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BackgroundGenome-wide association studies (GWAS) have identified more than 250 loci associated with body mass index (BMI) and obesity. However, post-GWAS functional genomic investigations have been inadequate for understanding how these genetic loci physiologically impact disease development.MethodsWe performed a PCR-free expression assay targeting genes located nearby the GWAS-identified SNPs associated with BMI/obesity in a large panel of human tissues. Furthermore, we analyzed several genetic risk scores (GRS) summing GWAS-identified alleles associated with increased BMI in 4236 individuals.ResultsWe found that the expression of BMI/obesity susceptibility genes was strongly enriched in the brain, especially in the insula (p = 4.7 × 10–9) and substantia nigra (p = 6.8 × 10–7), which are two brain regions involved in addiction and reward. Inversely, we found that top obesity/BMI-associated loci, including FTO, showed the strongest gene expression enrichment in the two brain regions.ConclusionsOur data suggest for the first time that the susceptibility genes for common obesity may have an effect on eating addiction and reward behaviors through their high expression in substantia nigra and insula, i.e., a different pattern from monogenic obesity genes that act in the hypothalamus and cause hyperphagia. Further epidemiological studies with relevant food behavior phenotypes are necessary to confirm these findings.

Philippe Froguel and colleagues report an analysis of large chromosomal clonal mosaic events in individuals with type 2 diabetes. They find a significant association between CME occurrence and T2D with vascular complications. Large chromosomal clonal mosaic events (CMEs) have been suggested to be linked to aging 1 , 2 , 3 and to predict cancer 2 , 3 . Type 2 diabetes (T2D) has been conceptualized as an accelerated-aging disease 4 , 5 , 6 and is associated with higher prevalence of cancers 7 , 8 , 9 , 10 , 11 . Here we aimed to assess the association between T2D and CME occurrence in blood. We evaluated the presence of CMEs in 7,659 individuals (including 2,208 with T2D) using DNA arrays. A significant association between CME occurrence and T2D was found (odds ratio (OR) = 5.3; P = 5.1 × 10 −5 ) and was stronger when we only considered non-obese individuals with T2D (OR = 5.6; P = 4.9 × 10 −5 ). Notably, CME carriers with T2D had higher prevalence of vascular complications than non-carriers with T2D (71.4% versus 37.1%, respectively; P = 7.7 × 10 −4 ). In CME carriers, we found an increase in the percentage of abnormal cells over 6 years ( P = 8.60 × 10 −3 ). In conclusion, given the increased risk of cancer in CME carriers 2 , 3 , our results may have profound clinical implications in patients with severe T2D.

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. 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. 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<0·001). 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<0·001). The three equations for childhood obesity were converted into simple Excel risk calculators for potential clinical use. 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.

The \"mechanistic target of rapamycin\" (mTOR) is a central controller of growth, proliferation and/or motility of various cell-types ranging from adipocytes to immune cells, thereby linking metabolism and immunity. mTOR signaling is overactivated in obesity, promoting inflammation and insulin resistance. Therefore, great interest exists in the development of mTOR inhibitors as therapeutic drugs for obesity or diabetes. However, despite a plethora of studies characterizing the metabolic consequences of mTOR inhibition in rodent models, its impact on immune changes associated with the obese condition has never been questioned so far. To address this, we used a mouse model of high-fat diet (HFD)-fed mice with and without pharmacologic mTOR inhibition by rapamycin. Rapamycin was weekly administrated to HFD-fed C57BL/6 mice for 22 weeks. Metabolic effects were determined by glucose and insulin tolerance tests and by indirect calorimetry measures of energy expenditure. Inflammatory response and immune cell populations were characterized in blood, adipose tissue and liver. In parallel, the activities of both mTOR complexes (e. g. mTORC1 and mTORC2) were determined in adipose tissue, muscle and liver. We show that rapamycin-treated mice are leaner, have enhanced energy expenditure and are protected against insulin resistance. These beneficial metabolic effects of rapamycin were associated to significant changes of the inflammatory profiles of both adipose tissue and liver. Importantly, immune cells with regulatory functions such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were increased in adipose tissue. These rapamycin-triggered metabolic and immune effects resulted from mTORC1 inhibition whilst mTORC2 activity was intact. Taken together, our results reinforce the notion that controlling immune regulatory cells in metabolic tissues is crucial to maintain a proper metabolic status and, more generally, comfort the need to search for novel pharmacological inhibitors of the mTOR signaling pathway to prevent and/or treat metabolic diseases.

