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1.
Nat Commun ; 10(1): 4130, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

2.
Hepatology ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31520399

RESUMO

Assay of γ-glutamyl transferase (GGT) activity is a widely used test to indicate and monitor liver and biliary tract injury. We observed dominant inheritance of highly elevated plasma GGT levels, designated GGTemia, in two unrelated families. Neither clinical symptoms nor alterations of GGT substrates were associated with GGTemia. A plasma GGT fractions pattern distinguishes this trait from common liver diseases. Heterozygous GGT1 mutations that disrupt the GGT1 transmembrane domain were identified. We establish GGTemia as a benign condition; GGT1 mutation testing can prevent repeated and invasive diagnostic workup in such patients.

3.
J Am Coll Cardiol ; 73(24): 3118-3131, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221261

RESUMO

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.

4.
Nat Commun ; 9(1): 4455, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367059

RESUMO

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

5.
Hum Genet ; 136(6): 743-757, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28374192

RESUMO

After the success of genome-wide association studies to uncover complex trait loci, attempts to explain the remaining genetic heritability (h 2) are mainly focused on unraveling rare variant associations and gene-gene or gene-environment interactions. Little attention is paid to the possibility that h 2 estimates are inflated as a consequence of the epidemiological study design. We studied the time series of 54 biochemical traits in 4373 individuals from the Cooperative Health Research In South Tyrol (CHRIS) study, a pedigree-based study enrolling ten participants/day over several years, with close relatives preferentially invited within the same day. We observed distributional changes of measured traits over time. We hypothesized that the combination of such changes with the pedigree structure might generate a shared-environment component with consequent h 2 inflation. We performed variance components (VC) h 2 estimation for all traits after accounting for the enrollment period in a linear mixed model (two-stage approach). Accounting for the enrollment period caused a median h 2 reduction of 4%. For 9 traits, the reduction was of >20%. Results were confirmed by a Bayesian Markov chain Monte Carlo analysis with all VCs included at the same time (one-stage approach). The electrolytes were the traits most affected by the enrollment period. The h 2 inflation was independent of the h 2 magnitude, laboratory protocol changes, and length of the enrollment period. The enrollment process may induce shared-environment effects even under very stringent and standardized operating procedures, causing h 2 inflation. Including the day of participation as a random effect is a sensitive way to avoid overestimation.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Teorema de Bayes , Humanos , Itália
6.
J Transl Med ; 13: 348, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26541195

RESUMO

The Cooperative Health Research In South Tyrol (CHRIS) study is a population-based study with a longitudinal lookout to investigate the genetic and molecular basis of age-related common chronic conditions and their interaction with life style and environment in the general population. All adults of the middle and upper Vinschgau/Val Venosta are invited, while 10,000 participants are anticipated by mid-2017. Family participation is encouraged for complete pedigree reconstruction and disease inheritance mapping. After a pilot study on the compliance with a paperless assessment mode, computer-assisted interviews have been implemented to screen for conditions of the cardiovascular, endocrine, metabolic, genitourinary, nervous, behavioral, and cognitive system. Fat intake, cardiac health, and tremor are assessed instrumentally. Nutrient intake, physical activity, and life-course smoking are measured semi-quantitatively. Participants are phenotyped for 73 blood and urine parameters and 60 aliquots per participant are biobanked (cryo-preserved urine, DNA, and whole and fractionated blood). Through liquid-chromatography mass-spectrometry analysis, metabolite profiling of the mitochondrial function is assessed. Samples are genotyped on 1 million variants with the Illumina HumanOmniExpressExome array and the first data release including 4570 fully phenotyped and genotyped samples is now available for analysis. Participants' follow-up is foreseen 6 years after the first visit. The target population is characterized by long-term social stability and homogeneous environment which should both favor the identification of enriched genetic variants. The CHRIS cohort is a valuable resource to assess the contribution of genomics, metabolomics, and environmental factors to human health and disease. It is awaited that this will result in the identification of novel molecular targets for disease prevention and treatment.


Assuntos
Predisposição Genética para Doença , Nível de Saúde , Estilo de Vida , Adolescente , Adulto , Idoso , Bancos de Espécimes Biológicos , Proteínas Sanguíneas/metabolismo , Meio Ambiente , Ética Médica , Exoma , Feminino , Seguimentos , Genótipo , Humanos , Itália/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Linhagem , Fenótipo , Projetos Piloto , Projetos de Pesquisa , Software , Inquéritos e Questionários , Urinálise , Adulto Jovem
7.
Biopreserv Biobank ; 12(4): 225-33, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25075723

