Altered immune system in frailty: Genetics and diet may influence inflammation.

Frailty is a complex geriatric syndrome associated with biological vulnerability to stressors and decreased physiological reserve. Its etiology and pathogenesis are not completely understood, although various causes and complex pathways have been proposed. Immune system alterations (immunosenescence and "InflammAging") have been suggested to contribute to frailty, but a precise causative role of such alterations remains to be determined. Genetic studies support the suggestion of immune system involvement in frailty: genetic variants in genes involved in immune system function have been associated with the syndrome. Interestingly, nutritional status, through its effects on cellular metabolism, may also influence the immune system, i.e. hormone and cytokine (mainly adipocytokine) levels, and immune cell populations and function, increasing inflammation and contributing to frailty. This review aims to discuss the role of immune system alterations in frailty, analyzing the role of genetic factors in frailty onset and the impact of diet on inflammation and, in turn, on frailty

TWIST1 Is Expressed in Colorectal Carcinomas and Predicts Patient Survival

TWIST1 is a transcription factor that belongs to the family of basic helix-loop-helix proteins involved in epithelial-to-mesenchymal transition and invasion processes. The TWIST1 protein possesses oncogenic, drug-resistant, angiogenic and invasive properties, and has been related with several human tumors and other pathologies. Colorectal cancer is one of the tumors in which TWIST1 is over-expressed, but its involvement in the clinical outcome of the disease is still unclear. We tested, by RT-PCR, the expression levels of TWIST1 in normal and tumor paired-sample tissues from a series of 151 colorectal cancer patients, in order to investigate its prognostic value as a tumor marker. TWIST1 expression was restricted to tumor tissues (86.1%) and correlated with lymph node metastasis (LNM). Adjusted analysis showed that the expression levels of TWIST1 correlated with overall survival (OS) and disease-free survival (DFS). Importantly, TWIST1 expression levels predicted OS specifically at stages I and II. Moreover, patients with stage II tumors and high TWIST1 levels showed even shorter survival than patients with stage III tumors. These results suggest that TWIST1 expression levels could be a tumor indicator in stage II patients and help select patients at greater risk of poor prognosis who might benefit from adjuvant chemotherapy

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Influence of Serotonin Transporter Gene Polymorphisms and Adverse Life Events on Depressive Symptoms in the Elderly: A Population-Based Study

<div><p>Background</p><p>Depression is common in the elderly. The role of genetic and environmental factors in modulating depressive symptoms is not clear.</p><p>Methods</p><p>We evaluated the influence of serotonin transporter gene polymorphisms and recent adverse life events on depressive symptoms in an elderly Italian population. We used data from “InveCe.Ab”, a population-based study of 1321 subjects aged 70–74 years. We used the 15-item Geriatric Depression Scale (GDS) to assess depressive symptoms–a GDS score ≥5 points (GDS≥5) indicated the presence of clinically relevant symptoms–and performed 5-HTTLPR and rs25531 genotyping to obtain the triallelic polymorphism of the serotonin transporter. We used the Geriatric Adverse Life Events Scale to measure adverse life events, and logistic regression models to evaluate the role of genotype and recent adverse life events in depressive symptoms, controlling for potential confounders and independent predictors.</p><p>Results</p><p>Two hundred subjects (15.76%) had a GDS≥5. The 5-HTTLPR triallelic polymorphism was significantly associated with GDS≥5. Only S′S′ carriers showed an increased risk of depressive symptoms (OR_adj = 1.81, <i>p</i> = .022); one extra adverse life event increased this risk by 14% (<i>p</i> = .061) independently of genotype. Other factors significantly related to GDS≥5 were: female gender (OR_adj = 2.49, <i>p</i> < .001), age (OR_adj = 1.19, <i>p</i> = .007), a history of depression (OR_adj = 4.73, <i>p</i> < .001), and comorbidity (OR_adj = 1.23, <i>p</i> = .001). One extra adverse life event increased the risk of depressive symptoms by 57% (<i>p</i> = .005) only in the L′L′ carriers, while antidepressant intake was directly related to GDS≥5 in the L′S′ carriers (OR_adj = 2.46, <i>p</i> = .036) and borderline significant in the S′S′ carriers (OR_adj = 2.41, <i>p</i> = .081).</p><p>Discussion</p><p>The S′S′ genotype and recent exposure to adverse life events were independently associated with depressive symptoms. The S′S′ genotype, compared with the environment, exerted a predominant effect on depressive symptoms, suggesting that it reduces the efficacy of antidepressant therapy. We conclude that genetics may be an important risk factor for depressive symptoms in late adulthood.</p></div

Overview of the baseline characteristics of the cohort.

<p>The summary statistics (mean and standard deviation) or the frequency distribution of each variable are shown in the overall population and by the presence/absence of clinically relevant depressive symptoms (GDS≥5 vs GDS<5).The statistical tests and p-values relative to analyses by GDS categories are also reported.</p

Mutually adjusted associations of depressive symptoms^* (relevant vs not relevant) with genotype, adverse life events, pharmacological treatment for depression, history of depression, marital status, comorbidity index, gender and age distribution.

<p>* Depressive symptomatology was defined using GDS: relevant = GDS≥5 points, not relevant = GDS<5 points.</p><p>^ Unconditional logistic regression analysis was applied to estimate adjusted OR with 95%CI and p-value.</p><p><b>Adjusted odds ratios (OR</b>_<b>adj</b><b>) with confidence intervals (95%CI) and p-values are reported^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0143395#t002fn002" target="_blank">^</a>}</b>.</p