Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity

<p>Abstract</p> <p>Background</p> <p>7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, <it>SGNE1 </it>is located. The aim of this study is to analyze associations of <it>SGNE1 </it>genetic variation with obesity and metabolism related quantitative traits.</p> <p>Methods</p> <p>We screened <it>SGNE1 </it>for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort.</p> <p>Results</p> <p>We did not find any association between <it>SGNE1 </it>SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55–1.01]; p = 0.06) in the prospective cohort.</p> <p>Conclusion</p> <p><it>SGNE1 </it>genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.</p

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Etude épidémiologique de prévention de l obésité infantile (EPIPOI)

L obésité infantile est devenue un problème majeur de santé publique, une d épidémie mondiale selon l OMS. En France la prévalence des enfants en surcharge pondérale atteint approximativement 18% et 4% sont des obésités massives. Une revue de la littérature sur les actions de préventions primaire, secondaire et tertiaire dans le milieu scolaire n a montré que très peu d études chez les enfants âgés de 3 à 4 ans. Pourtant deux études dans la région Midi-Pyrénées réalisées en 1997 et 1998 ont montré que la prévalence de l obésité était d environ 3% entre 3 et 4 ans et qu elle passait à 12% entre 6 et 10 ans. Il nous a donc semblé crucial de mettre en place un dépistage et une prise en charge de l obésité chez l enfant dès le plus jeune âge ; l école nous a paru le lieu idéal pour mener des actions éducatives centrées sur la nutrition et l activité physique. L étude EPIPOI (EPIdémiologie Obésité Infantile) a démarré en octobre 2002 et s est déroulée sur 18 mois dans 79 écoles maternelles de la Haute Garonne. C est une étude prospective de prévention primaire et secondaire chez 1878 enfants âgés de 3 à 4 ans à l inclusion. Deux groupes ont été formés : un premier groupe limité au dépistage et à la prise en charge des enfants à risque, en surpoids et obèses, et un deuxième groupe où en plus du dépistage étaient menées des actions éducatives. Cette étude s est récemment achevée, ce qui n a permis de faire qu une description de la population à l inclusion : 8,9% des enfants sont en surcharge pondérale et 3,5% sont à risque de le devenir. L étude EPIPOI a initié une collaboration efficace entre les médecins de ville, de PMI et de santé scolaire. Actuellement ces derniers (PMI et santé scolaire) tracent les courbes d indice de masse corporelle (IMC), formidable outil de dépistage, de façon systématique et orientent les enfants vers les partenaires du réseau ville-hôpital de prévention et prise en charge de l obésité pédiatrique (REPOP).TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Evaluation des Journées d'éducation et suivi à moyen terme de 380 enfants et adolescents obèses

L'obésité infantile est un enjeu de Santé Publique. Une prise en charge multidisciplinaire (médecins, diététiciennes, kinésithérapeutes, psychologues, éducateurs) des enfants et adolescents obèses en JOE (Journées Obésité Education), est organisée à l'Hôpital des enfants de Toulouse et au centre Paul Dottin de Ramonville. Nous avons réalisé une étude rétrospective sur 380 enfants obèses âgés de 5 à 15 ans, venus depuis 2001 à l'Hôpital et depuis 1998 au centre P.Dottin, ayant effectué un cycle complet de 5 JOE et un suivi variant de 6 mois à 3 ans. Afin d'évaluer l'efficacité de ces journées nous avons analysé l'évolution de l'IMC en Zscore, la pratique sportive et les habitudes alimentaires. L'IMC, à la dernière visite, a diminué significativement, et 17,63 % ne sont plus obèses. Un IMC inférieur à 2 Zscore est très significativement lié, à la diminution du Zscore pendant les JOE, à l'IMC de la mère et aux connaissances diététiques. Parmi les arrêts de suivi, 69 % ont une évolution favorable et 31 % défavorable, parmi lesquels 48 % sont perdus de vue. Notre étude souligne l'importance d'un accompagnement individuel. Le pharmacien d'officine à une vraie place à prendre.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Recueil de pratiques visant à harmoniser les évaluations pédagogiques des compétences de soins chez les enfants de 9–11 ans en surpoids ou obèses

Introduction : Le groupe « éducation thérapeutique » de l’APOP a choisi comme axe de travail l’évaluation de l’éducation thérapeutique de l’enfant obèse ou en surpoids avec le souhait d’harmoniser les pratiques d’évaluation pédagogique de l’enfant. Objectifs : Cette recherche d’une évaluation de nature formative a pour but de rendre compte des acquisitions de l’enfant et d’engager ainsi la discussion sur les modalités de son suivi éducatif. Méthode : En l’absence d’un modèle opératoire, le groupe de travail a réalisé un recueil de pratiques d’évaluation des compétences de soins chez les enfants de 9 à 11 ans en surcharge pondérale. Résultats : Basé sur les développements cognitifs et émotionnels des enfants, ce recueil comprend 16 outils d’évaluation, permettant d’apprécier l’acquisition de 11 compétences jugées les plus importantes pour se soigner. Discussion : La période d’essai des différents outils confirme après ajustement, leur intérêt pédagogique. Cependant, il revient aux soignants de déterminer les compétences à évaluer au moment de la rencontre. Conclusion : Cette première proposition d’un recueil de pratiques ouvre des perspectives intéressantes pour le suivi éducatif de l’enfant notamment grâce à la place donnée à sa participation

Bardet-Biedl syndrome gene variants are associated with both childhood and adult common obesity in French Caucasians.

