Genome wide association study identifies KCNMA1 contributing to human obesity

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population. Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity.</p> <p>Methods</p> <p>We performed a GWA analysis in 164 morbidly obese subjects (BMI:body mass index > 40 kg/m²) and 163 Swedish subjects (> 45 years) who had always been lean. The 700 SNPs displaying the strongest association with obesity in the GWA were analyzed in a second cohort comprising 460 morbidly obese subjects and 247 consistently lean Swedish adults. 23 SNPs remained significantly associated with obesity (nominal <it>P</it>< 0.05) and were in a step-wise manner followed up in five additional cohorts from Sweden, France, and Germany together comprising 4214 obese and 5417 lean or population-based control individuals. Three samples, n = 4133, were used to investigate the population-based associations with BMI. Gene expression in abdominal subcutaneous adipose tissue in relation to obesity was investigated for14 adults.</p> <p>Results</p> <p>Potassium channel, calcium activated, large conductance, subfamily M, alpha member <it>(KCNMA1) </it>rs2116830*G and <it>BDNF </it>rs988712*G were associated with obesity in five of six investigated case-control cohorts. In meta-analysis of 4838 obese and 5827 control subjects we obtained genome-wide significant allelic association with obesity for <it>KCNMA1 </it>rs2116830*G with <it>P </it>= 2.82 × 10^-10and an odds ratio (OR) based on cases vs controls of 1.26 [95% C.I. 1.12-1.41] and for <it>BDNF </it>rs988712*G with <it>P </it>= 5.2 × 10^-17and an OR of 1.36 [95% C.I. 1.20-1.55]. <it>KCNMA1 </it>rs2116830*G was not associated with BMI in the population-based samples. Adipose tissue (<it>P </it>= 0.0001) and fat cell (<it>P </it>= 0.04) expression of <it>KCNMA1 </it>was increased in obesity.</p> <p>Conclusions</p> <p>We have identified <it>KCNMA1 </it>as a new susceptibility locus for obesity, and confirmed the association of the <it>BDNF </it>locus at the genome-wide significant level.</p

Novel therapeutics in rare genetic obesities: A narrative review

The better understanding of the molecular causes of rare genetic obesities and its associated phenotype involving the hypothalamus allows today to consider innovative therapeutics focused on hunger control. Several new pharmacological molecules benefit patients with monogenic or syndromic obesity. They are likely to be among the treatment options for these patients in the coming years, helping clinicians and patients prevent rapid weight progression and eventually limit bariatric surgery procedures, which is less effective in these patients. Their positioning in the management of such patients will be needed to be well defined to develop precision medicine in genetic forms of obesity

Etude du comportement alimentaire des enfants ayant un syndrome de Silver-Russell

National audienceIntroduction et but de l’étude. – Le syndrome de Silver-Russell (SSR) est une maladie épigénétique rare caractérisée par un retard de croissance intra-utérin avec périmètre crânien relativement préservé, une petite taille post-natale associée à une dysmorphie et une asymétrie corporelle inconstante. Des difficultés alimentaires majeures sont souvent décrites pouvant nécessiter le recours à une nutrition entérale prolongée. À ce jour, aucune étude n’a décrit précisément les troubles du comportement alimentaire de ces enfants. Le but de notre travail était donc de caractériser les différentes composantes du comportement alimentaire d’enfants ayant un SSR. Matériel et méthodes. – Un questionnaire validé évaluant la sensibilité tactile orale, le comportement, les préférences et les habitudes alimentaires a été complété pour 21 enfants ayant un SSR (âge moyen 6,0 ± 3,9 ans), 59 enfants ayant des troubles de l’oralité (TO) d’autres étiologies (âge moyen 4,9 ans ± 2,4 ans) et 101 enfants témoins sans troubles de l’oralité (STO) (âge moyen 5,2 ± 1,8 ans). Les réponses des SSR, TO et STO ont été comparées par des t-tests. Résultats et Analyse statistique. – La sensibilité tactile orale était significativement altérée chez les enfants SSR par rapport aux enfants STO (p < 0,0001), mais était identique aux enfants avec TO. Le comportement alimentaire était significativement anormal chez les enfants SSR par rapport aux enfants STO (p < 0,001) mais non différent des enfants avec TO d’autres causes. Par comparaison aux enfants STO, les enfants SSR et avec TO étaient caractérisés par une autonomie alimentaire significativement réduite, des repas plus difficiles et lents, la présence plus fréquente de rituels lors des repas et un manque de plaisir à manger. En revanche, chez les SSR, la sélectivité des aliments et le refus de la tétine étaient moins fréquents (p = 0,0001) par comparaison aux enfants avec TO. Concernant le choix des saveurs, le sucré, l’acide et les aliments au goût fort étaient mieux acceptés chez les enfants SSR que chez les enfants avec TO (p < 0,0001), alors que l’amer était moins bien accepté (p < 0,0001). Il n’y avait pas de différence significative concernant l’acceptation des boissons gazeuses, des aliments épicés et salés, ni dans le choix des textures entre les 3 groupes. Conclusion. – Notre travail décrit pour la première fois le comportement alimentaire des enfants ayant un SSR et montre qu’il est proche, mais pas identique, de celui des enfants ayant un TO d’autre cause. Ces résultats permettent donc d’adapter la prise en charge nutritionnelle des enfants SSR chez lesquels la dénutrition est particulièrement fréquente en raison des troubles alimentaires

