CNR Institute of Neurogenetics and Neuropharmacology


CNR Institute of Neurogenetics and Neuropharmacology


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Sutin A.R.,U.S. National Institute on Aging | Terracciano A.,U.S. National Institute on Aging | Deiana B.,CNR Institute of Neurogenetics and Neuropharmacology | Naitza S.,CNR Institute of Neurogenetics and Neuropharmacology | And 4 more authors.
Psychological Medicine | Year: 2010

Background High Neuroticism and low Conscientiousness are frequently implicated in health-risk behaviors, such as smoking and overeating, as well as health outcomes, including mortality. Their associations with physiological markers of morbidity and mortality, such as inflammation, are less well documented. The present research examines the association between the five major dimensions of personality and interleukin-6 (IL-6), a pro-inflammatory cytokine often elevated in patients with chronic morbidity and frailty.Method A population-based sample (n=4923) from four towns in Sardinia, Italy, had their levels of IL-6 measured and completed a comprehensive personality questionnaire, the NEO-PI-R. Analyses controlled for factors known to have an effect on IL-6: age; sex; smoking; weight; aspirin use; disease burden.Results High Neuroticism and low Conscientiousness were both associated with higher levels of IL-6. The findings remained significant after controlling for the relevant covariates. Similar results were found for C-reactive protein, a related marker of chronic inflammation. Further, smoking and weight partially mediated the association between impulsivity-related traits and higher IL-6 levels. Finally, logistic regressions revealed that participants either in the top 10% of the distribution of Neuroticism or the bottom 10% of conscientiousness had an approximately 40% greater risk of exceeding clinically relevant thresholds of IL-6.Conclusions Consistent with the literature on personality and self-reported health, individuals high on Neuroticism or low on Conscientiousness show elevated levels of this inflammatory cytokine. Identifying critical medical biomarkers associated with personality may help to elucidate the physiological mechanisms responsible for the observed connections between personality traits and physical health. Copyright © Cambridge University Press 2009 This is a work of the U.S. Government and is not subject to copyright protection in the United States.

Scuteri A.,U.S. National Institute on Aging | Scuteri A.,CNR Institute of Neurogenetics and Neuropharmacology | Najjar S.S.,U.S. National Institute on Aging | Orru' M.,CNR Institute of Neurogenetics and Neuropharmacology | And 7 more authors.
European Heart Journal | Year: 2010

Aims We evaluated whether specific clusters of metabolic syndrome (MetS) components differentially impact on arterial structure and function, and whether the impact is similar in men and in women.Methods and results Components of the MetS and arterial properties were assessed in 6148 subjects, aged 14-102 in a cluster of four towns in Sardinia, Italy. MetS was defined in accordance with the ATP III criteria. Age groups were classified as: <35, 35-49, 50-64, and ≥65 years. Systolic blood pressure (BP), diastolic BP, pulse pressure, common carotid artery (CCA) diameter, intima-media thickness, distensibility, strain, stiffness index, wall stress, and aortic pulse wave velocity were measured. Common carotid artery plaque was defined as focal encroachment of the arterial wall and CCA calcification as acoustic shadowing. In any age group, subjects with MetS presented thicker, stiffer or less distensible, and wider large arteries than controls. The arterial burden of MetS increased as the number of altered MetS components increased. However, not all MetS components were associated with the same changes in arterial properties. In fact, specific clusters of MetS components, i.e. any combination of altered glucose tolerance, elevated BP, and elevated triglycerides (with or without abdominal obesity), dramatically increased age-associated arterial changes. The impact of MetS on arterial function was similar in men and women.ConclusionMetS accelerates age-associated arterial changes, even in older persons. However, not all the clusters of MetS components render the same burden on arterial structure and function.

Pruim R.J.,Calvin College | Welch R.P.,University of Michigan | Sanna S.,CNR Institute of Neurogenetics and Neuropharmacology | Teslovich T.M.,University of Michigan | And 5 more authors.
Bioinformatics | Year: 2011

Summary: Genome-wide association studies (GWAS) have revealed hundreds of loci associated with common human genetic diseases and traits. We have developed a web-based plotting tool that provides fast visual display of GWAS results in a publication-ready format. LocusZoom visually displays regional information such as the strength and extent of the association signal relative to genomic position, local linkage disequilibrium (LD) and recombination patterns and the positions of genes in the region. © The Author(s) 2010.

