interaction = 0.05). Conclusions: Our results suggest that leptin may regulate weight gain differentially at 1st versus 2nd trimester of pregnancy: at 2nd trimester, higher leptin levels were associated with greater subsequent weight gain – the opposite of its physiologic regulation in non-pregnancy – and this association was stronger in overweight women. We suspect the existence of a feed-forward signal from leptin in second half of pregnancy, stimulating a positive energy balance and leading to greater weight gain. Electronic supplementary material The online version of this article (doi:10.1186/s12884-016-0842-y) contains supplementary material, which is available to authorized users.

ABSTRACT Cord blood is widely used as surrogate tissue in epigenome-wide association studies of prenatal conditions. Cell type composition variation across samples can be an important confounder of epigenome-wide association studies in blood that constitute a mixture of cells. We evaluated a newly developed cord blood reference panel to impute cell type composition from DNA methylation levels, including nucleated red blood cells (nRBCs). We estimated cell type composition from 154 unique cord blood samples with available DNA methylation data as well as direct measurements of nucleated cell types. We observed high correlations between the estimated and measured composition for nRBCs (r = 0.92, R2 = 0.85), lymphocytes (r = 0.77, R2 = 0.58), and granulocytes (r = 0.72, R2 = 0.52), and a moderate correlation for monocytes (r = 0.51, R2 = 0.25) as well as relatively low root mean square errors from the residuals ranging from 1.4 to 5.4%. These results validate the use of the cord blood reference panel and highlight its utility and limitations for epidemiological studies.

Purpose Hepatocyte nuclear factor 1 alpha (HNF1α) defects cause Mature Onset Diabetes of the Young type 3 (MODY3), characterized by defects in beta-cell insulin secretion. However, HNF1α is involved in many other metabolic pathways with relevance for monogenic or polygenic type 2 diabetes. We aimed to investigate gut hormones, lipids, and insulin regulation in response to a meal test in HNF1α defect carriers (MODY3) compared to non-diabetic subjects (controls) and type 2 diabetes (T2D). Methods: We administered a standardized liquid meal to each participant. Over 6 hours, we measured post-meal responses of insulin regulation (blood glucose, c-peptide, insulin), gut hormones (ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) and lipids (non-esterified fatty acids [NEFA] and triglycerides). Results: We found that MODY3 participants had lower insulin secretion indices than controls and T2D participants, showing the expected β-cell defect. MODY3 had similar glycated hemoglobin levels (HbA1c median [IQR]: 6.5 [5.6–7.6]%) compared to T2D (median: 6.6 [6.2–6.9]%; P<0.05). MODY3 had greater insulin sensitivity (Matsuda index: 71.9 [29.6; 125.5]) than T2D (3.2 [4.0; 6.0]; P<0.05). MODY3 experienced a larger decrease in the ratio of NEFA to insulin (NEFA 30–0 / insulin 30–0: -39 [-78; -30] x104) in the early post-prandial period (0–30 minutes) compared to controls and to T2D (-2.0 [-0.6; -6.4] x104; P<0.05). MODY3 had lower fasting (0.66 [0.46; 1.2] mM) and post-meal triglycerides levels compared to T2D (fasting: 2.3 [1.7; 2.7] mM; P<0.05). We did not detect significant post-meal differences in ghrelin and incretins between MODY3 and other groups. Conclusion: In response to a standard meal test, MODY3 showed greater early post-prandial NEFA diminution in response to relatively low early insulin secretion, and they maintained very low post-prandial triglycerides levels.

Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.

Prenatal exposure to mercury, a known neurotoxic metal, is associated with lower cognitive performance during childhood. Disruption of fetal epigenetic programming could explain mercury’s neurodevelopmental effects. We screened for epigenome-wide methylation differences associated with maternal prenatal blood mercury levels in 321 cord blood DNA samples and examined the persistence of these alterations during early (n = 75; 2.9–4.9 years) and mid-childhood (n = 291; 6.7–10.5 years). Among males, prenatal mercury levels were associated with lower regional cord blood DNA methylation at the Paraoxonase 1 gene (PON1) that persisted in early childhood and was attenuated in mid-childhood blood. Cord blood methylation at the PON1 locus predicted lower cognitive test scores measured during early childhood. Methylation at the PON1 locus was associated with PON1 expression in an independent set of cord blood samples. The observed persistent epigenetic disruption of the PON1 gene may modulate mercury toxicity in humans and might serve as a biomarker of exposure and disease susceptibility.