Sleep disordered breathing in Silver−Russell syndrome patients: a new outcome

International audienceOBJECTIVE: Imprinting disorders (ID), such as Prader-Willi syndrome (PWS), are associated with sleep-disordered breathing (SDB). No data are available for Silver-Russell syndrome (SRS), another ID that shares clinical features with PWS, although many patients describe excessive daytime sleepiness, disturbed sleep, and snoring. The aim of this study was to characterize sleep in children with SRS and to evaluate the impact of recombinant growth hormone (rGH) therapy.METHODS: We performed a retrospective analysis of sleep recordings in 40 patients with molecularly proven SRS (methylation anomaly in 11p15 [n = 32] or maternal uniparental disomy of chromosome 7 [n = 16]). Sleep recordings were either by means of polygraphy or polysomnography (PSG) (n = 16). A total of 34 patients received rGH therapy.RESULTS: We collected 61 sleep recordings. The mean apnea-hypopnea index (AHI) was 3.4 events/h (0-12.4), with a mean central AHI of 0.5 events/h (0-2.4). SDB was identified in 73.8% (n = 45) of the recordings and was severe in 4.9%. SDB was present in 86.4% of patients before rGH therapy and was severe in 13.6%. AHI worsened for 5 of 12 patients with sleep recordings before and after rGH therapy initiation, reaching mild impairment. The mean rGH dose was 32.3 μg/kg/(12.9-51.4), with a mean insulin-like growth factor 1 plasma level of 1.7 SDS (-1.9 to 6.6).CONCLUSION: Most patients with SRS present with SDB with an obstructive profile, possibly explained by narrowing of the airways and lymphoid organ hypertrophy. We recommend systematic ear-nose-throat evaluation of SRS patients and PSG if there are clinical anomalies, preferably before initiating rGH therapy, to monitor and adapt the management of patients with SDB

Diagnostic de la dénutrition de l’adulte de moins de 70 ans : recommandation de bonne pratique HAS-FFN 2019

International audienceLa dénutrition est un problème majeur de santé publique qui concerne plus de 2 millions de personnes en France. Elle se traduit par une perte de poids involontaire. Elle majore le risque d’infection et réduit la force musculaire et la mobilité. Elle augmente le risque de complications médicales et chirurgicales. L’objectif de cette recommandation de bonne pratique est de définir la dénutrition chez l’adulte (<70 ans) et de proposer des critères afin d’améliorer son diagnostic à l’aide d’outils adaptés

Diagnostic de la dénutrition de l’enfant : recommandation de bonne pratique HAS-FFN 2019

International audienceUndernutrition in children results in stunted growth and involuntary weight loss. It compromises the psychomotor development of young children. It increases the risk of infection and the risk of medical and surgical complications. The objective of this good practice guideline is to define undernutrition in children (< 18 years old) and to propose criteria to improve its diagnosis using adapted tools.La dénutrition chez l’enfant se traduit par un retard de croissance et une perte de poids involontaire. Elle compromet le développement psychomoteur du jeune enfant. Elle majore le risque d’infection et augmente le risque de complications médicales et chirurgicales. L’objectif de cette recommandation de bonne pratique est de définir la dénutrition chez l’enfant (< 18 ans) et de proposer des critères afin d’améliorer son diagnostic à l’aide d’outils adaptés

Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations.

