Prevalence of purging at age 16 and associations with negative outcomes among girls in three community-based cohorts.

The comorbidity of purging behaviours, such as vomiting, inappropriate use of laxatives, diuretics or slimming medications, has been examined in literature. However, most studies do not include adolescents, individuals who purge in the absence of binge eating, or those purging at subclinical frequency. This study examines the prevalence of purging among 16-year-old girls across three countries and their association with substance use and psychological comorbidity

Work-related stress and well-being in association with epigenetic age acceleration: a Northern Finland Birth Cohort 1966 Study

Recent evidence indicates consistent association of low socioeconomic status with epigenetic age acceleration, measured from DNA methylation. As work characteristics and job stressors are crucial components of socioeconomic status, we investigated their association with various measures of epigenetic age acceleration. The study population included employed and unemployed men and women (n=604) from the Northern Finland Birth Cohort 1966. We investigated the association of job strain, effort-reward imbalance and work characteristics with five biomarkers of epigenetic aging (Hannum, Horvath, PhenoAge, GrimAge, and DunedinPoAm). Our results indicate few significant associations between work stress indicators and epigenetic age acceleration, limited to a range of ±2 years, and smoking recording the highest effect on GrimAge age acceleration biomarker between current and no smokers (median difference 4.73 years (IQR 1.18, 8.41). PhenoAgeAA was associated with job strain active work (β=-1.301 95%CI -2.391, -0.212), slowing aging of less than 1.5 years, and working as white-collar slowed aging six months (GrimAgeAA β=-0.683, 95%CI -1.264, -0.102) when compared to blue collars. Association was found for working for more than 40 hours per week that increased the aging over 1.5 years, (HorvathAA β =2.058 95%CI 0.517,3.599, HannumAA β=1.567, 95%CI 0.415,2.719). The pattern of associations was different between women and men and some of the estimated effects are inconsistent with current literature. Our results provide the first evidence of association of work conditions with epigenetic aging biomarkers. However, further epidemiological research is needed to fully understand how work-related stress affects epigenetic age acceleration in men and women in different societies

Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth

OBJECTIVE: Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS: We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11-31], P = 2 x 10(-5), and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none (P(trend) = 5 x 10(-7)). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS: Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype

Association between Birth Characteristics and Cardiovascular Autonomic Function at Mid-Life

Background Low birth weight is associated with an increased risk of cardiovascular diseases in adulthood. As abnormal cardiac autonomic function is a common feature in cardiovascular diseases, we tested the hypothesis that low birth weight may also be associated with poorer cardiac autonomic function in middle-aged subjects. Methods At the age of 46, the subjects of the Northern Finland Birth Cohort 1966 were invited to examinations including questionnaires about health status and life style and measurement of vagally-mediated heart rate variability (rMSSD) from R-R intervals (RRi) and spontaneous baroreflex sensitivity (BRS) in both seated and standing positions. Maternal parameters had been collected in 1965–1966 since the 16th gestational week and birth variables immediately after delivery. For rMSSD, 1,799 men and 2,279 women without cardiorespiratory diseases and diabetes were included and 902 men and 1,020 women for BRS. The analyses were adjusted for maternal (age, anthropometry, socioeconomics, parity, gestational smoking) and adult variables (life style, anthropometry, blood pressure, glycemic and lipid status) potentially confounding the relationship between birth weight and autonomic function. Results In men, birth weight correlated negatively with seated (r = -0.058, p = 0.014) and standing rMSSD (r = -0.090, p<0.001), as well as with standing BRS (r = -0.092, p = 0.006). These observations were verified using relevant birth weight categories (<2,500 g; 2,500–3,999 g; ≥4,000 g). In women, birth weight was positively correlated with seated BRS (r = 0.081, p = 0.010), but none of the other measures of cardiovascular autonomic function. These correlations remained significant after adjustment for potential confounders (p<0.05 for all). Conclusions In men, higher birth weight was independently associated with poorer cardiac autonomic function at mid-life. Same association was not observed in women. Our findings suggest that higher, not lower, birth weight in males may contribute to less favourable cardiovascular autonomic regulation and potentially to an elevated cardiovascular risk in later life

