Anna Maria Di Blasio

Accelerated epigenetic aging in Down syndrome

Down Syndrome (DS) entails an increased risk of many chronic diseases that are typically associated with older age. The clinical manifestations of accelerated aging suggest that trisomy 21 increases the biological age of tissues, but molecular evidence for this hypothesis has been sparse. Here, we utilize a quantitative molecular marker of aging (known as the epigenetic clock) to demonstrate that trisomy 21 significantly increases the age of blood and brain tissue (on average by 6.6 years, P = 7.0 × 10−14).

The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients

objective  We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low‐dose dexamethasone (0·25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a BclI restriction site polymorphism in a group of Italian patients with severe obesity.

Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians' offspring.

The role of epigenetics in the modulation of longevity has not been studied in humans. To this aim, (1) we evaluated the DNA methylation from peripheral leukocytes of 21 female centenarians, their 21 female offspring, 21 offspring of both non-long-lived parents, and 21 young women through ELISA assay, pyrosequencing analysis of Alu sequences, and quantification of methylation in CpG repeats outside CpG islands; (2) we compared the DNA methylation profiles of these populations through Infinium array for genome-wide CpG methylation analysis. We observed an age-related decrease in global DNA methylation and a delay of this process in centenarians’ offspring. Interestingly, literature data suggest a link between the loss of DNA methylation observed during aging and the development of age-associated diseases. Genome-wide methylation analysis evidenced DNA methylation profiles specific for aging and longevity: (1) aging-associated DNA hypermethylation occurs predominantly in genes involved in the development of anatomical structures, organs, and multicellular organisms and in the regulation of transcription; (2) genes involved in nucleotide biosynthesis, metabolism, and control of signal transmission are differently methylated between centenarians’ offspring and offspring of both non-long-lived parents, hypothesizing a role for these genes in human longevity. Our results suggest that a better preservation of DNA methylation status, a slower cell growing/metabolism, and a better control in signal transmission through epigenetic mechanisms may be involved in the process of human longevity. These data fit well with the observations related to the beneficial effects of mild hypothyroidism and insulin-like growth factor I system impairment on the modulation of human lifespan.

Deep Subcutaneous Adipose Tissue: A Distinct Abdominal Adipose Depot

Objective: Abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) display significant metabolic differences, with VAT showing a functional association to metabolic/cardiovascular disorders. A third abdominal adipose layer, derived by the division of SAT and identified as deep subcutaneous adipose tissue (dSAT), may play a significant and independent metabolic role. The aim of this study was to evaluate depot‐specific differences in the expression of proteins key to adipocyte metabolism in a lean population to establish a potential physiologic role for dSAT.

A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis

Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

Expression of intercellular adhesion molecule-1 (ICAM-1) on cultured human endometrial stromal cells and its role in the interaction with natural killers

PROBLEM: Recent evidence emphasizes the role of natural killer cells (NKs) as potential effectors of peritoneal immune surveillance directed against the outgrowth of endometrial cells, refluxed with menstrual debris, in ectopic sites. This NK‐mediated cytotoxicity toward autologous endometrial antigens seems to be significantly decreased in endometriosis patients.

Genetics of endometriosis: A role for the progesterone receptor gene polymorphism PROGINS?

objective  Endometriosis is a steroid‐dependent disease with a particular genetic background, but the locations of possible genomic aberrations are still poorly clarified. We have investigated the potential association between endometriosis and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor (PR) gene, which has been reported previously to segregate with this disease.

Sporadic mutations in melanocortin receptor 3 in morbid obese individuals

Several mutations in the melanocortin receptor 4 gene have been identified in humans and account for 3–6% of morbid obesity. In contrast, strong evidence of a causative role for melanocortin receptor 3 (MC3R) mutations are still lacking. In MC3R knockout mice, high feed efficiency rather than hyperphagia seems to contribute to increased fat mass. On the basis of this evidence, the objective of the present study was to investigate the presence of MC3R mutations in a group of 290 obese subjects (mean BMI 44.2±5.9 kg/m2). As a control, a group of 215 normal-weight subjects (mean BMI 22.4±2.7 kg/m2) was also screened. Three novel mutations in the MC3R gene (A293T, I335S and X361S) were identified among the obese patients. The mutations segregated with obesity in the members of the families studied. In vitro expression studies of each mutation demonstrated a loss of function of the I335S-mutated receptor. These findings suggest that, in humans, MC3R mutations may be a cause of a dominantly inherited form of obesity. However, this association as well as the specific phenotypic characteristics resulting from these mutations need to be further evaluated in larger series of obese subjects.

Genetics of endometriosis: Current status and prospects

Family and twin studies have shown that heritability accounts for endometriosis development to an extent similar to other complex genetic diseases. Both linkage analysis and association studies have been performed to identify genetic determinants for the disease. Results from the linkage scan of 1,176 families collected thanks to a joint effort between an Australian and a UK group supported significant linkage to a novel susceptibility locus on chromosome 10q26. Although gene variants with effects on the disease predisposition have been proposed to exist and several candidates have been put forward, their effects have not been or are yet to be confirmed. The main categories of candidate genes studied have been those involved in detoxification processes, sex steroid biosynthesis and action, immune system regulation. Genetic studies on endometriosis face numerous challenges as the disease has several manifestations and different forms. Moreover, strong gene-environmental interactions might definitively influence approaches to identify genetic variants involved. Genome-wide association studies that survey most of the genome for causal genetic variants provide the potential for future progress.

Basic fibroblast growth factor and its receptor messenger ribonucleic acids are expressed in human ovarian epithelial neoplasms

OBJECTIVE Our purpose was to determine whether basic fibroblast growth factor is present in, and synthesized by, human ovarian epithelial neoplasms and to evaluate the expression of gene for the basic fibroblast growth factor receptor. STUDY DESIGN The synthesis of basic fibroblast growth factor and its receptor was investigated in seven primary human ovarian epithelial neoplasms. Neoplastic tissues were homogenized and the cytoplasmic extracts purified by heparin-sepharose chromatography with a linear salt gradient of 0.6 to 3 mol/L sodium chloride in Tris-hydrochloric acid. The in situ synthesis of basic fibroblast growth factor and its receptor was demonstrated by polymerase chain reaction. Total ribonucleic acid was reverse transcribed and then amplified with two oligonucleotide primers specific for the bovine and human basic fibroblast growth factor gene and its human receptor gene. RESULTS As assessed by both bioassay and radioimmunoassay a peak of basic fibroblast growth factor-like activity was present in all tumors in the chromatographic fractions eluted with 3 mol/L sodium chloride. The mitogenic effect on bovine adrenocortical endothelial cell proliferation varied from 35% to 153% above control cultures. Levels of basic fibroblast growth factor-like immunoreactivity were between 4 and 33 ng/ml. Qualitatively similar results were obtained after purifying the cytoplasmic extract of dispersed human ovarian tumor cells. The mitogenic effect was completely abolished by a specific neutralizing anti-basic fibroblast growth factor antibody. Single major deoxyribonucleic acid bands of the expected size (354 and 661 bp) were detected in all tumors studied. The identify of this material with the human basic fibroblast growth factor sequence was confirmed by restriction enzyme analysis. CONCLUSION These data demonstrate that both basic fibroblast growth factor and its receptor are present in and synthesized by human ovarian tumor cells. Thus basic fibroblast growth factor might stimulate their abnormal proliferation through an autocrine mechanism.