Circadian genes polymorphisms, night work and prostate cancer risk: Findings from the EPICAP study.

Over the past two decades, several studies have attempted to understand the hypothesis that disrupting the circadian rhythm may promote the development of cancer. Some have suggested that night work and some circadian genes polymorphisms are associated with cancer, including prostate cancer. Our study aims to test the hypothesis that prostate cancer risk among night workers may be modulated by genetic polymorphisms in the circadian pathway genes based on data from the EPICAP study, a population-based case-control study including 1511 men (732 cases/779 controls) with genotyped data. We estimated odds ratio (ORs) and P values of the association between prostate cancer and circadian gene variants using logistic regression models. We tested the interaction between circadian genes variants and night work indicators that were significantly associated with prostate cancer at pathway, gene and SNP levels. Analyses were also stratified by each of these night work indicators and by cancer aggressiveness. The circadian pathway was significantly associated with aggressive prostate cancer among night workers (P = .004), particularly for men who worked at night for <20 years (P = .0002) and those who performed long night shift (>10 hours, P = .001). At the gene level, we observed among night workers significant associations between aggressive prostate cancer and ARNTL, NPAS2 and RORA. At the SNP-level, no significant association was observed. Our findings provide some clues of a potential modulating effect of circadian genes in the relationship between night work and prostate cancer. Further investigation is warranted to confirm these findings and to better elucidate the biological pathways involved.

Changes in the number of suicide re-attempts in a French region since the inception of VigilanS, a regionwide program combining brief contact interventions (BCI).

BACKGROUND: Brief Contact Interventions (BCIs) after a suicide attempt (SA) are an important element of prevention against SA and suicide. They are easier to generalize to an entire population than other forms of intervention. VigilanS generalizes to a whole French region a BCI combining resource cards, telephone calls and mailings, according to a predefined algorithm. It was implemented gradually in the Nord-Pas-de-Calais (NPC), France, between 2015 and 2018. Here, we evaluate the effectiveness of VigilanS, in terms of SA reduction, using annual data collected by participating centers. Hypothesis tested: the higher the VigilanS implementation in a center (measured by penetrance), the greater the decrease in the number of SA observed in this center. METHODS: The study period was from 2014 to 2018, across all of NPC centers. We performed a series of linear regressions, each center representing a statistical unit. The outcome was the change in the number of SA, relative to the initial number, and the predictive variable was VigilanS' penetrance: number of patients included in VigilanS over the total number of SA. Search for influential points (points beyond threshold values of 3 influence criteria) and weighted least squares estimations were performed. RESULTS: Twenty-one centers were running VigilanS in 2018, with an average penetrance of 32%. A significant relationship was identified, showing a sharp decrease in SA as a function of penetrance (slope = - 1.13; p = 3*10- 5). The model suggested that a 25% of penetrance would yield a SA decrease of 41%. CONCLUSION: VigilanS has the potential to reduce SA. Subgroup analyzes are needed to further evaluate its effectiveness. Subgroup analyses remain to be done, in order to evaluate the specific variations of SA by group.

Circadian genes and risk of prostate cancer: Findings from the EPICAP study.

Circadian rhythms regulate several physiological functions and genes controlling the circadian rhythm were found to regulate cell proliferation, cell cycle and apoptosis. Few studies have investigated the role of those circadian genes in prostate cancer occurrence. We aim to investigate the relationship between circadian genes polymorphisms and prostate cancer risk based on data from the EPICAP study, a population-based case-control study including 1,515 men (732 cases / 783 controls) with genotyped data. Odds Ratios (ORs) for association between prostate cancer and circadian gene variants were estimated for each of the 872 single nucleotide polymorphisms (SNPs) in 31 circadian clock genes. We also used a gene-based and pathway-based approach with a focus on the pathway including 9 core circadian genes. Separate analyses were conducted by prostate cancer aggressiveness. The core-circadian pathway (p = 0.0006) was significantly associated to prostate cancer, for either low (p = 0.002) or high (p = 0.01) grade tumor. At the gene level, we observed significant associations between all prostate cancer and NPAS2 and PER1 after correcting for multiple testing, while only RORA was significant for aggressive tumors. At the SNP-level, no significant association was observed. Our findings provide additional evidence of a potential link between genetic variants in circadian genes and prostate cancer risk. Further investigation is warranted to confirm these findings and to better understand the biological pathways involved.

Exhaustive methylation analysis revealed uneven profiles of methylation at IGF2/ICR1/H19 11p15 loci in Russell Silver syndrome.

