Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation.

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 = 1.85×10−8 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 = 4.84×10−7), 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 ∼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.

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ECMO treatment does not predict mortality in patients with most severe ARDS.

Pulmonary artery hypertension has a high prevalence in patients with severe ARDS. Measurement of PAT diameter on admission CT scan is an unreliable tool for identification of ARDS patients with pulmonary hypertension.

During the 2003 heat wave an increase in mortality was observed in several European countries. Evidence suggests that the heat wave effect on mortality varies based upon underlying disease. In this study we examined the effects of the 2003 heat wave on all-cause and cause-specific mortality (neoplasms, cardiovascular and respiratory diseases) in a large west German city. Daily weather data for Essen was obtained from the German meteorological service. Death certificates for all deaths in Essen from 2002 to 2003 were coded according to the World Health Organization (WHO) guidelines. Mean numbers of daily deaths during and after the heat wave were compared with the average mortality in summer months (reference period). Poisson generalized additive models, adjusted for weekday and season, were fitted for overall and cause-specific mortality for the entire study period. During the 2003 heat wave (August 6-12), daily mortality increased by 15% (neoplasms), 30% (cardiovascular), and 61% (respiratory), with a decrease in the week after the heat wave of 17% for neoplasms and a sustained rise for respiratory mortality (77%). Regression analysis showed an association between heat and overall mortality in 2003 and greatest associations for respiratory mortality. Even the comparatively short heat wave in Essen in the year 2003 was associated with a rise in overall and cause-specific mortality. Different mechanisms appear to influence cause-specific mortality, with strongest associations for respiratory mortality. Harvesting might play a role in mortality due to neoplasms.

GeneticsRecent genome-wide association studies (GWAS) conducted in population-based samples assessed for BMI or in case-control samples assessed for extreme obesity led to the discovery of genetic loci relevant for body-weight regulation (reviewed in ref. 1). Taken together variants at 32 loci have been reported to be associated to BMI (ref. 2, n = 249,796). In addition, Meyre et al. (3) reported five loci to be relevant for extreme obesity (n = 16,982). Common to all these studies is their relative focus on adults.Focusing on children and adolescents, a GWAS meta-analysis (ref. 4; n = 2,258) confirmed three known loci for obesity (FTO, MC4R, and TMEM18) and provided evidence for two new loci (SDCCAG8 and TNKS/MSRA) with the latter finding being limited to children and adolescents. A total of 36,468 individuals (8,092 children and adolescents) were genotyped for the confirmation.Here, we explore the effect of 10 single-nucleotide polymorphisms (SNPs) representative of the five loci on measures of weight loss and cardiometabolic risk profile change after a lifestyle intervention for obese humans. We analyzed the SNPs in 401 overweight children and adolescents completing a 1-year lifestyle intervention. In addition, we investigated the SNPs which were significantly associated with weight loss in an independent sample of 626 adults who completed a 10-week intervention with a focus on a hypoenergetic diet (NUGENOB).Baseline characteristics and their changes of the overweight children and adolescents who completed the "Obeldicks" intervention are shown in Table 1. Associations of the 10 analyzed "obesity-SNPs" to weight loss-related effects are shown in Table 2. Genotype-dependent effects on overweight reduction as measured by BMI-standard deviation score (SDS) changes were Genome-wide association analyses (GWAS) contributed to the detection of a number of single-nucleotide polymorphisms (SNPs) associated with obesity. However, little is known about the impact of the obesity-risk alleles on weight loss-related phenotypes after lifestyle interventions. A recent meta-analysis of GWAS reported five genomic loci near or in the genes FTO, MC4R, TMEM18, SDCCAG8, TNKS/MSRA that were associated with obesity in children and adolescents. Here, we analyzed the effect of the 10 SNPs representative of the five loci on measures of weight loss and cardiometabolic risk after a 1-year lifestyle intervention in 401 children and adolescents (mean age 10.74 years; 55.4% female; mean BMI 27.42 kg/m 2 , mean BMI-standard deviation score (SDS) 2.37). For confirmation of one locus genotyping of three intronic SNPs in SDCCAG8 was performed in 626 obese adults who completed the 10-week hypoenergetic diet program. Intronic variants of SDCCAG8, which are associated with early onset obesity, are associated with reduced weight loss after a 1-year lifestyle intervention in overweight children and adolescents even after adjusting for age, sex, baseline measurement, or multiple testing (all P < 10 −6). However, our results could not be confirmed i...

Objective: Association with obesity and increased insulin levels have been reported for two variants (rs17782313 and rs12970134) located downstream of the melanocortin-4 receptor gene (MC4R). Methods: We investigated whether these variants have sex-specific effects on overweight, obesity and 14 related phenotypes in 889 overweight and obese children and adolescents. We also explored the impact of the variants on weight change in 367 of the 889 cases who participated in an intervention program. Prior to these analyses we showed that both variants were associated with overweight/obesity in the analyzed 889 cases versus 442 normal-weight and lean controls (case-control study). Results: In explorative analyses we observed higher diastolic blood pressure levels in males (rs17782313: β = 2.52 mm Hg per risk allele; p = 0.003) but reduced blood pressure level in females for the same risk allele (β = –1.72 mm Hg; p = 0.039). We also detected a greater BMI standard deviation score (BMI-SDS) reduction in females with the risk allele at rs17782313 (β = 0.086 per risk allele; p = 0.021). Additionally, we observed evidence for an association of the same risk allele with insulin levels (β = 0.029 log (µU/ml); p = 0.044) with no sex-specific effect. For the remaining 11 phenotypes, we observed no evidence for a (sex-specific) association. Conclusions: In sum, our data support the associations of variants rs17782313 and rs12970134 near MC4R with early onset obesity and increased insulin levels. Exploratory evidence for sex-specific effects of the risk alleles were observed for diastolic blood pressure and BMI-SDS reduction.