Galanello R.,University of Cagliari | Cao A.,CNR Institute of Neurogenetics and Neuropharmacology
Genetics in Medicine | Year: 2011

Alpha-thalassemia is one of the most common hemoglobin genetic abnormalities and is caused by the reduced or absent production of the alpha globin chains. Alpha-thalassemia is prevalent in tropical and subtropical world regions where malaria was and still is epidemic, but as a consequence of the recent massive population migrations, alpha-thalassemia has become a relatively common clinical problem in North America, North Europe, and Australia. Alpha-thalassemia is very heterogeneous at a clinical and molecular level. Four clinical conditions of increased severity are recognized: the silent carrier state, the alpha-thalassemia trait, the intermediate form of hemoglobin H disease, and the hemoglobin Bart hydrops fetalis syndrome that is lethal in utero or soon after birth.Alpha-thalassemia is caused most frequently by deletions involving one or both alpha globin genes and less commonly by nondeletional defects. A large number of alpha-thalassemia alleles have been described and their interaction results in the wide spectrum of hematological and clinical phenotypes. Genotype-phenotype correlation has been only partly clarified. Carriers of alpha-thalassemia do not need any treatment. Usually, patients with hemoglobin H disease are clinically well and survive without any treatment, but occasional red blood cell transfusions may be needed if the hemoglobin level suddenly drops because of hemolytic or aplastic crisis likely due to viral infections. Hemoglobin Bart hydrops fetalis syndrome currently has no effective treatment although attempts at intrauterine transfusion and hematopoietic stem cell transplantation have been made. © 2011 Lippincott Williams & Wilkins.

Scuteri A.,U.S. National Institute on Aging | Orru' M.,CNR Institute of Neurogenetics and Neuropharmacology | Morrell C.H.,U.S. National Institute on Aging | Morrell C.H.,Loyola University Maryland | And 4 more authors.
Atherosclerosis | Year: 2012

In the context of obesity epidemic, no large population study has extensively investigated the relationships between total and abdominal adiposity and large artery structure and function nor have such relationships been examined by gender, by age, by hypertensive status. We investigated these potential relationships in a large cohort of community dwelling volunteers participating the SardiNIA Study. Methods and results: Total and visceral adiposity and arterial properties were assessed in 6148 subjects, aged 14-102 in a cluster of 4 towns in Sardinia, Italy. Arterial stiffness was measured as aortic pulse wave velocity (PWV), arterial thickness and lumen as common carotid artery (CCA) intima-media thickness (IMT) and diameter, respectively. We reported a nonlinear relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter. The association between adiposity and arterial properties was steeper in women than in men, in younger than in older subjects. Waist correlated with arterial properties better than BMI. Within each BMI quartile, increasing waist circumference was associated with further significant changes in arterial structure and function. Conclusion: The relationship between total or abdominal adiposity and arterial aging (PWV and CCA IMT) is not linear as described in the current study. Therefore, BMI- and/or waist-specific reference values for arterial measurements might need to be defined. © 2011 .

Faa V.,CNR Institute of Neurogenetics and Neuropharmacology | Coiana A.,University of Cagliari | Incani F.,University of Cagliari | Costantino L.,Fondazione Policlinico Mangiagalli e Regina Elena | And 2 more authors.
Journal of Molecular Diagnostics | Year: 2010

Mutations within exons are responsible for aberrant splicing of pre-mRNA in several human disease genes and in some viral systems. Nonsense, missense, and even synonymous mutations can induce aberrant skipping of the mutant exon, producing nonfunctional proteins. In this paper, we describe the effect on the splicing efficiency of the synonymous variant 2811 G>T [Gly893Gly] detected in a patient of Italian descent affected by a mild form of cystic fibrosis, until now mentioned as sequence variation with unknown functional consequences. The study, performed through DNA as well as RNA analyses, shows that this mutation creates a new 5′ splice site within exon 15, resulting in a transcript lacking 76 amino acid residues. Although this aberrant splicing causes a shorter exon 15, the downstream exonic sequence from exon 16 to the end of the open reading frame is in frame. This study indicates that apparently neutral polymorphism, which may be erroneously classified as nonpathogenic, may indeed led to aberrant splicing thereby resulting in defective protein. Copyright © American Society for Investigative Pathology and the Association for Molecular Pathology.

Cao A.,CNR Institute of Neurogenetics and Neuropharmacology | Galanello R.,University of Cagliari
Genetics in Medicine | Year: 2010