RESUMO

The Italian Hub of Population Biobanks (HIBP) includes both ongoing and completed studies that are heterogeneous in both their purpose and in the specimens collected. The heterogeneity in starting conditions makes sharing study data very difficult because of technical, ethical, and collection rights issues that hamper collaboration and synergy. With the aim of overcoming these difficulties and establishing the "proof-of-concept" that sharing studies is achievable among Italian collections, a data-sharing pilot project has been agreed to by HIBP members. Participants agreed to the general methodology and signed a shared Data Transfer Agreement. The biobanks involved were: EURAC (Micros study), CIG (GEHA project), CNESPS (FINE, MATISS, MONICA, OEC1998, ITR (Italian Twin Register), and IPREA studies, and MOLIBANK (Moli-Sani project). Biobank data were uploaded into a common database using a dedicated informatics infrastructure. Demographic data, and anthropometric and hematochemical parameters were shared for each record. Each biobank uploaded into the common database a dataset with a minimum of 1000 subjects, for a total of 5071 records. After a harmonization process, the final dataset included 3882 records. Subjects were grouped into three main geographic areas of Italy (North, Center, and South) and separate analyses were performed for men and women. The 3882 records were analyzed through multivariate logistic regression analysis. Results were expressed as odds ratios with 95% confidence interval. Results show several geographical differences in the lipidemic pattern, mostly regarding cholesterol-HDL, which represents a strong basis for further, deeper sample-based studies. This HIBP pilot study aimed to prove the feasibility of such collaborations and it provides a methodological prototype for future studies based on the participation in the partnership of well-established quality collections.


Assuntos
Bancos de Espécimes Biológicos , Comportamento Cooperativo , Demografia , Disseminação de Informação , Lipídeos/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Itália , Masculino , Razão de Chances , Projetos Piloto , Adulto Jovem
8.
Genet Epidemiol ; 37(2): 214-21, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23280596

RESUMO

Prioritization is the process whereby a set of possible candidate genes or SNPs is ranked so that the most promising can be taken forward into further studies. In a genome-wide association study, prioritization is usually based on the P-values alone, but researchers sometimes take account of external annotation information about the SNPs such as whether the SNP lies close to a good candidate gene. Using external information in this way is inherently subjective and is often not formalized, making the analysis difficult to reproduce. Building on previous work that has identified 14 important types of external information, we present an approximate Bayesian analysis that produces an estimate of the probability of association. The calculation combines four sources of information: the genome-wide data, SNP information derived from bioinformatics databases, empirical SNP weights, and the researchers' subjective prior opinions. The calculation is fast enough that it can be applied to millions of SNPS and although it does rely on subjective judgments, those judgments are made explicit so that the final SNP selection can be reproduced. We show that the resulting probability of association is intuitively more appealing than the P-value because it is easier to interpret and it makes allowance for the power of the study. We illustrate the use of the probability of association for SNP prioritization by applying it to a meta-analysis of kidney function genome-wide association studies and demonstrate that SNP selection performs better using the probability of association compared with P-values alone.


Assuntos
Teorema de Bayes , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Bases de Dados Genéticas , Humanos , Rim/fisiologia , Metanálise como Assunto , Modelos Genéticos , Probabilidade
9.
Genet Epidemiol ; 37(2): 205-13, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23307621

RESUMO

Biological plausibility and other prior information could help select genome-wide association (GWA) findings for further follow-up, but there is no consensus on which types of knowledge should be considered or how to weight them. We used experts' opinions and empirical evidence to estimate the relative importance of 15 types of information at the single-nucleotide polymorphism (SNP) and gene levels. Opinions were elicited from 10 experts using a two-round Delphi survey. Empirical evidence was obtained by comparing the frequency of each type of characteristic in SNPs established as being associated with seven disease traits through GWA meta-analysis and independent replication, with the corresponding frequency in a randomly selected set of SNPs. SNP and gene characteristics were retrieved using a specially developed bioinformatics tool. Both the expert and the empirical evidence rated previous association in a meta-analysis or more than one study as conferring the highest relative probability of true association, whereas previous association in a single study ranked much lower. High relative probabilities were also observed for location in a functional protein domain, although location in a region evolutionarily conserved in vertebrates was ranked high by the data but not by the experts. Our empirical evidence did not support the importance attributed by the experts to whether the gene encodes a protein in a pathway or shows interactions relevant to the trait. Our findings provide insight into the selection and weighting of different types of knowledge in SNP or gene prioritization, and point to areas requiring further research.


Assuntos
Seguimentos , Pesquisa em Genética , Polimorfismo de Nucleotídeo Único , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla , Humanos , Metanálise como Assunto , Probabilidade
10.
J Med Genet ; 48(8): 549-56, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21690246

