A shared mechanism of muscle wasting in cancer and Huntington's disease.

Skeletal muscle loss and dysfunction in aging and chronic diseases is one of the major causes of mortality in patients, and is relevant for a wide variety of diseases such as neurodegeneration and cancer. Muscle loss is accompanied by changes in gene expression and metabolism that lead to contractile impairment and likely affect whole-body metabolism and function. The changes may be caused by inactivity, inflammation, age-related factors or unbalanced nutrition. Although links with skeletal muscle loss have been found in diseases with disparate aetiologies, for example both in Huntingtons disease (HD) and cancer cachexia, the outcome is a similar impairment and mortality. This short commentary aims to summarize recent achievements in the identification of common mechanisms leading to the skeletal muscle wasting syndrome seen in diseases as different as cancer and HD. The latter is the most common hereditary neurodegenerative disorder and muscle wasting is an important component of its pathology. In addition, possible therapeutic strategies for anti-cachectic treatment will be also discussed in the light of their translation into possible therapeutic approaches for HD

Overweight in relation to allergic disease in childhood and adolescence

The prevalences of childhood overweight and allergic diseases have increased in parallel during the last decades. The overall aim of this thesis was to investigate the associations between overweight (maternal and childhood) and allergic diseases, as well as lung function, throughout childhood up to adolescence. In addition, we investigated the validity of self-reported height, weight and corresponding body mass index (BMI) among Swedish adolescents. All studies were based on the BAMSE study, a population-based birth cohort of 4,089 children followed until age 16 years. Maternal BMI was obtained from the Swedish medical birth register, while childhood BMI was measured at clinical investigations, collected from child and school health care records and self-reported. Allergic diseases were assessed by repeated questionnaires regarding symptoms and medications, while allergic sensitization to inhalant allergens was defined by the presence of specific immunoglobulin E (IgE)-antibodies in blood. Lung function was measured by spirometry at 8 and 16 years and by impulse oscillometry (IOS) at 16 years. The results of Study I showed that maternal BMI in early pregnancy was associated with asthma, but not rhinitis, eczema or allergic sensitization in the offspring up to 16 years. The association was strongest for persistent asthma, while no increased risk was observed for transient asthma. Categorization of maternal BMI showed that maternal obesity, but not overweight, was significantly associated with childhood asthma. However, the child’s own weight status could partly explain the observed association between maternal BMI and asthma in the offspring. In Study II, we found that girls with persistent asthma had a higher BMI and an increased risk of overweight throughout childhood, compared to girls without asthma. Girls with transient asthma had an increased risk of overweight at ages 4-7.9 years, whereas girls with late-onset asthma had a tendency towards an increased risk of overweight at age ≥15 years. In boys, the difference in BMI between children with and without asthma was smaller, and no consistent association was observed between asthma phenotypes and overweight. In Study III, we observed that overweight and obesity at age 8 years were associated with increased forced vital capacity (FVC) and to some extent forced expiratory volume in one second (FEV1), but reduced FEV1/FVC ratios at 8 and 16 years. The strongest association with FEV1/FVC was observed for persistent overweight at both 8 and 16 years, whereas no significant association was found for transient overweight. Cross-sectional analyses of IOS showed that overweight and obesity were associated with higher peripheral airway resistance and reactance at 16 years. The result of Study IV showed that self-reported and measured height and weight were highly correlated at 16 years (r=0.98 for height, r=0.96 for weight). On average, self-reported weight was underreported by 1.1 kg and height was overreported by 0.5 cm, leading to an underestimation of BMI by 0.5 kg/m2. The accuracy of self-reported BMI was somewhat lower among girls and among overweight and obese participants, compared to normal weight participants. Our results suggest that maternal and childhood overweight and obesity are associated with asthma and evidence of airway obstruction in children and adolescents. The association between maternal BMI and asthma may, to some extent, be mediated through childhood overweight and seems to be explained by non-allergic mechanisms. In addition, we conclude that web-based self-reported BMI can be used as a valid, quick and cost-effective alternative to measured BMI among Swedish adolescents. The accuracy however declines with increasing BMI, and is somewhat lower among girls compared to boys

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz

HTT-lowering reverses Huntington's disease immune dysfunction caused by NF kappa B pathway dysregulation

Huntington’s disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system contributes to Huntington’s disease pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant huntingtin expression in immune cells has been lacking. Here we demonstrate that human Huntington’s disease myeloid cells produce excessive inflammatory cytokines as a result of the cell-intrinsic effects of mutant huntingtin expression. A direct effect of mutant huntingtin on the NFκB pathway, whereby it interacts with IKKγ, leads to increased degradation of IκB and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signalling pathways are also observed. Using a novel method of small interfering RNA delivery to lower huntingtin expression, we show reversal of disease-associated alterations in cellular function–the first time this has been demonstrated in primary human cells. Glucan-encapsulated small interfering RNA particles were used to lower huntingtin levels in human Huntington’s disease monocytes/macrophages, resulting in a reversal of huntingtin-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce glucan-encapsulated small interfering RNA particles as tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of immune cell-directed HTT-lowering as a therapeutic in Huntington’s disease

1 Personality Polygenes, Positive Affect, and Life Satisfaction

Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizesPeer reviewe

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

The impact of low-frequency and rare variants on lipid levels

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing

Discovery and fine-mapping of glycaemic and obesity-related trait loci using high-density imputation

Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency &ge;0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated

From monogenic to polygenic obesity: recent advances

The heritability of obesity and body weight in general is high. A small number of confirmed monogenic forms of obesity—the respective mutations are sufficient by themselves to cause the condition in food abundant societies—have been identified by molecular genetic studies. The elucidation of these genes, mostly based on animal and family studies, has led to the identification of important pathways to the disorder and thus to a deeper understanding of the regulation of body weight. The identification of inborn deficiency of the mostly adipocyte-derived satiety hormone leptin in extremely obese children from consanguineous families paved the way to the first pharmacological therapy for obesity based on a molecular genetic finding. The genetic predisposition to obesity for most individuals, however, has a polygenic basis. A polygenic variant by itself has a small effect on the phenotype; only in combination with other predisposing variants does a sizeable phenotypic effect arise. Common variants in the first intron of the ‘fat mass and obesity associated’ gene (FTO) result in an elevated body mass index (BMI) equivalent to approximately +0.4 kg/m² per risk allele. The FTO variants were originally detected in a genome wide association study (GWAS) pertaining to type 2 diabetes mellitus. Large meta-analyses of GWAS have subsequently identified additional polygenic variants. Up to December 2009, polygenic variants have been confirmed in a total of 17 independent genomic regions. Further study of genetic effects on human body weight regulation should detect variants that will explain a larger proportion of the heritability. The development of new strategies for diagnosis, treatment and prevention of obesity can be anticipated