Beta-thalassemia is caused by the reduced (beta+) or absent (beta') synthesis of the beta globin chains of the hemoglobin tetramer. Three clinical and hematological conditions of increasing severity are recognized, i.e., the beta-thalassemia carrier state, thalassemia intermedia, and thalassemia major. The beta-thalassemia carrier state, which results from heterozygosity for beta-thalassemia, is clinically asymptomatic and is defined by specific hematological features. Thalassemia major is a severe transfusion-dependent anemia. Thalassemia intermedia comprehend a clinically and genotypically very heterogeneous group of thalassemia-like disorders, ranging in severity from the asymptomatic carrier state to the severe transfusion-dependent type. The clinical severity of beta-thalassemia is related to the extent of imbalance between the alpha and nonalpha globin chains. The beta globin (HBB) gene maps in the short arm of chromosome 11, in a region containing also the delta globin gene, the embryonic epsilon gene, the fetal A-gamma and G-gamma genes, and a pseudogene (ψB1). Beta-thalassemias are heterogeneous at the molecular level. More than 200 disease-causing mutations have been so far identified. The majority of mutations are single nucleotide substitutions, deletions, or insertions of oligonucleotides leading to frameshift. Rarely, beta-thalassemia results from gross gene deletion. In addition to the variation of the phenotype resulting from allelic heterogeneity at the beta globin locus, the phenotype of beta-thalassemia could also be modified by the action of genetic factors mapping outside the globin gene cluster and not influencing the fetal hemoglobin. Among these factors, the ones best delineated so far are those affecting bilirubin, iron, and bone metabolisms. Because of the high carrier rate for HBB mutations in certain populations and the availability of genetic counseling and prenatal diagnosis, population screening is ongoing in several at-risk populations in the Mediterranean. Population screening associated with genetic counseling was extremely useful by allowing couples at risk to make informed decision on their reproductive choices. Clinical management of thalassemia major consists in regular long-life red blood cell transfusions and iron chelation therapy to remove iron introduced in excess with transfusions. At present, the only definitive cure is bone marrow transplantation. Therapies under investigation are the induction of fetal hemoglobin with pharmacologic compounds and stem cell gene therapy. © 2010 Lippincott Williams & Wilkins.

Satta S.,University of Cagliari | Perseu L.,CNR Institute of Neurogenetics and Neuropharmacology | Moi P.,University of Cagliari | Asunis I.,University of Cagliari | And 6 more authors.
Haematologica | Year: 2011

The persistence of high fetal hemoglobin level in adults may ameliorate the clinical phenotype of beta-thalassemia and sickle cell anemia. Several genetic variants responsible for hereditary persistence of fetal hemoglobin, linked and not linked to the beta globin gene cluster, have been identified in patients and in normal individuals. Monoallelic loss of KLF1, a gene with a key role in erythropoiesis, has been recently reported to be responsible for persistence of high levels of fetal hemoglobin. In a Sardinian family, high levels of HbF (22.1-30.9%) were present only in compound heterozygotes for the S270X nonsense and K332Q missense mutations, while the isolated S270X nonsense (haploinsufficiency) or K332Q missense mutation were associated with normal HbF levels (<1.5%). Functionally, the K332Q Klf1 mutation impairs binding to the BCl11A gene and activation of the γ- and β- globin promoters. Moreover, we report for the first time the association of KLF1 mutations with very high levels of zinc protoporphyrin. ©2011 Ferrata Storti Foundation. This is an open-access paper.

Li Y.,University of North Carolina at Chapel Hill | Li Y.,University of Michigan | Sidore C.,CNR Institute of Neurogenetics and Neuropharmacology | Sidore C.,University of Sassari | And 4 more authors.
Genome Research | Year: 2011

New sequencing technologies allow genomic variation to be surveyed in much greater detail than previously possible. While detailed analysis of a single individual typically requires deep sequencing, when many individuals are sequenced it is possible to combine shallow sequence data across individuals to generate accurate calls in shared stretches of chromosome. Here, we show that, as progressively larger numbers of individuals are sequenced, increasingly accurate genotype calls can be generated for a given sequence depth. We evaluate the implications of low-coverage sequencing for complex trait association studies. We systematically compare study designs based on genotyping of tagSNPs, sequencing of many individuals at depths ranging between 2x and 30x, and imputation of variants discovered by sequencing a subset of individuals into the remainder of the sample. We show that sequencing many individuals at low depth is an attractive strategy for studies of complex trait genetics. For example, for disease-associated variants with frequency >0.2%, sequencing 3000 individuals at 4x depth provides similar power to deep sequencing of >2000 individuals at 30x depth but requires only ∼20% of the sequencing effort. We also show low-coverage sequencing can be used to build a reference panel that can drive imputation into additional samples to increase power further. We provide guidance for investigators wishing to combine results from sequenced, genotyped, and imputed samples. © 2011 by Cold Spring Harbor Laboratory Press.

Sutin A.R.,U.S. National Institute on Aging | Terracciano A.,U.S. National Institute on Aging | Kitner-Triolo M.H.,U.S. National Institute on Aging | Uda M.,CNR Institute of Neurogenetics and Neuropharmacology | And 2 more authors.
Psychology and Aging | Year: 2011

In a community-dwelling sample (N = 4,790; age range 14-94), we examined whether personality traits prospectively predicted performance on a verbal fluency task. Open, extraverted, and emotionally stable participants had better verbal fluency. At the facet level, dispositionally happy and self-disciplined participants retrieved more words; those prone to anxiety and depression and those who were deliberative retrieved fewer words. Education moderated the association between conscientiousness and fluency such that participants with lower education performed better on the fluency task if they were also conscientious. Age was not a moderator at the domain level, indicating that the personality-fluency associations were consistent across the life span. A disposition toward emotional vulnerability and being less open, less happy, and undisciplined may be detrimental to cognitive performance. © 2011 American Psychological Association.

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