Gene variants influencing measures of inflammation or predisposing to autoimmune and inflammatory diseases are not associated with the risk of type 2 diabetes.

AIMS/HYPOTHESIS: There are strong associations between measures of inflammation and type 2 diabetes, but the causal directions of these associations are not known. We tested the hypothesis that common gene variants known to alter circulating levels of inflammatory proteins, or known to alter autoimmune-related disease risk, influence type 2 diabetes risk. METHODS: We selected 46 variants: (1) eight variants known to alter circulating levels of inflammatory proteins, including those in the IL18, IL1RN, IL6R, MIF, PAI1 (also known as SERPINE1) and CRP genes; and (2) 38 variants known to predispose to autoimmune diseases, including type 1 diabetes. We tested the associations of these variants with type 2 diabetes using a meta-analysis of 4,107 cases and 5,187 controls from the Wellcome Trust Case Control Consortium, the Diabetes Genetics Initiative, and the Finland-United States Investigation of NIDDM studies. We followed up associated variants (p < 0.01) in a further set of 3,125 cases and 3,596 controls from the UK. RESULTS: We found no evidence that inflammatory or autoimmune disease variants are associated with type 2 diabetes (at p <or= 0.01). The OR observed between the variant altering IL-18 levels, rs2250417, and type 2 diabetes (OR 1.00 [95% CI 0.99-1.03]), is much lower than that expected given (1) the effect of the variant on IL-18 levels (0.28 SDs per allele); and (2) estimates, based on other studies, of the correlation between IL-18 levels and type 2 diabetes risk (approximate OR 1.15 [95% CI 1.09-1.21] per 0.28 SD increase in IL-18 levels). CONCLUSIONS/INTERPRETATION: Our study provided no evidence that variants known to alter measures of inflammation, autoimmune or inflammatory disease risk, including type 1 diabetes, alter type 2 diabetes risk

Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing

This is the final version. Available on open access from Wiley via the DOI in this recordSummary: Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30-104years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n=458), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. Of 16571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P<0.002, false discovery rate (FDR) q<0.05]. This is supported by our observation of age-associated disruption to the balance of alternatively expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging. © 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.National Institute for Health Research (NIHR

Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers

This is the final version of the article. Available from Public Library of Science via the DOI in this record.INTRODUCTION: Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers. RESULTS: A large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%, <50 year olds, 28.4%). RDW was associated with 194 independent genetic signals; 71 are known for conditions including autoimmune disease, certain cancers, BMI, Alzheimer's disease, longevity, age at menopause, bone density, myositis, Parkinson's disease, and age-related macular degeneration. Exclusion of anemic participants did not affect the overall findings. Pathways analysis showed enrichment for telomere maintenance, ribosomal RNA, and apoptosis. The majority of RDW-associated signals were intronic (119 of 194), including SNP rs6602909 located in an intron of oncogene GAS6, an eQTL in whole blood. CONCLUSIONS: Although increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks, and a RDW genetic score was not predictive of incident disease. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.This work was supported by an award to DM, TF, AM and LH by the UK Medical Research Council (grant number MR/M023095/1). SEJ is funded by the Medical Research Council (grant: MR/M005070/1). JT is funded by a Diabetes Research and Wellness Foundation Fellowship. RB is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. MAT, MNW and AM are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). ARW, HY, and TF are supported by the European Research Council grant: 323195:GLUCOSEGENES-FP7-IDEAS-ERC. LF is supported by the Intramural Research Program of the National Institute on Aging, U.S. National Institutes of Health. Input from MD, CLK and GK was supported by the University of Connecticut Health Center. This research has been conducted using the UK Biobank Resource under Application Number 14631. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10-40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. © 2008 Melzer et al

A water-based training program that include perturbation exercises to improve stepping responses in older adults: study protocol for a randomized controlled cross-over trial

<p>Abstract</p> <p>Background</p> <p>Gait and balance impairments may increase the risk of falls, the leading cause of accidental death in the elderly population. Fall-related injuries constitute a serious public health problem associated with high costs for society as well as human suffering. A rapid step is the most important protective postural strategy, acting to recover equilibrium and prevent a fall from initiating. It can arise from large perturbations, but also frequently as a consequence of volitional movements. We propose to use a novel water-based training program which includes specific perturbation exercises that will target the stepping responses that could potentially have a profound effect in reducing risk of falling. We describe the water-based balance training program and a study protocol to evaluate its efficacy (Trial registration number #NCT00708136).</p> <p>Methods/Design</p> <p>The proposed water-based training program involves use of unpredictable, multi-directional perturbations in a group setting to evoke compensatory and volitional stepping responses. Perturbations are made by pushing slightly the subjects and by water turbulence, in 24 training sessions conducted over 12 weeks. Concurrent cognitive tasks during movement tasks are included. Principles of physical training and exercise including awareness, continuity, motivation, overload, periodicity, progression and specificity were used in the development of this novel program. Specific goals are to increase the speed of stepping responses and improve the postural control mechanism and physical functioning. A prospective, randomized, cross-over trial with concealed allocation, assessor blinding and intention-to-treat analysis will be performed to evaluate the efficacy of the water-based training program. A total of 36 community-dwelling adults (age 65–88) with no recent history of instability or falling will be assigned to either the perturbation-based training or a control group (no training). Voluntary step reaction times and postural stability using stabiliogram diffusion analysis will be tested before and after the 12 weeks of training.</p> <p>Discussion</p> <p>This study will determine whether a water-based balance training program that includes perturbation exercises, in a group setting, can improve speed of voluntary stepping responses and improve balance control. Results will help guide the development of more cost-effective interventions that can prevent the occurrence of falls in the elderly.</p