Heterozygous mutations in the coding region of the serpentine Melanocortin 4 receptor are the most common genetic cause of human obesity described to date. There are still conflicting data regarding the overall prevalence of such mutations in obesity and limited information is available on the functional defects caused by most obesity-associated MC4R mutations. We report here the screening for mutations in the coding region of the MC4R of a new cohort of 172 patients presenting with severe childhood obesity and a family history of obesity. Three heterozygous MC4R mutations (Ser127Leu, Ala244Glu and Pro299His) were found in three patients of this cohort (1.74%), confirming that such mutations are implicated in a significant number of childhood obesity cases. A functional analysis of these mutant receptors, in addition to 11 other childhood obesity-associated MC4R mutations, indicates that they all alter the activation of the receptor by the endogenous agonist alpha-MSH. To further examine the functional defects caused by childhood obesity-associated MC4R mutations, we developed a novel, sensitive technique to quantitatively analyze the effect of a mutation on MC4R cell surface expression. Using this method we analyzed the cell surface expression of all the 14 described childhood obesity-associated MC4R missense mutations. We demonstrate that 81.3% of childhood obesity-associated heterozygous MC4R mutations lead to intracellular retention of the receptor. This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition

Molecular genetics of human obesity-associated MC4R mutations

Heterozygous coding mutations in the melanocortin 4 receptor (MC4R) are implicated in 1 to 6% of early onset or severe adult obesity cases. To better address the problem of the genotype:phenotype relationship within this specific form of obesity, we systematically studied the functional characteristics of 50 different obesity-associated MC4R mutations. Structure modeling of MC4R indicates that obesity-associated MC4R mutations are not localized in a single domain of the protein. We developed a flow cytometry-based assay to compare cell membrane expression of obesity-associated MC4R mutants. Using this assay, we demonstrate that over 54% of the obesity-associated MC4R mutations impair the membrane expression of MC4R. All other mutations impair the basal constitutive activity and/or the EC(50) for the physiological agonist alpha-MSH as measured in a cAMP- dependent luciferase assay. The extent of the alterations in receptor activity ranges from a total suppression of MC4R activation in response to alpha-MSH to a mild alteration of the basal constitutive activity of the receptor. Since most patients are heterozygous for MC4R mutations, these data indicate that a small decrease in overall MC4R activity can cause obesity, strongly supporting the hypothesis that the MC4R is a critical component of the adipostat in humans.Journal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.ReviewFLWINinfo:eu-repo/semantics/publishedThe Melanocortin Syste

Association between CST3 rs2424577 polymorphism and corpulence related phenotypes during lifetime in populations of European ancestry

Objective: Cystatin C, a protein coded by CST3 gene, is implicated in adipose tissue biology. Our hypothesis is that common variants in CST3 gene could play a role in the development of corpulence during lifetime. Methods: Two tag SNPs were selected to capture all SNPs in the CST3 region. We first investigated the association of the two tag SNPs individually and combined into haplotypes with corpulence related phenotypes in 4,288 French subjects (BMI = 24.31 +/- 3.74 kg/m(2)). Significant findings were replicated in five independent populations 790 Danish lean men (BMI = 24.63 +/- 2.30 kg/m(2)), 672 Danish obese men (BMI = 33.23 +/- 2.34 kg/m(2)), 763 Swedish women (BMI = 21.73 +/- 2.87 kg/m(2)), 1,848 Danish lean women (BMI = 22.66 +/- 2.85 kg/m(2)) and 2,061 Danish obese women (BMI = 37.01 +/- 3.59 kg/m(2)). Results: Rs2424577 was associated with BMI in three independent populations - G/G carriers were less corpulent than A/A carriers in the French individuals (p = 0.045) and in the Danish lean men (p = 0.021), and they were more corpulent in the group of Swedish women (p = 0.004). This phenomenon has been described as a flip-flop phenomenon, probably caused by a multi-locus effect. Conclusion: CST3 rs2424577 is associated with BMI in a complex fashion. This association is probably caused by the interaction between several functional variants

Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity

International audienceIn contrast to the melanocortin 4 receptor, the possible role of the melanocortin 3 receptor (MC3R) in regulating body weight is still debated. We have previously reported three mutations in the MC3R gene showing association with human obesity, but these results were not confirmed in a study of severe obese North American adults. In this study, we evaluated the entire coding region of MC3R in 839 severely obese subjects and 967 lean controls of Italian and French origin. In vitro functional analysis of the mutations detected was also performed. The total prevalence of rare MC3R variants was not significantly different in obese subjects when compared with controls (P = 0.18). However, the prevalence of mutations with functional alterations was significantly higher in the obese group (P = 0.022). In conclusions, the results of this large study demonstrate that in the populations studied functionally significant MC3R variants are associated with obesity supporting the current hypothesis that rare variants might have a stronger impact on the individual susceptibility to gain weight. They also underline the importance of detailed in vitro functional studies in order to prove the pathogenic effect of such variants. Further investigations in larger cohorts will be needed in order to define the specific phenotypic characteristics potentially correlated with reduced MC3R signallin