A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

Maternal occupation during pregnancy, birth weight, and length of gestation: Combined analysis of 13 European birth cohorts

Objectives We assessed whether maternal employment during pregnancy – overall and in selected occupational sectors – is associated with birth weight, small for gestational age (SGA), term low birth weight (LBW), length of gestation, and preterm delivery in a population-based birth cohort design. Methods We used data from >200 000 mother-child pairs enrolled in 13 European birth cohorts and compared employed versus non-employed women. Among employees, we defined groups of occupations representing the main sectors of employment for women where potential reproductive hazards are considered to be present. The comparison group comprised all other employed women not included in the occupational sector being assessed. We performed meta-analyses of cohort-specific estimates and explored heterogeneity. Results Employees had a lower risk of preterm delivery than non-employees [adjusted odds ratio (ORadj) 0.86, 95% confidence interval (95% CI) 0.81–0.91]. Working in most of the occupational sectors studied was not associated with adverse birth outcomes. Being employed as a nurse was associated with lower risk SGA infants (ORadj 0.91, 95% CI 0.84–0.99) whereas food industry workers had an increased risk of preterm delivery (ORadj 1.50, 95% CI 1.12–2.02). There was little evidence for heterogeneity between cohorts. Conclusions This study suggests that, overall, employment during pregnancy is associated with a reduction in the risk of preterm birth and that work in certain occupations may affect pregnancy outcomes. This exploratory study provides an important platform on which to base further prospective studies focused on the potential consequences of maternal occupational exposures during pregnancy on child development

Exposure of pregnant women to persistent organic pollutants and cord sex hormone levels

International audienceStudy question - Is prenatal exposure to persistent organic pollutants (POPs) associated with variations of sex hormone levels in cord blood? Summary answer - Prenatal exposure to a number of POPs is associated with a disruption of hormone levels in cord blood, with sex specificities. What is known already - Epidemiological studies have reported disorders of reproductive health, in relation with POPs exposure during early life and the endocrine disruption properties of these chemicals have been suggested as possible mechanisms. Study design, size, duration - A subset of 282 mother-child pairs was selected from the prospective population-based PELAGIE birth cohort (n = 3421, 2002-2006, Brittany, France). Pregnant women were recruited before 19 weeks of gestation and followed until delivery. Participants/materials, setting, methods - Sex hormone levels including sex hormone-binding globulin (SHBG), estradiol (E2), total testosterone (T), free testosterone (fT = T/SHBG) and the aromatase index (AI = T/E2) were measured in 282 cord blood samples. Anti-Müllerian hormone (AMH) was measured in male newborns only. Pesticide concentrations of α-endosulfan, β-hexachlorocyclohexane (β-HCH), γ-HCH, dieldrin, pp'-dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), heptachlor epoxide (HCE), as well as PCBs (congeners 153, 187 and the sum of anti-estrogenic PCBs 118, 138, and 170) and decabrominated diphenyl ether (BDE209) were also measured in cord blood. Associations between sex hormones and POPs exposure were explored using multiple linear regressions adjusted for potential confounders. Main results and the role of chance - High PCB levels were associated with an increase of SHBG (P-trend < 0.01) and AMH (P-trend < 0.05) and a decrease of fT (P-trend < 0.05) and AI (P-trend < 0.01). High pesticide levels, particularly α-endosulfan and HCE, were associated with an increase of SHBG (P < 0.05) and E2 (P < 0.01) and a decrease of fT (P < 0.05) and AI (P < 0.01). Several of these associations were stronger, or specific, among male or female newborns. The associations were not altered in the sensitivity analyses. Limitations, reasons for caution - The study population was of relatively small sample size, and some compounds rarely detected in cord blood. The high level of correlation between POPs makes it difficult to identify the most contributing POPs. Hormone measurements were performed at birth (in cord blood) and may not adequately represent the infant endocrine system. Multiple statistical testing may have led to false-positive associations. Wider implications of the findings - Our results are in discordance with those reported in the only published study of the kind but in accordance with studies about prenatal exposure to other endocrine disruptors such as phthalates. These findings may help understanding the pathways involved in adverse reproductive outcomes associated with POPs exposure. Study funding/competing interests - The PELAGIE cohort is funded by Inserm, French Ministry of Health, French Ministry of Labor, InVS, ANR, ANSES, and French Ministry of Ecology. None of the authors has any competing interest to declare

