Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels.

Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5-C-phosphate-G-3 (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother-child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (β = -2.69, p = 0.05) and fat distribution (β = -0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (β = -0.01, p = 0.04) and neonatal leptinemia (β = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood

Allele length of the DMPK CTG repeat is a predictor of progressive myotonic dystrophy type 1 phenotypes

Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited disorder caused by expansion of a germline and somatically unstable CTG repeat in the DMPK gene. Previously, CTG repeat length at birth has been correlated to patient age at symptom onset. Attempts to correlate CTG repeat length with progressive DM1 phenotypes, such as muscle power, have proven difficult. To better correlate genotype with progressive phenotypes, we have measured CTG repeat tract length and screened for interrupting variant repeats in 192 study participants from a well-characterized Canadian cohort. We have assessed genotype–phenotype correlations with nine progressive measures of skeletal muscle power and respiratory function. We have built statistical models that include confounding factors such as sex, age, height and weight to further explain variation in muscle power. Our analysis reveals a strong correlation between DM1 genotype and respiratory function and skeletal muscle power, as part of a complex model that includes additional modulators such as sex, age, height, weight and the presence or absence of interrupting variant repeats. Distal skeletal muscle measurements, such as hand pinch and grip strength, show the strongest correlation with disease genotype. Detailed analysis of CTG repeat length, and incorporation of confounding factors, greatly improves the predictive ability of these models. They reveal a greater genetic influence on individual progressive phenotypes than on age at symptom onset and for clinical trials will help optimize stratification and explain patient variability. They will also help practitioners prioritize assessment of the muscular power measurements that correlate best with disease severity

Acetylsalicylic acid, aging and coronary artery disease are associated with ABCA1 DNA methylation in men

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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

Facteurs déterminants de l’attitude des professionnels en santé mentale envers le rétablissement - une revue de littérature

Objective: The attitudes of mental health professionals towards consumers’ recovery are far more pessimistic than what is needed for the recovery-orientation to truly permeate systems of care. It has become pressing to depict determinants for these attitudes and how they evolve during professionalization. This, in the hopes to adjust not only medical education, but also ongoing training of professionals. Methods: A systematic search of PubMed and PsycINFO databases was conducted, yielding a net 15 303 records. Twenty-two publications from specific educational journals and reference lists were added. Finally, thirty-four full texts were read, from which twenty-two articles were included. Results: From the reviewed studies emerged five main determinants: profession, education, age, clinical experience, and nature of the contact with consumers. Traditional clinical placements during residency, negative experiences with acute patients, younger age and the professional attitudes of psychiatrists seem to all be determining factors for professionals’ pessimistic attitudes towards recovery. Conclusions: This review found specific determinants for attitudes in recovery and four out of five can be acted upon. For a recovery-orientation to be implemented across our mental health system, we formulate recommendations within the Canadian context for revision of curriculum, recovery-specific training, and operationalisation through state/provincial technical assistance centers

Familial resemblance in eating behaviors in men and women from the Quebec Family Study

Objective: It is commonly recognized that genetic, environmental, behavioral, and social factors are involved in the development of obesity. The family environment may play a key role in shaping children's eating behaviors. The purpose of this study was to estimate the degree of familial resemblance in eating behavioral traits (cognitive dietary restraint, disinhibition, and susceptibility to hunger). Research Methods and Procedures: Eating behavioral traits were assessed with the Three-Factor Eating Questionnaire in 282 men and 402 women (202 families) from the Quebec Family Study. Familial resemblance for each trait (adjusted for age, sex, and BMI) was investigated using a familial correlation model. Results: The pattern of familial correlation showed significant spouse correlation for the three eating behavior phenotypes, as well as significant parent-offspring and sibling correlations for disinhibition and susceptibility to hunger. According to the most parsimonious model, generalized heritability estimates (including genetic and shared familial environmental effects) reached 6%, 18%, and 28% for cognitive dietary restraint, disinhibition, and susceptibility to hunger, respectively. Discussion: These results suggest that there is a significant familial component to eating behavioral traits but that the additive genetic component appears to be small, with generalized heritability estimates ranging from 6% to 28%. Thus, non-familial environmental factors and gene-gene and gene-environmental interactions seem to be the major determinants of the eating/behavioral traits

gene DNA methylation levels are associated with muscular and respiratory profiles in DM1