The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians

BACKGROUND: Klotho has an important role in insulin signalling and the development of ageing-like phenotypes in mice. The common functional "KL-VS" variant in the KLOTHO (KL) gene is associated with longevity in humans but its role in type 2 diabetes is not known. We performed a large case-control and family-based study to test the hypothesis that KL-VS is associated with type 2 diabetes in a UK Caucasian population. METHODS: We genotyped 1793 cases, 1619 controls and 1616 subjects from 509 families for the single nucleotide polymorphism (SNP) F352V (rs9536314) that defines the KL-VS variant. Allele and genotype frequencies were compared between cases and controls. Family-based analysis was used to test for over- or under-transmission of V352 to affected offspring. RESULTS: Despite good power to detect odds ratios of 1.2, there were no significant associations between alleles or genotypes and type 2 diabetes (V352 allele: odds ratio = 0.96 (0.84–1.09)). Additional analysis of quantitative trait data in 1177 healthy control subjects showed no association of the variant with fasting insulin, glucose, triglycerides, HDL- or LDL-cholesterol (all P > 0.05). However, the HDL-cholesterol levels observed across the genotype groups showed a similar, but non-significant, pattern to previously reported data. CONCLUSION: This is the first large-scale study to examine the association between common functional variation in KL and type 2 diabetes risk. We have found no evidence that the functional KL-VS variant is a risk factor for type 2 diabetes in a large UK Caucasian case-control and family-based study

Balance perturbation system to improve balance compensatory responses during walking in old persons

Ageing commonly disrupts the balance control and compensatory postural responses that contribute to maintaining balance and preventing falls during perturbation of posture. This can lead to increased risk of falling in old adults (65 years old and over). Therefore, improving compensatory postural responses during walking is one of the goals in fall prevention programs. Training is often used to achieve this goal. Most fall prevention programs are usually directed towards improving voluntary postural control. Since compensatory postural responses triggered by a slip or a trip are not under direct volitional control these exercises are less expected to improve compensatory postural responses due to lack of training specificity. Thus, there is a need to investigate the use balance perturbations during walking to train more effectively compensatory postural reactions during walking

Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS)

BACKGROUND: The polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS. METHODS: We conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4). RESULTS: The FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously. CONCLUSION: The stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease

Multiple Frequencies Sequential Coding for SSVEP-Based Brain-Computer Interface

BACKGROUND: Steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI) has become one of the most promising modalities for a practical noninvasive BCI system. Owing to both the limitation of refresh rate of liquid crystal display (LCD) or cathode ray tube (CRT) monitor, and the specific physiological response property that only a very small number of stimuli at certain frequencies could evoke strong SSVEPs, the available frequencies for SSVEP stimuli are limited. Therefore, it may not be enough to code multiple targets with the traditional frequencies coding protocols, which poses a big challenge for the design of a practical SSVEP-based BCI. This study aimed to provide an innovative coding method to tackle this problem. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we present a novel protocol termed multiple frequencies sequential coding (MFSC) for SSVEP-based BCI. In MFSC, multiple frequencies are sequentially used in each cycle to code the targets. To fulfill the sequential coding, each cycle is divided into several coding epochs, and during each epoch, certain frequency is used. Obviously, different frequencies or the same frequency can be presented in the coding epochs, and the different epoch sequence corresponds to the different targets. To show the feasibility of MFSC, we used two frequencies to realize four targets and carried on an offline experiment. The current study shows that: 1) MFSC is feasible and efficient; 2) the performance of SSVEP-based BCI based on MFSC can be comparable to some existed systems. CONCLUSIONS/SIGNIFICANCE: The proposed protocol could potentially implement much more targets with the limited available frequencies compared with the traditional frequencies coding protocol. The efficiency of the new protocol was confirmed by real data experiment. We propose that the SSVEP-based BCI under MFSC might be a promising choice in the future

Walk to me when I smile, step back when I’m angry: emotional faces modulate whole-body approach–avoidance behaviors

Facial expressions are potent social cues that can induce behavioral dispositions, such as approach–avoidance tendencies. We studied these tendencies by asking participants to make whole-body forward (approach) or backward (avoidance) steps on a force plate in response to the valence of social cues (happy or angry faces) under affect-congruent and incongruent mappings. Posturographic parameters of the steps related to automatic stimulus evaluation, step initiation (reaction time), and step execution were determined and analyzed as a function of stimulus valence and stimulus–response mapping. The main result was that participants needed more time to initiate a forward step towards an angry face than towards a smiling face (which is evidence of a congruency effect), but with backward steps, this difference failed to reach significance. We also found a reduction in spontaneous body sway prior to the step with the incongruent mapping. The results provide a crucial empirical link between theories of socially induced action tendencies and theories of postural control and suggest a motoric basis for socially guided motivated behavior