Genomic insights into early-onset obesity

The biological causes of childhood obesity are complex. Environmental factors, such as massive marketing campaigns for food leading to over-nutrition and snacking and the decline in physical activity, have undoubtedly contributed to the increased prevalence of overweight and obesity in children, but these cannot be considered as the only causes. Susceptibility to obesity is also determined to a great extent by genetic factors. Furthermore, molecular mechanisms involved in the regulation of gene expression, such as epigenetic mechanisms, can increase the risk of developing early-onset obesity. There is evidence that early-onset obesity is a heritable disorder, and a range of genetic factors have recently been shown to cause monogenic, syndromic and polygenic forms of obesity, in some cases interacting with environmental exposures. Modifications of the transcriptome can lead to increased adiposity, and the gut microbiome has recently been shown to be key to the genesis of obesity. These new genomic discoveries complement previous knowledge on the development of early-onset obesity and provide new perspectives for research on the complex molecular and physiological mechanisms involved in this disease. Personalized preventive strategies and genomic medicine may become possible in the near future

ENPP1, premier exemple d’un déterminant génétique commun à l’obésité et au diabète de type 2

L’obésité, en particulier ses formes sévères, est l’un des principaux facteurs de risque de diabète de type 2. Par ailleurs, l’explosion de l’épidémie d’obésité infantile s’accompagne de l’apparition de formes précoces de diabète de type 2, avec un syndrome métabolique et une intolérance au glucose détectables dès l’adolescence. Ces données suggèrent l’existence de déterminants moléculaires primitifs communs entre obésité sévère et précoce et diabète de type 2, qui partageraient une insulinorésistance génétiquement déterminée. Dans ce contexte, l’identification, sur la région chromosomique 6q liée à la « diabésité », du gène ENPP1 codant pour un inhibiteur du récepteur de l’insuline, dont des variants codants et non codants contribuent au risque génétique de cette affection, est un pas vers la dissection génétique des obésités les plus diabétogènes. Ces résultats ouvrent des perspectives nouvelles vers le profilage génétique et biologique des adolescents obèses, dans une optique de prévention et de traitement de la « diabésité » et de ses complications vasculaires.Clinical studies have established the strong link between obesity and type 2 diabetes, especially in children, where the rising prevalence of childhood severe obesity has preceded the recent emergence of early-onset forms of “diabesity”. These data suggested a common genetic background shared by both conditions, which was also supported by the identification by genome scans of several diabesity chromosomal regions of linkage. The genetic investigation of early-onset form of familial obesity linkage to chromosome 6q led to the identification of ENPP1, an inhibitor of the insulin receptor, as a possible molecular mechanism behind both obesity and type 2 diabetes. Analysis of the DNA variations of ENPP1 in 6,147 subjects showed association between a combination of variants and both childhood obesity, morbid or moderate obesity in adults and also with type 2 diabetes. This study provides a first molecular basis for the physiopathologic association between severe insulin resistance and obesity, and further type 2 diabetes, and offers a new perspective for prevention and treatment of these conditions

Molecular Basis of Obesity: Current Status and Future Prospects

Obesity is a global health problem that is gradually affecting each continent of the world. Obesity is a heterogeneous disorder, and the biological causes of obesity are complex. The rapid increase in obesity prevalence during the past few decades is due to major societal changes (sedentary lifestyle, over-nutrition) but who becomes obese at the individual level is determined to a great extent by genetic susceptibility. In this review, we evidence that obesity is a strongly heritable disorder, and provide an update on the molecular basis of obesity. To date, nine loci have been involved in Mendelian forms of obesity and 58 loci contribute to polygenic obesity, and rare and common structural variants have been reliably associated with obesity. Most of the obesity genes remain to be discovered, but promising technologies, methodologies and the use of “deep phenotyping” lead to optimism to chip away at the ‘missing heritability’ of obesity in the near future. In the longer term, the genetic dissection of obesity will help to characterize disease mechanisms, provide new targets for drug design, and lead to an early diagnosis, treatment, and prevention of obesity

Genetics of Obesity: What have we Learned?

Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics and obesity. We comment on the existence of the genetic continuum between monogenic and polygenic forms of obesity that pinpoints the role of genes involved in the central regulation of food intake and genetic predisposition to obesity. We explain how the identification of novel obesity predisposing genes has clarified unsuspected biological pathways involved in the control of energy balance that have helped to understand past human history and to explore causality in epidemiology. We provide evidence that obesity predisposing genes interact with the environment and influence the response to treatment relevant to disease prediction

Approaches to detect genetic effects that differ between two strata in genome-wide meta-analyses: Recommendations based on a systematic evaluation.

Genome-wide association meta-analyses (GWAMAs) conducted separately by two strata have identified differences in genetic effects between strata, such as sex-differences for body fat distribution. However, there are several approaches to identify such differences and an uncertainty which approach to use. Assuming the availability of stratified GWAMA results, we compare various approaches to identify between-strata differences in genetic effects. We evaluate type I error and power via simulations and analytical comparisons for different scenarios of strata designs and for different types of between-strata differences. For strata of equal size, we find that the genome-wide test for difference without any filtering is the best approach to detect stratum-specific genetic effects with opposite directions, while filtering for overall association followed by the difference test is best to identify effects that are predominant in one stratum. When there is no a priori hypothesis on the type of difference, a combination of both approaches can be recommended. Some approaches violate type I error control when conducted in the same data set. For strata of unequal size, the best approach depends on whether the genetic effect is predominant in the larger or in the smaller stratum. Based on real data from GIANT (>175 000 individuals), we exemplify the impact of the approaches on the detection of sex-differences for body fat distribution (identifying up to 10 loci). Our recommendations provide tangible guidelines for future GWAMAs that aim at identifying between-strata differences. A better understanding of such effects will help pinpoint the underlying mechanisms