Accurate molecular diagnosis of monogenic non-autoimmune neonatal diabetes mellitus (NDM) is critical for patient care, as patients carrying a mutation in KCNJ11 or ABCC8 can be treated by oral sulfonylurea drugs instead of insulin therapy. This diagnosis is currently based on Sanger sequencing of at least 42 PCR fragments from the KCNJ11, ABCC8, and INS genes. Here, we assessed the feasibility of using the next-generation whole exome sequencing (WES) for the NDM molecular diagnosis. We carried out WES for a patient presenting with permanent NDM, for whom mutations in KCNJ11, ABCC8 and INS and abnormalities in chromosome 6q24 had been previously excluded. A solution hybridization selection was performed to generate WES in 76 bp paired-end reads, by using two channels of the sequencing instrument. WES quality was assessed using a high-resolution oligonucleotide whole-genome genotyping array. From our WES with high-quality reads, we identified a novel non-synonymous mutation in ABCC8 (c.1455G>C/p.Q485H), despite a previous negative sequencing of this gene. This mutation, confirmed by Sanger sequencing, was not present in 348 controls and in the patient's mother, father and young brother, all of whom are normoglycemic. WES identified a novel de novo ABCC8 mutation in a NDM patient. Compared to the current Sanger protocol, WES is a comprehensive, cost-efficient and rapid method to identify mutations in NDM patients. We suggest WES as a near future tool of choice for further molecular diagnosis of NDM cases, negative for chr6q24, KCNJ11 and INS abnormalities.

ACDC/Adiponectin Polymorphisms Are Associated With Severe Childhood and Adult Obesity Nabila Bouatia-Naji 1 , David Meyre 1 , Stéphane Lobbens 1 , Karin Séron 1 , Frédéric Fumeron 2 , Beverley Balkau 3 , Barbara Heude 3 , Béatrice Jouret 4 , Philipp E. Scherer 5 , Christian Dina 1 , Jacques Weill 6 and Philippe Froguel 1 7 1 Centre National de la Recherche Scientifique UMR8090, Pasteur Institute of Lille, Lille, France 2 Institut National de la Santé et de la Recherche Médicale (INSERM) U695, Faculty of Medicine Xavier Bichat, Paris, France 3 INSERM, U258-IFR69, Faculty of Medicine Paris Sud, Villejuif, France 4 INSERM U563, Children’s Hospital, Toulouse, France 5 Department of Cell Biology and Diabetes Research and Training Centre, Albert Einstein College of Medicine, Bronx, New York 6 Pediatric Endocrine Unit, Jeanne de Flandre Hospital, Lille, France 7 Genomic Medicine and Genome Centre, Hammersmith Campus, Imperial College, London, U.K Address correspondence and reprint requests to Philippe Froguel, Genomic Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, U.K. E-mail: p.froguel{at}imperial.ac.uk Abstract Common single nucleotide polymorphisms (SNPs) in the ACDC adiponectin encoding gene have been associated with insulin resistance and type 2 diabetes in several populations. Here, we investigate the role of SNPs −11,377C>G, −11,391G>A, +45T>G, and +276G>T in 2,579 French Caucasians (1,229 morbidly obese and 1,350 control subjects). We found an association between severe forms of obesity and −11,377C (odds ratio 1.23, P = 0.001) and +276T (1.19, P = 0.006). Surprisingly, alternative alleles −11,377G and +276G have been previously reported as risk factors for type 2 diabetes. Transmission disequilibrium tests showed a trend in overtransmission (56.7%) of a risk haplotype 1 (C) -1 (G) -1 (T) -2 (T) including −11,377C and +276T in 634 obesity trios ( P = 0.097). Family-based analysis in 400 trios from the general population indicated association between obesity haplotype and higher adiponectin levels, suggesting a role of hyperadiponectinemia in weight gain. However, experiments studying the putative roles of SNPs −11,377C>G and +276G>T on ACDC functionality were not conclusive. In contrast, promoter SNP −11,391G>A was associated with higher adiponectin levels in obese children ( P = 0.005) and in children from the general population (0.00007). In vitro transcriptional assays showed that −11,391A may increase ACDC activity. In summary, our study suggests that variations at the ACDC /adiponectin gene are associated with risk of severe forms of obesity. However, the mechanisms underlying these possible associations are not fully understood. EMSA, electrophoretic mobility shift assay FLVS, Fleurbaix-Laventie Ville Santé SNP, single nucleotide polymorphism TDT, transmission disequilibrium test Footnotes Additional information on this brief genetics report can be found in an online appendix available from http://diabetes.diabetesjournals.org . Accepted October 19, 2005. Received July 29, 2005. DIABETES

