To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 × 10−17), 8q24.21 (rs4295627, CCDC26; P = 2.34 × 10−18), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 × 10−15), 20q13.33 (rs6010620, RTEL1; P = 2.52 × 10−12) and 11q23.3 (rs498872, PHLDB1; P = 1.07 × 10−8). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that actsas an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs. AMP-activated protein kinase (AMPK)1 plays a pivotal role in the regulation of energy metabolism and has been dubbed a cellular fuel gauge (1). AMPK is activated following an increase in the AMP:ATP ratio within the cell that occurs following a decrease in ATP levels (2, 3). Once activated, AMPK switches on ATP-generating (catabolic) pathways, e.g. fatty acid oxidation, and switches off ATP-using pathways (anabolic) pathways, e.g. fatty acid synthesis, allowing the cell to restore its energy balance (2, 3). In addition to acute effects on metabolism, AMPK has more long term effects, altering both gene (4) and protein expression (5, 6). Recent results have demonstrated activation of AMPK in the absence of changes in adenine nucleotide levels, indicating that there may be multiple pathways upstream of AMPK (7,8). The molecular mechanisms leading to activation of AMPK have not been fully elucidated, but it is clear that activation of AMPK requires phosphorylation of threonine 172 (Thr 172 ) within the activation loop segment of the catalytic (␣) subunit (9, 10). Very recently, LKB1, a protein kinase that is inactivated in a hereditary form of cancer termed Peutz-Jeghers syndrome, was shown to account for most of the AMPK kinase activity in cell extracts (11,12) raising the possibility that AMPK could l...

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10−9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10−10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10−8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10−11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10−10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10−9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10−10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10−10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10−9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10−8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10−10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10−11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10−9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Background— Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Methods and Results— Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS 2 and CHA 2 DS 2 -VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 μg/L, n=2663; 0.010 to 0.019 μg/L, n=2006; 0.020 to 0.039 μg/L, n=1023; ≥0.040 μg/L, n=497; and on NT-proBNP concentration quartiles: <387; 387 to 800; 801 to 1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17–3.39]; P =0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41–4.07]; P =0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05–6.29]; P <0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95–11.49]; P <0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P <0.0001, for a composite of thromboembolic events. Conclusions— Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.