Structured diet and exercise guidance in pregnancy to improve health in women and their offspring: study protocol for the Be Healthy in Pregnancy (BHIP) randomized controlled trial

BackgroundEvidence from epidemiological and animal studies support the concept of programming fetal, neonatal, and adult health in response to in utero exposures such as maternal obesity and lifestyle variables. Excess gestational weight gain (GWG), maternal physical activity, and sub-optimal and excess nutrition during pregnancy may program the offspring\u27s risk of obesity. Maternal intake of dairy foods rich in high-quality proteins, calcium, and vitamin D may influence later bone health status. Current clinical practice guidelines for managing GWG are not founded on randomized trials and lack specific active intervention ingredients. The Be Healthy in Pregnancy (BHIP) study is a randomized controlled trial (RCT) designed to test the effectiveness of a novel structured and monitored Nutrition + Exercise intervention in pregnant women of all pre-pregnancy weight categories (except extreme obesity), delivered through prenatal care in community settings (rather than in hospital settings), on the likelihood of women achieving recommended GWG and a benefit to bone status of offspring and mother at birth and sixmonths postpartum.MethodsThe BHIP study is a two-site RCT that will recruit up to 242 participants aged \u3e18years at 12-17 weeks of gestation. After baseline measures, participants are randomized to either a structured and monitored Nutrition + Exercise (intervention) or usual care (control) program for the duration of their pregnancy. The primary outcome of the study is the percent of women who achieve GWG within the Institute of Medicine (IOM) guidelines. The secondary outcomes include: (1) maternal bone status via blood bone biomarkers during pregnancy; (2) infant bone status in cord blood; (3) mother and infant bone status measured by dual-energy absorptiometry scanning (DXA scan) at sixmonths postpartum; (4) other measures including maternal blood pressure, blood glucose and lipid profiles, % body fat, and postpartum weight retention; and (5) infant weight z-scores and fat mass at sixmonths of age.DiscussionIf effective, this RCT will generate high-quality evidence to refine the nutrition guidelines during pregnancy to improve the likelihood of women achieving recommended GWG. It will also demonstrate the importance of early nutrition on bone health in the offspring

Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 x 10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84 x 10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at similar to 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults

Estimation of newborn risk for child or adolescent obesity:lessons from longitudinal birth cohorts

OBJECTIVES: Prevention of obesity should start as early as possible after birth. We aimed to build clinically useful equations estimating the risk of later obesity in newborns, as a first step towards focused early prevention against the global obesity epidemic. METHODS: We analyzed the lifetime Northern Finland Birth Cohort 1986 (NFBC1986) (N = 4,032) to draw predictive equations for childhood and adolescent obesity from traditional risk factors (parental BMI, birth weight, maternal gestational weight gain, behaviour and social indicators), and a genetic score built from 39 BMI/obesity-associated polymorphisms. We performed validation analyses in a retrospective cohort of 1,503 Italian children and in a prospective cohort of 1,032 U.S. children. RESULTS: In the NFBC1986, the cumulative accuracy of traditional risk factors predicting childhood obesity, adolescent obesity, and childhood obesity persistent into adolescence was good: AUROC = 0·78[0·74-0.82], 0·75[0·71-0·79] and 0·85[0·80-0·90] respectively (all p\u3c0·001). Adding the genetic score produced discrimination improvements ≤1%. The NFBC1986 equation for childhood obesity remained acceptably accurate when applied to the Italian and the U.S. cohort (AUROC = 0·70[0·63-0·77] and 0·73[0·67-0·80] respectively) and the two additional equations for childhood obesity newly drawn from the Italian and the U.S. datasets showed good accuracy in respective cohorts (AUROC = 0·74[0·69-0·79] and 0·79[0·73-0·84]) (all p\u3c0·001). The three equations for childhood obesity were converted into simple Excel risk calculators for potential clinical use. CONCLUSION: This study provides the first example of handy tools for predicting childhood obesity in newborns by means of easily recorded information, while it shows that currently known genetic variants have very little usefulness for such prediction

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

Helicobacter pylori colonization and obesity - A Mendelian randomization study

Obesity is associated with substantial morbidity, costs, and decreased life expectancy, and continues to rise worldwide. While etiological understanding is needed for prevention, epidemiological studies indicated that colonization with Helicobacter pylori (H. pylori) may affect body mass index (BMI), but with inconsistent results. Here, we examine the relationship between H. pylori colonization and BMI/obesity. Cross-sectional analyses were performed in two independent population-based cohorts of elderly from the Netherlands and Germany (n = 13,044). Genetic risk scores were conducted based on genetic loci associated with either H. pylori colonization or BMI/obesity. We performed a bi-directional Mendelian randomization. Meta-analysis of cross-sectional data revealed no association between anti-H. pylori IgG titer and BMI, nor of H. pylori positivity and BMI. Anti-H. pylori IgG titer was negatively associated with obesity (OR 0.99972; 95% CI 0.99946-0.99997, p = 0.03) and with obesity classes (Beta -6.91 •10-5; 95% CI -1.38•10-4, -5.49•10-7, p = 0.048), but the magnitude of these effects was limited. Mendelian randomization showed no causal relation between H. pylori genetic risk score and BMI/obesity, nor between BMI or obesity genetic risk scores and H. pylori positivity. This study provides no evidence for a clinically relevant association between H. pylori and BMI/obesity