Risks of overweight and abdominal obesity at age 16 years associated with prenatal exposures to maternal prepregnancy overweight and gestational diabetes mellitus

OBJECTIVE The associations of prenatal exposures to maternal prepregnancy overweight and gestational diabetes mellitus (GDM) with offspring overweight are controversial. Research estimating risk for offspring overweight due to these exposures, separately and concomitantly, is limited. RESEARCH DESIGN AND METHODS Prevalence of overweight and abdominal obesity at age 16 years and odds ratios (ORs) for prenatal exposures to maternal prepregnancy overweight and GDM were estimated in participants of the prospective longitudinal Northern Finland Birth Cohort of 1986 (N = 4,168). RESULTS The prevalence and estimates of risk for overweight and abdominal obesity were highest in those exposed to both maternal prepregnancy overweight and GDM (overweight prevalence 40% [OR 4.05], abdominal obesity prevalence 25.7% [3.82]). Even in offspring of mothers with a normal oral glucose tolerance test during pregnancy, maternal prepregnancy overweight is associated with increased risk for these outcomes (overweight prevalence 27.9% [2.56], abdominal obesity prevalence 19.5% [2.60]). In offspring of women with prepregnancy normal weight, the prevalence or risks of the outcomes were not increased by prenatal exposure to GDM. These estimates of risk were adjusted for parental prepregnancy smoking, paternal overweight, and offspring sex and size at birth. CONCLUSIONS Maternal prepregnancy overweight is an independent risk factor for offspring overweight and abdominal obesity at age 16 years. The risks are highest in offspring with concomitant prenatal exposure to maternal prepregnancy overweight and GDM, whereas the risks associated with GDM are only small

Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity

Glucose-Dependent Regulation of NR2F2 Promoter and Influence of SNP-rs3743462 on Whole Body Insulin Sensitivity

Background: The Nuclear Receptor 2F2 (NR2F2/COUP-TFII) heterozygous knockout mice display low basal insulinemia and enhanced insulin sensitivity. We previously established that insulin represses NR2F2 gene expression in pancreatic β-cells. The cis-regulatory region of the NR2F2 promoter is unknown and its influence on metabolism in humans is poorly understood. The present study aimed to identify the regulatory regions that control NR2F2 gene transcription and to evaluate the effect of NR2F2 promoter variation on glucose homeostasis in humans. Methodology/Principal Findings: Regulation of the NR2F2 promoter was assessed using gene reporter assays, ChIP and gel shift experiments. The effects of variation at SNP rs3743462 in NR2F2 on quantitative metabolic traits were studied in two European prospective cohorts. We identified a minimal promoter region that down-regulates NR2F2 expression by attenuating HNF4α activation in response to high glucose concentrations. Subjects of the French DESIR population, who carried the rs3743462 T-to-C polymorphism, located in the distal glucose-responsive promoter, displayed lower basal insulin levels and lower HOMA-IR index. The C-allele at rs3743462 was associated with increased NR2F2 binding and decreased NR2F2 gene expression. Conclusions/Significance: The rs3743462 polymorphism affects glucose-responsive NR2F2 promoter regulation and thereby may influence whole-body insulin sensitivity, suggesting a role of NR2F2 in the control of glucose homeostasis in humans. © 2012 Boutant et al

Genetic and Functional Assessment of the Role of the rs13431652-A and rs573225-A Alleles in the G6PC2 Promoter That Are Strongly Associated With Elevated Fasting Glucose Levels

OBJECTIVE Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal. RESEARCH DESIGN AND METHODS We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding. RESULTS Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: β = 0.075, P = 3.6 × 10−35; rs573225 β = 0.073 P = 3.6 × 10−34), in addition to rs560887 (β = 0.071, P = 1.2 × 10−31). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity. CONCLUSIONS Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out