Objective: To assess the effects of dystrophia myotonica protein kinase (DMPK) DNA methylation (DNAme) epivariation on muscular and respiratory profiles in patients with myotonic dystrophy type 1 (DM1). Methods: Phenotypes were assessed with standardized measures. Pyrosequencing of bisulfite-treated DNA was used to quantify DNAme levels in blood from 90 patients with DM1 (adult form). Modal CTG repeat length was assessed using small-pool PCR. The presence of Acil-sensitive variant repeats was also tested. Results: DNAme levels upstream of the CTG expansion (exon and intron 11) were correlated with modal CTG repeat length (rs = −0.224, p = 0.040; rs = −0.317, p = 0.003; and rs = −0.241, p = 0.027), whereas correlations were observed with epivariations downstream of the CTG repeats (rs = 0.227; p = 0.037). The presence of a variant repeat was associated with higher DNAme levels at multiple CpG sites (up to 10% higher; p = 0.001). Stepwise multiple linear regression modeling showed that DNAme contributed significantly and independently to explain phenotypic variability in ankle dorsiflexor (3 CpGs: p = 0.001, 0.013, and 0.001), grip (p = 0.089), and pinch (p = 0.028) strengths and in forced vital capacity (2 CpGs: p = 0.002 and 0.021) and maximal inspiratory pressure (p = 0.012). Conclusions: In addition to the CTG repeat length, DMPK epivariations independently explain phenotypic variability in DM1 and could thus improve prognostic accuracy for patients

Maternal lipid profile differs by gestational diabetes physiologic subtype

Aim To characterize lipid profiles in women with different gestational diabetes mellitus (GDM) physiologic subtypes. Methods We measured seven lipid markers (total cholesterol, LDL, HDL, triglycerides, non-esterified fatty acids (NEFA), ApoA, ApoB) in fasting plasma collected in a prospective cohort of 805 pregnant women during second trimester. We estimated insulin sensitivity and secretion using oral glucose tolerance test-based validated indices. We categorized GDM physiologic subtypes by insulin sensitivity and secretion defects defined as values below the 25th percentile among women with normal glucose tolerance (NGT), as previously established. We compared lipid markers across NGT and GDM subtypes. We explored associations between lipid markers and newborn anthropometry in the overall group and stratified by glucose tolerance status. Results Among 805 women, 67 (8.3%) developed GDM. Women with GDM had higher body mass index (BMI; 29.3 vs. 26.6 kg/m2), while ethnicity (97.3% vs. 97.0% European ancestry) and age (28 vs. 29 years) were similar. In comparison to women with NGT, women with GDM characterized by a predominant insulin sensitivity defect had significantly higher triglycerides (2.20 vs. 1.82, P = 0.002), lower HDL (1.64 vs. 1.90, P = 0.01) and higher NEFA (0.34 vs. 0.24, P < 0.0001). GDM women with a predominant insulin secretion defect differed from women with NGT with respect to NEFA (0.32 vs. 0.24, P = 0.003) while other lipid markers were similar. These associations remained significant after adjusting for maternal age and BMI. Greater maternal levels of NEFA were associated with higher birth weight z-scores in women with an insulin secretion defect (BMI-adjusted r = 0.58, P = 0.01). We did not find significant associations between other lipid markers and newborn anthropometry in other groups. Conclusion Women with GDM have distinct lipid profiles based on their GDM physiologic subtype which may not be apparent when investigating GDM as a single group

DUSP1 gene polymorphisms are associated with obesity-related metabolic complications among severely obese patients and impact on gene methylation and expression

The DUSP1 gene encodes a member of the dual-specificity phosphatase family previously identified as being differentially expressed in visceral adipose tissue (VAT) of severely obese men with versus without the metabolic syndrome. Objective. To test the association between DUSP1 polymorphisms, obesity-related metabolic complications, gene methylation, and expression levels in VAT. Methods. The DUSP1 locus and promoter region were sequenced in 25 individuals. SNPs were tested for association with obesity-related complications in a cohort of more than 1900 severely obese individuals. The impact of SNPs on methylation levels of 36 CpG sites and correlations between DNA methylation and gene expression levels in VAT were computed in a subset of 14 samples. Results. Heterozygotes for rs881150 had lower HDL-cholesterol levels (HDL-C; = 0.01), and homozygotes for the minor allele of rs13184134 and rs7702178 had increased fasting glucose levels ( = 0.04 and 0.01, resp.). rs881150 was associated with methylation levels of CpG sites located ∼1250 bp upstream the transcription start site. Methylation levels of 4 CpG sites were inversely correlated with DUSP1 gene expression. Conclusion.These results suggest that DUSP1 polymorphisms modulate plasma glucose and HDL-C levels in obese patients possibly through alterations of DNA methylation and gene expression levels