Background: Gestational weight gain (GWG) is an important predictor of short and long-term pregnancy outcomes for both mother and child, and women who set a GWG goal are more likely to gain within recommended ranges. Little information is available regarding potentially modifiable factors that underlie a woman’s GWG goals. Our aims were to explore women’s perceptions regarding factors that affect GWG, their understanding of appropriate GWG, their goal-setting experiences including patient-health care provider (HCP) conversations, and supportive interventions they would most like to help them achieve the recommended GWG. Methods: We conducted nine in-depth interviews and seven focus groups with a total of 33 Boston, Massachusetts (MA) area women who were pregnant and had delivered within the prior 6 months. We recorded and transcribed all interviews. Two investigators independently coded resulting transcripts. We managed data using MAXQDA2 and conducted a content analysis. Results: Perceived factors that contributed to GWG goal-setting included the mother’s weight control behaviors concerning exercise and diet—including a “new way of eating for two” and “semblance of control”, experiences during prior pregnancies, conversations with HCPs, and influence from various information sources. Women focused on behaviors with consistent messaging across multiple sources of information, but mainly trusted their HCP, valued one-to-one conversations with them about GWG, preferred that the HCP initiate the conversation about GWG goals, and would be open to have the conversation started based on visual aid based on their own GWG progression. Conclusions: Pregnant women highly value discussions with their HCP to set GWG goals. Pregnant women view their clinicians as the most reliable source of information and believe that clinicians should open weight-related discussions throughout pregnancy.

Background: Leptin (LEP) and adiponectin (ADIPOQ) genes encode adipokines that are mainly secreted by adipose tissues, involved in energy balance and suspected to play a role in the pathways linking adiposity to impaired glucose and insulin homeostasis. We have thus hypothesized that LEP and ADIPOQ DNA methylation changes might be involved in obesity development and its related complications. The objective of this study was to assess whether LEP and ADIPOQ DNA methylation levels measured in subcutaneous (SAT) and visceral adipose tissues (VAT) are associated with anthropometric measures and metabolic profile in severely obese men and women. These analyses were repeated with DNA methylation profiles from blood cells obtained from the same individuals to determine whether they showed similarities. Methods: Paired SAT, VAT and blood samples were obtained from 73 severely obese patients undergoing a bioliopancreatic diversion with duodenal switch. LEP and ADIPOQ DNA methylation and mRNA levels were quantified using bisulfite-pyrosequencing and qRT-PCR respectively. Pearson’s correlation coefficients were computed to determine the associations between LEP and ADIPOQ DNA methylation levels, anthropometric measures and metabolic profile. Results: DNA methylation levels at the ADIPOQ gene locus in SAT was positively associated with BMI and waist girth whereas LEP DNA methylation levels in blood cells were negatively associated with body mass index (BMI). Fasting LDL-C levels were found to be positively correlated with DNA methylation levels at LEP-CpG11 and -CpG17 in blood and SAT and with ADIPOQ DNA methylation levels in SAT (CpGE1 and CpGE3) and VAT (CpGE1). Conclusions: These results confirm that LEP and ADIPOQ epigenetic profiles are associated with obesity. We also report associations between LDL-C levels and both LEP and ADIPOQ DNA methylation levels suggesting that LDL-C might regulate their epigenetic profiles in adipose tissues. Furthermore, similar correlations were observed between LDL-C and LEP blood DNA methylation levels suggesting a common regulatory pathway of DNA methylation in both adipose tissues and blood. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0174-1) contains supplementary material, which is available to authorized users.