BACKGROUND: The structural organisation of the human IGF2/ICR1/H19 11p15 domain is very complex, and the mechanisms underlying its regulation are poorly understood. The Imprinted Center Region 1 (ICR1) contains seven binding sites for the zinc-finger protein CTCF (CBS: CTCF Binding Sites); three additional differentially methylated regions (DMR) are located at the H19 promoter (H19DMR) and two in the IGF2 gene (DMR0 and DMR2), respectively. Loss of imprinting at the IGF2/ICR1/H19 domain results in two growth disorders with opposite phenotypes: Beckwith-Wiedemann syndrome and Russell Silver syndrome (RSS). Despite the IGF2/ICR1/H19 locus being widely studied, the extent of hypomethylation across the domain remains not yet addressed in patients with RSS. METHODS: We assessed a detailed investigation of the methylation status of the 11p15 ICR1 CBS1-7, IGF2DMR0 and H19DMR (H19 promoter) in a population of controls (n=50) and RSS carrying (n=104) or not (n=65) carrying a hypomethylation at the 11p15 ICR1 region. RESULTS: The methylation indexes (MI) were balanced at all regions in the control population and patients with RSS without any as yet identified molecular anomaly. Interestingly, patients with RSS with ICR1 hypomethylation showed uneven profiles of methylation among the CBSs and DMRs. Furthermore, normal MIs at CBS1 and CBS7 were identified in 9% of patients. CONCLUSIONS: The hypomethylation does not spread equally throughout the IGF2/ICR1/H19 locus, and some loci could have normal MI, which may lead to underdiagnosis of patients with RSS with ICR1 hypomethylation. The uneven pattern of methylation suggests that some CBSs may play different roles in the tridimensional chromosomal looping regulation of this locus.

Association between genetic obesity susceptibility and mother-reported eating behaviour in children up to 5 years.

BACKGROUND: Many genetic polymorphisms identified by genome-wide association studies for adult body mass index (BMI) have been suggested to regulate food intake. OBJECTIVE: The objective was to study the associations between a genetic obesity risk score, appetitive traits, and growth of children up to age 5 years, with a longitudinal design. METHODS: In 1142 children from the Etude des Déterminants pre et post natals de la santé de l'ENfant (EDEN) birth cohort, a combined obesity risk-allele score (BMI genetic risk score [GRS]) was related to appetitive traits (energy intake up to 12 mo, a single item on appetite from 4 mo to 3 y, a validated appetite score at 5 y) using Poisson regressions with robust standard errors. The potential mediation of appetitive traits on the association between BMI-GRS and growth was assessed by the Sobel test. RESULTS: Children with a high BMI-GRS were more likely to have high energy intake at 1 year and high appetite at 2 and 5 years. High energy intake in infancy and high appetite from 1 year were related to higher subsequent BMI. High 2-year appetite seemed to partially mediate the associations between BMI-GRS and BMI from 2 to 5 years (all P ≤ 0.05). CONCLUSIONS: Genetic susceptibility to childhood obesity seems to be partially explained by appetitive traits in infancy, followed by an early childhood rise in BMI.

Mediation and modification of genetic susceptibility to obesity by eating behaviors.

Background: Many genetic variants show highly robust associations with body mass index (BMI). However, the mechanisms through which genetic susceptibility to obesity operates are not well understood. Potentially modifiable mechanisms, including eating behaviors, are of particular interest to public health.Objective: Here we explore whether eating behaviors mediate or modify genetic susceptibility to obesity.Design: Genetic risk scores for BMI (BMI-GRSs) were calculated for 3515 and 2154 adults in the Fenland and EDEN (Etude des déterminants pré et postnatals de la santé et du développement de l'enfant) population-based cohort studies, respectively. The eating behaviors-emotional eating, uncontrolled eating, and cognitive restraint-were measured through the use of a validated questionnaire. The mediating effect of each eating behavior on the association between the BMI-GRS and measured BMI was assessed by using the Sobel test. In addition, we tested for interactions between each eating behavior and the BMI-GRS on BMI.Results: The association between the BMI-GRS and BMI was mediated by both emotional eating (EDEN: P-Sobel = 0.01; Fenland: P-Sobel = 0.02) and uncontrolled eating (EDEN: P-Sobel = 0.04; Fenland: P-Sobel = 0.0006) in both sexes combined. Cognitive restraint did not mediate this association (P-Sobel > 0.10), except among EDEN women (P-Sobel = 0.0009). Cognitive restraint modified the relation between the BMI-GRS and BMI among men (EDEN: P-interaction = 0.0001; Fenland: P-interaction = 0.04) and Fenland women (P-interaction = 0.0004). By tertiles of cognitive restraint, the association between the BMI-GRS and BMI was strongest in the lowest tertile of cognitive restraint, and weakest in the highest tertile.Conclusions: Genetic susceptibility to obesity was partially mediated by the "appetitive" eating behavior traits (uncontrolled and emotional eating) and, in 3 of the 4 population groups studied, was modified by cognitive restraint. High levels of cognitive control over eating appear to attenuate the genetic susceptibility to obesity. Future research into interventions designed to support restraint may help to protect genetically susceptible individuals from weight gain.

Night work and breast cancer risk defined by human epidermal growth factor receptor-2 (HER2) and hormone receptor status: A population-based case-control study in France.