Bardet-Biedl syndrome (BBS) is a rare developmental disorder with the cardinal features of abdominal obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, hypertension, and diabetes. BBS is genetically heterogeneous, with nine genes identified to date and evidence for additional loci. In this study, we performed mutation analysis of the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 48 French Caucasian individuals. Among the 36 variants identified, 12 were selected and genotyped in 1,943 French-Caucasian case subjects and 1,299 French-Caucasian nonobese nondiabetic control subjects. Variants in BBS2, BBS4, and BBS6 showed evidence of association with common obesity in an age-dependent manner, the BBS2 single nucleotide polymorphism (SNP) being associated with common adult obesity (P = 0.0005) and the BBS4 and BBS6 SNPs being associated with common early-onset childhood obesity (P = 0.0003) and common adult morbid obesity (0.0003 < P < 0.007). The association of the BBS4 rs7178130 variant was found to be supported by transmission disequilibrium testing (P = 0.006). The BBS6 variants also showed nominal evidence of association with quantitative components of the metabolic syndrome (e.g., dyslipidemia, hyperglycemia), a complication previously described in BBS patients. In summary, our preliminary data suggest that variations at BBS genes are associated with risk of common obesity

Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children?

Low birth weight is a risk factor for obesity and type 2 diabetes. The fetal insulin hypothesis proposes that low birth weight might be mediated partly by genetic factors that impair insulin secretion/sensitivity during the fetal stage, as shown for glucokinase, the ATP-sensitive K+ channel subunit Kir6.2, and the small heterodimer partner genes. Glutamic acid decarboxylase 2 gene (GAD2) overexpression impairs insulin secretion in animals. Recently, polymorphisms in the GAD2 gene were associated with adult morbid obesity. In the present study, we investigated potential effects of the functional -243 A-->G polymorphism in the 5' promoter region of the GAD2 gene on fetal growth, insulin secretion, food intake, and risk of obesity in 635 French Caucasian severely obese children from three different medical centers. The case/control study confirmed the association between the GAD2 single-nucleotide polymorphism (SNP) -243 A-->G and obesity (odds ratio, 1.25; P = 0.04). In addition, SNP -243 GG children carriers showed a 270 g lower birth weight and a 1.5 cm lower birth height compared with AA carriers (P = 0.009 and P = 0.013, respectively). The relation between birth weight and Z score of BMI was linear in AA carrier children (P = 0.00001) and quadratic (U-shaped curve) in AG/GG carrier children (P = 0.0009). G allele children carriers presented a trend toward lower insulinogenic index with 25% reduction of insulin secretion in response to glucose load compared with A carriers (P = 0.09). Eighteen percent of GG obese carriers vs. 5.7% of AA carriers reported binge eating phenotype (P = 0.04). These results confirm the association between GAD2-243 promoter SNP and the risk for obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking birth weight to further risk for metabolic diseases, possibly involving the pleiotropic effect of insulin on fetal growth and later on feeding behavior

Pituitary Stalk Interruption Syndrome from Infancy to Adulthood: Clinical, Hormonal, and Radiological Assessment According to the Initial Presentation.

Patients with pituitary stalk interruption syndrome (PSIS) are initially referred for hypoglycemia during the neonatal period or growth retardation during childhood. PSIS is either isolated (nonsyndromic) or associated with extra-pituitary malformations (syndromic).To compare baseline characteristics and long-term evolution in patients with PSIS according to the initial presentation.Sixty-seven patients with PSIS were included. Data from subgroups were compared: neonates (n = 10) versus growth retardation patients (n = 47), and syndromic (n = 32) versus nonsyndromic patients (n = 35).Neonates displayed a more severe hormonal and radiological phenotype than children referred for growth retardation, with a higher incidence of multiple hormonal deficiencies (100% versus 34%; P = 0.0005) and a nonvisible anterior pituitary lobe (33% versus 2%; P = 0.0017). Regular follow-up of growth might have allowed earlier diagnosis in the children with growth retardation, as decreased growth velocity and growth retardation were present respectively 3 and 2 years before referral. We documented a progressive worsening of endocrine impairment throughout childhood in these patients. Presence of extra-pituitary malformations (found in 48%) was not associated with more severe hormonal and radiological characteristics. Growth under GH treatment was similar in the patient groups and did not vary according to the pituitary MRI findings.PSIS diagnosed in the neonatal period has a particularly severe hormonal and radiological phenotype. The progressive worsening of endocrine impairment throughout childhood justifies periodic follow-up to check for additional hormonal deficiencies