Environmental determinants of the urinary concentrations of herbicides during pregnancy: The PELAGIE mother–child cohort (France)

International audienceHerbicides are generally the most extensively used of the pesticides applied to agricultural crops. However, the literature contains little evidence useful in assessing the potential sources of the general population's exposure to herbicides, including by residential proximity to crops.The objective of this study was to take advantage of data from the PELAGIE mother–child cohort to identify the main determinants of the body burden of exposure to the chloroacetanilide and triazine herbicides commonly used on corn crops in Brittany, France, before 2006. Urine samples from a randomly selected subcohort of women in the first trimester of pregnancy (n=579) were assayed for herbicide metabolites. The residential exposure resulting from proximity to corn crops was assessed with satellite-image-based scores combined with meteorological data. Data on diet, drinking tap water (from the public water supply), occupations, and household herbicide use were collected by questionnaires.Herbicides were quantified in 5.3% to 39.7% of urine samples. Alachlor and acetochlor were found most frequently in the urine of women living in rural areas. The presence of dealkylated triazine metabolites in urine samples was positively associated with residential proximity to corn crops (OR=1.38, 95% CI: 1.05–1.80). Urinary metabolites of both atrazine and dealkylated triazine were correlated with tap water consumption (OR=2.94, 1.09–7.90, and OR=1.82, 1.10–3.03, respectively); hydroxylated triazine metabolites were correlated with fish intake (OR=1.48, 1.09–1.99).This study reinforces previous results that suggest that environmental contamination resulting from agricultural activities may contribute to the general population's exposure to herbicides

Exposure of pregnant women to organophosphate insecticides and motor inhibition evaluated by functional MRI at the age of 10 to 12 years (PELAGIE mother-child cohort)

International audienceOrganophosphate insecticides (OP) are widely used for agricultural purposes because of their acute toxicity and non-persistence. Epidemiological studies suggest a neurotoxicity in children, after exposure at low levels but possible pathways remain unclear. The present study aims at investigating effects of prenatal exposure to OP on inhibition control of 10-12 year-old children assessed by a motor inhibition task during functional MRI (fMRI) sequence.Ninety-five children from the PELAGIE cohort (Brittany-France, from 2002) underwent fMRI examination during which inhibition was assessed with a Go/No-Go task: they were asked to press a button as quickly as possible in response to green smileys but not press when seeing a red smiley (300 items, 10 minutes). Task performance was assessed by average reaction time (RT), commission rate (CR) and composite performance score (PS). Whole brain activations were estimated by modeling hemodynamic response related to successful inhibition and inhibition demand perception.OP exposure was assessed by measuring six dialkylphosphate (DAP) metabolites in urine of women in early pregnancy (<19 WG). Concentrations were summed to obtain overall levels of diethylphosphate (DE), dimethylphosphate (DM) and total non-specific metabolites (DAP), standardized to homogenize sampling conditions and categorized into levels of exposure: low (reference), moderate or high. Regression models were adjusted onpotential cofounders considered by restriction and statistical criteria. Moderate levels of DAP were associated with decreased CR (p=0.04), without increased PS. There was a suggested lower PS in association with moderate DE levels (p=0.06). Moderate DE and highest DM levels were associated with decreased brain activities in bilateral middlefrontal or left anterior cingular regions during successful inhibition. We didn’t report any differential activitions related to inhibition demand perception. We suggested associations between prenatal OP exposure and motor inhibition, in particular differential brain activity in areas related to inhibition, which required to be confirmed by others studies

Design methods for the projection of uses for vulnerable people

International audienceThe VOCADOM research project aims to design a new technology (voice control usable at home) to encourage the well-being and autonomy of the elderly with loss of autonomy at home. To guide design choices, we develop a user-centered design for all so that all actors are involved in the design process and we develop new methods of uses prospecting so that target profiles can project themselves into the use of an innovative device in ecological situation. We are in a process of methodological triangulation. Especially for the study of needs where through an ethnographic study we identify the problems encountered at home where the device can help. We ask end users and caregivers who are part of the eco system. After we use activity simulation methods to evaluate the acceptance , usefulness and usability of the device. This will allow us to improve the device so that it matches the real needs of users