Night work has been associated with risk of breast cancer but this association needs to be confirmed. Because breast cancer is an etiologically heterogeneous disease, we explored the association of night work with breast cancer subtypes defined by tumor status (positive of negative) for estrogen-receptor (ER), progesterone-receptor (PR) and human epidermal growth factor-receptor 2 (HER2). Using the data from a case-control study in France including 975 cases and 1317 controls, we found that the odds ratios for ER+, PR+ or HER2+ breast cancers subtypes were significantly elevated, while no association with night shift work was observed for ER, PR or HER2-negative tumors. After stratification by menopausal status, the associations of night work with receptor-positive breast tumor subtypes were clearly seen in premenopausal women (odds ratios 2.04, 1.98 and 2.80, respectively) but did not appear in postmenopausal women. This study provides evidence that working at night may increase risk of ER, PR and HER2-positive subtypes of breast cancer particularly among premenopausal women.

Growth pattern from birth to adulthood in African pygmies of known age.

The African pygmy phenotype stems from genetic foundations and is considered to be the product of a disturbance in the growth hormone-insulin-like growth factor (GH-IGF) axis. However, when and how the pygmy phenotype is acquired during growth remains unknown. Here we describe growth patterns in Baka pygmies based on two longitudinal studies of individuals of known age, from the time of birth to the age of 25 years. Body size at birth among the Baka is within standard limits, but their growth rate slows significantly during the first two years of life. It then more or less follows the standard pattern, with a growth spurt at adolescence. Their life history variables do not allow the Baka to be distinguished from other populations. Therefore, the pygmy phenotype in the Baka is the result of a change in growth that occurs during infancy, which differentiates them from East African pygmies revealing convergent evolution.

Degree of methylation of ZAC1 (PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort.

The ZAC1 gene, mapped to the 6q24 region, is part of a network of co-regulated imprinted genes involved in the control of embryonic growth. Loss of methylation at the ZAC1 differentially methylated region (DMR) is associated with transient neonatal diabetes mellitus, a developmental disorder involving growth retardation and diabetes in the first weeks of post-natal life. We assessed whether the degree of methylation of the ZAC1 DMR in leukocytes DNA extracted from cord blood is associated with fetal, birth and post-natal anthropometric measures or with C-peptide concentrations in cord serum. We also searched for an influence of dietary intake and maternal parameters on ZAC1 DMR methylation. We found positive correlations between the ZAC1 DMR methylation index (MI) and estimated fetal weight (EFW) at 32 weeks of gestation, weight at birth and weight at one year of age (respectively, r = 0.15, 0.09, 0.14; P values = 0.01, 0.15, 0.03). However, there were no significant correlations between the ZAC1 DMR MI and cord blood C-peptide levels. Maternal intakes of alcohol and of vitamins B2 were positively correlated with ZAC1 DMR methylation (respectively, r = 0.2 and 0.14; P = 0.004 and 0.04). The influence of ZAC1 seems to start in the second half of pregnancy and continue at least until the first year of life. The maternal environment also appears to contribute to the regulation of DNA methylation.

Associations between genetic obesity susceptibility and early postnatal fat and lean mass: an individual participant meta-analysis.

IMPORTANCE: Patterns of body size and body composition associated with genetic obesity susceptibility inform the mechanisms that increase obesity risk. OBJECTIVE: To test associations between genetic obesity susceptibility, represented by a combined obesity risk-allele score, and body size or body composition at birth to age 5 years. DESIGN, SETTING, AND PARTICIPANTS: A total of 3031 children from 4 birth cohort studies in England, France, and Spain were included in a meta-analysis. EXPOSURES: A combined obesity risk-allele score was calculated from genotypes at 16 variants identified by genome-wide association studies of adult body mass index (BMI). MAIN OUTCOMES AND MEASURES: Outcomes were age- and sex-adjusted SD scores (SDS) for weight, length/height, BMI, fat mass, lean mass, and percentage of body fat at birth as well as at ages 1, 2 to 3, and 4 to 5 years. RESULTS: The obesity risk-allele score was not associated with infant size at birth; at age 1 year it was positively associated with weight (ß [SE], 0.020 [0.008] SDS per allele; P = .009) and length (ß [SE], 0.020 [0.008] SDS per allele; P = .01), but not with BMI (ß [SE], 0.013 [0.008] SDS per allele; P = .11). At age 2 to 3 years these associations were stronger (weight: ß [SE], 0.033 [0.008] SDS per allele; P < .001; height: ß [SE], 0.025 [0.008] SDS per allele; P < .001) and were also seen for BMI (ß [SE], 0.024 [0.008] SDS per allele; P = .003). The obesity risk-allele score was positively associated with both postnatal fat mass (1 year: ß [SE], 0.032 [0.017] SDS per allele; P = .05; 2-3 years: ß [SE], 0.049 [0.018] SDS per allele; P = .006; and 4-5 years: ß [SE], 0.028 [0.011] SDS per allele; P = .009) and postnatal lean mass (1 year: ß [SE], 0.038 [0.014] SDS per allele; P = .008; 2-3 years: ß [SE], 0.064 [0.017] SDS per allele; P < .001; and 4-5 years: ß [SE], 0.047 [0.011] SDS per allele; P < .001), but not with the percentage of body fat (P > .15 at all ages). CONCLUSIONS AND RELEVANCE: Genetic obesity susceptibility appears to promote a normally partitioned increase in early postnatal, but not prenatal, growth. These findings suggest that symmetrical rapid growth may identify infants with high life-long susceptibility for obesity.