Analysis of sequence variability in the CART gene in relation to obesity in a Caucasian population

BACKGROUND: Cocaine and amphetamine regulated transcript (CART) is an anorectic neuropeptide located principally in hypothalamus. CART has been shown to be involved in control of feeding behavior, but a direct relationship with obesity has not been established. The aim of this study was to evaluate the effect of polymorphisms within the CART gene with regards to a possible association with obesity in a Caucasian population. RESULTS: Screening of the entire gene as well as a 3.7 kb region of 5' upstream sequence revealed 31 SNPs and 3 rare variants ; 14 of which were subsequently genotyped in 292 French morbidly obese subjects and 368 controls. Haplotype analysis suggested an association with obesity which was found to be mainly due to SNP-3608T>C (rs7379701) (p = 0.009). Genotyping additional cases and controls also of European Caucasian origin supported further this possible association between the CART SNP -3608T>C T allele and obesity (global p-value = 0.0005). Functional studies also suggested that the SNP -3608T>C could modulate nuclear protein binding. CONCLUSION: CART SNP -3608T>C may possibly contribute to the genetic risk for obesity in the Caucasian population. However confirmation of the importance of the role of the CART gene in energy homeostasis and obesity will require investigation and replication in further populations

Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features

Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi–like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi–like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi–like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers’ relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi–like features.Amélie Bonnefond, Anne Raimondo, Fanny Stutzmann, Maya Ghoussaini, Shwetha Ramachandrappa, David C. Bersten, Emmanuelle Durand, Vincent Vatin, Beverley Balkau, Olivier Lantieri, Violeta Raverdy, François Pattou, Wim Van Hul, Luc Van Gaal, Daniel J. Peet, Jacques Weill, Jennifer L. Miller, Fritz Horber, Anthony P. Goldstone, Daniel J. Driscoll, John B. Bruning, David Meyre, Murray L. Whitelaw and Philippe Frogue

The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: an updated meta-analysis in 49 279 subjects

A recent study reported an association between the brain natriuretic peptide (BNP) promoter T-381C polymorphism (rs198389) and protection against type 2 diabetes (T2D). As replication in several studies is mandatory to confirm genetic results, we analyzed the T-381C polymorphism in seven independent case-control cohorts and in 291 T2D-enriched pedigrees totalling 39 557 subjects of European origin. A meta-analysis of the seven case-control studies (n = 39 040) showed a nominal protective effect [odds ratio (OR) = 0.86 (0.79-0.94), P = 0.0006] of the CC genotype on T2D risk, consistent with the previous study. By combining all available data (n = 49 279), we further confirmed a modest contribution of the BNP T-381C polymorphism for protection against T2D [OR = 0.86 (0.80-0.92), P = 1.4 × 10−5]. Potential confounders such as gender, age, obesity status or family history were tested in 4335 T2D and 4179 normoglycemic subjects and they had no influence on T2D risk. This study provides further evidence of a modest contribution of the BNP T-381C polymorphism in protection against T2D and illustrates the difficulty of unambiguously proving modest-sized associations even with large sample size

Interdisciplinary European guidelines on surgery of severe obesity

W 2005 roku, dzięki wspólnemu wysiłkowi głównych europejskich towarzystw naukowych aktywnych na polu leczenia otyłości został powołany zespół ekspertów nazwany Bariatryczno-Naukową Grupą Badawczą (BSCG). Towarzystwami, które stworzyły ten zespół i oddelegowały swoich przedstawicieli do prac w opracowaniu wytycznych były: Międzynarodowe Towarzystwo Chirurgicznego Leczenia Otyłości (IFSO), Oddział Europejski Międzynarodowego Towarzystwa Chirurgicznego Leczenia Otyłości (IFSO-EC), Europejskie Towarzystwo Badań nad Otyłością (EASO), Europejska Grupa ds. Otyłości u Dzieci (ECOG) (razem z Międzynarodową Grupą Zwalczania Otyłości). Bariatryczno-Naukowa Grupa Badawcza składała się z władz reprezentujących powyższe towarzystwa (czterech czynnych przewodniczących, dwóch byłych, jeden honorowy, dwóch dyrektorów wykonawczych), a także najwybitniejszych ekspertów w tej dziedzinie. Skład BSCG pozwolił na całościowe objęcie zagadnienia leczenia otyłości olbrzymiej z uwzględnieniem różnorodności geograficznej i etnicznej Europy. Członkowie BSCG odbyli wiele spotkań poświęconych stworzeniu wytycznych, które odzwierciedlałyby współczesną wiedzę i doświadczenie w zakresie leczenia otyłości olbrzymiej.In 2005, for the first time in European history, an extraordinary expert panel named BSCG (Bariatric Scientific Collaborative Group), was appointed through joint effort of the major European scientific societies which are active in the field of obesity management. Societies that constituted this panel were: IFSO - International Federation for the Surgery of Obesity, IFSO-EC - International Federation for the Surgery of Obesity - European Chapter, EASO - European Association for Study of Obesity, ECOG - European Childhood Obesity Group, together with the IOTF (International Obesity Task Force) which was represented during the completion process by its representative. The BSCG was composed not only of the top officers representing the respective scientific societies (four acting presidents, two past presidents, one honorary president, two executive directors), but was balanced with the presence of many other key opinion leaders in the field of obesity. The BSCG composition allowed the coverage of key disciplines in comprehensive obesity management, as well as reflecting European geographical and ethnic diversity. This joint BSCG expert panel convened several meetings which were entirely focused on guidelines creation, during the past 2 years. There was a specific effort to develop clinical guidelines, which will reflect current knowledge, expertise and evidence based data on morbid obesity treatment

Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control–Related Traits

OBJECTIVE A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice. RESEARCH DESIGN AND METHODS The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients. RESULTS Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10−7). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10−6) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10−4), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018). CONCLUSIONS HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state

Exploiting nanotechnology to target cancer

Nanotechnology is increasingly finding use in the management of cancer. Nanoscale devices have impacted cancer biology at three levels: early detection using, for example, nanocantilevers or nanoparticles; tumour imaging using radiocontrast nanoparticles or quantum dots; and drug delivery using nanovectors and hybrid nanoparticles. This review addresses some of the major milestones in the integration of nanotechnology and cancer biology, and the future of nanoscale approaches for cancer management

The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies

<p>Abstract</p> <p>Background</p> <p>Considering that a portion of the heterogeneity amongst previous replication studies may be due to a variable proportion of obese subjects in case-control designs, we assessed the association of genetic variants with type 2 diabetes (T2D) in large groups of obese and non-obese subjects.</p> <p>Methods</p> <p>We genotyped <it>RETN</it>, <it>KCNJ11</it>, <it>HNF4A</it>, <it>HNF1A</it>, <it>GCK</it>, <it>SLC30A8</it>, <it>ENPP1</it>, <it>ADIPOQ</it>, <it>PPARG</it>, and <it>TCF7L2 </it>polymorphisms in 1,283 normoglycemic (NG) and 1,581 T2D obese individuals as well as in 3,189 NG and 1,244 T2D non-obese subjects of European descent, allowing us to examine T2D risk over a wide range of BMI.</p> <p>Results</p> <p>Amongst non-obese individuals, we observed significant T2D associations with <it>HNF1A </it>I27L [odds ratio (OR) = 1.14, <it>P </it>= 0.04], <it>GCK </it>-30G>A (OR = 1.23, <it>P </it>= 0.01), <it>SLC30A8 </it>R325W (OR = 0.87, <it>P </it>= 0.04), and <it>TCF7L2 </it>rs7903146 (OR = 1.89, <it>P </it>= 4.5 × 10^-23), and non-significant associations with <it>PPARG </it>Pro12Ala (OR = 0.85, <it>P </it>= 0.14), <it>ADIPOQ </it>-11,377C>G (OR = 1.00, <it>P </it>= 0.97) and <it>ENPP1 </it>K121Q (OR = 0.99, <it>P </it>= 0.94). In obese subjects, associations with T2D were detected with <it>PPARG </it>Pro12Ala (OR = 0.73, <it>P </it>= 0.004), <it>ADIPOQ </it>-11,377C>G (OR = 1.26, <it>P </it>= 0.02), <it>ENPP1 </it>K121Q (OR = 1.30, <it>P </it>= 0.003) and <it>TCF7L2 </it>rs7903146 (OR = 1.30, <it>P </it>= 1.1 × 10^-4), and non-significant associations with <it>HNF1A </it>I27L (OR = 0.96, <it>P </it>= 0.53), <it>GCK </it>-30G>A (OR = 1.15, <it>P </it>= 0.12) and <it>SLC30A8 </it>R325W (OR = 0.95, <it>P </it>= 0.44). However, a genotypic heterogeneity was only found for <it>TCF7L2 </it>rs7903146 (<it>P </it>= 3.2 × 10^-5) and <it>ENPP1 </it>K121Q (<it>P </it>= 0.02). No association with T2D was found for <it>KCNJ11</it>, <it>RETN</it>, and <it>HNF4A </it>polymorphisms in non-obese or in obese individuals.</p> <p>Conclusion</p> <p>Genetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in non-obese individuals.</p

Surgical Prevention of Weight Regain and Type 2 Diabetes Recurrence in 3 Different Bariatric Operations and Their Differential Long-Term Outcome

Introduction:. Comparative data on long-term outcomes of mechanistically different bariatric operations are scarce. Methods:. In this prospective, observational study, consecutive patients with severe obesity were studied using a predefined reoperation algorithm to determine long-term health outcomes after bariatric surgery (BS): adjustable gastric banding (AGB), Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD). All patients were assessed for mortality, postoperative weight loss, rate of reoperation, comorbidities, and quality of life (QoL) 8 years after surgery. Results:. Between 1996 and 2008, 2364 Swiss patients, with a mean body mass index of 43 ± 7 kg/m2 (mean ± SD) underwent AGB (n = 1404), RYGB (n = 790), or BPD (n = 170). Two thousand two hundred twenty-eight (94%) were followed for 8 years after BS. Eight-year mortality of the whole study group was 34.3 per 104 person-years. Percent excessive weight loss at 8 years was 56.7 ± 1.4% (95% confidence interval) in AGB, 62.5 ± 2.4% in RYGB and 64.8+-3.0% in BPD. The rate of major reoperation was highest in AGB and significantly lower in RYGB and BPD (63.4 vs 54.3 vs 47.2 per 103 person-years, P 60%) in procedures involving duodenal exclusion. Total improvement in QoL was similar between the 3 types of operations but was strongly correlated with weight loss preservation (P < 0.001). Conclusions:. BS, at the expense of a high reoperation rate but low procedural mortality, considerably improves the QoL and results in sustained remission of comorbidities, especially T2D using a predefined reoperation algorithm developed to prevent weight regain and operation-specific complications