Aims/hypothesis Genome-wide association studies have firmly established 65 independent European-derived loci associated with type 2 diabetes and 36 loci contributing to variations in fasting plasma glucose (FPG). Using individual data from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study, we evaluated the contribution of three genetic risk scores (GRS) to variations in metabolic traits, and to the incidence and prevalence of impaired fasting glycaemia (IFG) and type 2 diabetes. Methods Three GRS (GRS-1, 65 type 2 diabetes-associated single nucleotide polymorphisms [SNPs]; GRS-2, GRS-1 combined with 24 FPG-raising SNPs; and GRS-3, FPG-raising SNPs alone) were analysed in 4,075 DESIR study participants. GRS-mediated effects on longitudinal variations in quantitative traits were assessed in 3,927 nondiabetic individuals using multivariate linear mixed models, and on the incidence and prevalence of hyperglycaemia at 9 years using Cox and logistic regression models. The contribution of each GRS to risk prediction was evaluated using the C-statistic and net reclassification improvement (NRI) analysis. Results The two most inclusive GRS were significantly associated with increased FPG (β = 0.0011 mmol/l per year per risk allele, p GRS-1  = 8.2 × 10 −5 and p GRS-2  = 6.0 × 10 −6 ), increased incidence of IFG and type 2 diabetes (per allele: HR GRS-1 1.03, p  = 4.3 × 10 −9 and HR GRS-2 1.04, p  = 1.0 × 10 −16 ), and the 9 year prevalence (OR GRS-1 1.13 [95% CI 1.10, 1.17], p  = 1.9 × 10 −14 for type 2 diabetes only; OR GRS-2 1.07 [95% CI 1.05, 1.08], p  = 7.8 × 10 −25 , for IFG and type 2 diabetes). No significant interaction was found between GRS-1 or GRS-2 and potential confounding factors. Each GRS yielded a modest, but significant, improvement in overall reclassification rates (NRI GRS-1 17.3%, p  = 6.6 × 10 −7 ; NRI GRS-2 17.6%, p  = 4.2 × 10 −7 ; NRI GRS-3 13.1%, p  = 1.7 × 10 −4 ). Conclusions/interpretation Polygenic scores based on combined genetic information from type 2 diabetes risk and FPG variation contribute to discriminating middle-aged individuals at risk of developing type 2 diabetes in a general population.

It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.

Although cross-sectional studies have associated the Pro12Ala polymorphism of PPARG with type 2 diabetes, prospective studies offer more opportunities to investigate genetic variants. Associations between PPARG polymorphisms with insulin resistance parameters and with the 6-year incidence of impaired fasting glucose or type 2 diabetes were tested in 3,914 French Caucasians from the DESIR (Data From an Epidemiological Study on the Insulin Resistance Syndrome) cohort. In subjects normoglycemic at baseline (n = 3,498), the 6-year risk of hyperglycemia was lower in PPARG Ala carriers (odds ratio [OR] vs. ProPro = 0.66 [95% CI 0.44-0.99], P = 0.046 adjusted for sex, age, and BMI). Similar results were found with the PPARG C1431T single nucleotide polymorphism (SNP; adjusted OR = 0.65 [0.44-0.96], P = 0.036). Both alleles are in strong linkage disequilibrium (D' = 0.669, P < 0.001). The baseline mean fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in Ala carriers compared with ProPro homozygotes (P = 0.001 for both), with smaller increases in mean insulin and HOMA-IR during follow-up (P = 0.007 and 0.018, respectively). No association with insulin levels or HOMA-IR was found with C1431T. In this cohort, the APM1 G-11391A SNP is associated with the development of hyperglycemia. The combined effects of PPARG Pro12Ala and APM1 G-11391A SNPs showed no interaction on the risk of 6-year hyperglycemia. The PPARG Ala allele showed a relatively high protective effect in developing hyperglycemia and hyperinsulinemia during a 6-year period. Cumulative rather than synergistic effects of PPARG Pro12Ala and APM1 SNPs on diabetes risk are suggested.

Genetic and environmental factors are involved in insulin resistance (IR). IR and dyslipidemia associate with increased risk of cardiovascular diseases. Plasma low-density lipoprotein cholesterol (LDL-C) level is a marker of cardiovascular risk. In a Caucasian general population we aimed at determining the multifactorial components of LDL-C levels using 10 genes and 3 phenotypes. In the PPARG, UCP3, ADIPOQ, TNF, LIPC, CARTPT, PCSK9, SCAP, SCARB1 and ENPP1 genes known to be associated with IR or dyslipidemia we genotyped 19 single nucleotide polymorphisms (SNPs) in 846 subjects. When several SNPs were genotyped for a given gene we constructed haplotypes. Including genetic and environmental variables (gender, body mass index (BMI) and adiponectin level) we used (1) the multifactor dimensionality reduction method to explain clusters of high and low LDL-C, and (2) the restricted partition method to explain LDL-C levels. Both methods showed that BMI and haplotypes at the ADIPOQ adiponectin encoding gene but not adiponectin level itself, were discriminant regarding to LDL-C. Subjects bearing an at-risk combination of BMI and ADIPOQ genotypes were prone to have a higher LDL-C (OR=3.13, 95% CI=2.20–4.46, P <0.0001). Our results suggest that in interaction with BMI, ADIPOQ haplotypes capture genetic variation(s) from neighboring gene(s) that would modulate LDL-C level.