RESUMO

BACKGROUND: Thyroid hormones have important roles in growth, development and control of metabolism, and their dysregulation can lead to disease. OBJECTIVES: To identify genes contributing to hyperthyrotropinaemia. DESIGN, SETTING, PARTICIPANTS: Linkage and association analyses using 1258 individuals from three Alpine villages. OUTCOME MEASURES: The study applied two different upper limits of the reference range (URR) for serum thyroid stimulating hormone (TSH) values (TSH ≥4.6 mU/l and TSH >3.0 mU/l), along with normal or low fT4 (free thyroxine) values or thyroid medical treatment to define two groups of individuals for analysis: one hyperthyrotropinaemic or high-TSH (H-TSH) (TSH ≥4.6 mU/l) group; and a larger group (TSH >3.0 mU/l) called hyperthyrotropinaemic and upper reference range TSH (H+URR-TSH). RESULTS: Non-parametric genome-wide linkage analysis was performed on pedigrees generated from the two groups. Linkage analysis in the H+URR-TSH group revealed a significant peak on chromosome 3q28-q29 (LOD 3.34) and a suggestive linkage peak on chromosome 6q26-27 (LOD 2.66). Analysis in the smaller hyperthyrotropinaemic (H-TSH) group supported linkage to chromosome 6q26-27. Single SNP and gene based SNP association analyses under the linkage peaks identified the PDE10A and DACT2 genes as candidates at the chromosome 6 locus. CONCLUSIONS: PDE10A or DACT2 were identified as candidate genes contributing to hyperthyrotropinaemia (and possibly hypothyroidism) in this sample. Studies in additional populations support association of variants at this locus with TSH values, especially in the PDE10A gene. Genetic linkage in families with hyperthyrotropinaemia suggests the presence of functional variants that contribute to pathological disruption of the hypothalamus-pituitary-thyroid axis.


Assuntos
Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 6/genética , Ligação Genética , Loci Gênicos/genética , Predisposição Genética para Doença , Genética Populacional , Doenças da Glândula Tireoide/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Itália , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética
11.
Immunogenetics ; 62(8): 561-7, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20582410

RESUMO

Genomic copy number variants (CNVs) are a common, heritable source of inter-individual differences in genomic sequence. Their influence on phenotypic variability and their involvement in the pathogenesis of several common diseases is well established and the object of many current studies. In the course of examining CNV association to various quantitative traits in a general population, we have detected a strong association of CNVs over the four TCR genes to lymphocyte and neutrophil numbers in blood. In a small replication series, we have further characterized the nature of these CNVs and found them not to be germline, but dependent on the origin of analysed DNA. Germline deletion and rearrangement around the T-cell receptor (TCR) genes naturally occurs in white blood cells. Blood DNA derived from persons with high lymphocyte counts generates variable intensity signals which behave like germline CNVs over these genes. As DNA containing a relative high proportion of these CNV-like events involving the TCR genes has the ability to influence genotype counts of SNPs in the regions of these genes, care should be taken in interpreting and replicating association signals on variants within these genes when blood-derived DNA is the only source of data.


Assuntos
Variações do Número de Cópias de DNA , Genes Codificadores dos Receptores de Linfócitos T , Adulto , Bochecha , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Linfócitos/imunologia , Modelos Genéticos , Mucosa Bucal/metabolismo , Neutrófilos/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Deleção de Sequência
12.
BMC Med Genet ; 11: 41, 2010 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-20222955

RESUMO

BACKGROUND: Serum creatinine (S CR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in S CR level is explicable by genetic factors. METHODS: We performed a meta-analysis of genome-wide association studies of S CR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with SCR (candidate loci) were replicated in two additional population-based samples ('replication cohorts'). RESULTS: After the discovery meta-analysis, 29 loci were selected for replication. Association between SCR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 x 10(-6) and 1.7 x 10(-4), respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 x 10(-3)). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated. CONCLUSIONS: While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABAA receptors in the regulation of the glomerular basement membrane and a possible interaction between GABAA receptors and synaptotagmin-I at the podocyte level.


Assuntos
Autoantígenos/genética , Creatinina/sangue , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Colágenos não Fibrilares/genética , Receptores de GABA-A/genética , Sinaptotagmina I/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 8/genética , Estudos de Coortes , Croácia , Alemanha , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Adulto Jovem
13.
Am J Med Genet B Neuropsychiatr Genet ; 153B(1): 350-5, 2010 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-19526454

RESUMO

A co-occurrence of restless legs syndrome (RLS) and Parkin mutations has been described. In South Tyrolean RLS patients, a novel RLS locus has been found (RLS4) and recurrent Parkin mutations have been reported. By a systematic screen we investigated the presence of founder Parkin mutations in South Tyrolean RLS patients with known carrier status at the RLS4 locus and assessed whether these mutations alone or in combination influence the RLS phenotype measured by three quantitative RLS traits (age at onset (AAO) and two severity measurements). The Parkin mutation alone showed no effect, whereas RLS4 had a significant effect on the AAO (P = 0.0096, decrease of AAO of 9.1 years), but did not influence severity. Carriers of both, a Parkin mutation and the RLS4 haplotype, showed an association with AAO (P = 0.0016), corresponding to an anticipation of RLS onset age of 16.9 years. However, there was no effect on the disease severity. Our results suggest that the occurrence of a heterozygous Parkin mutation works in tandem with the gene at the RLS4 locus to lower the AAO in RLS.


Assuntos
Síndrome das Pernas Inquietas/genética , Ubiquitina-Proteína Ligases/genética , Idade de Início , Epistasia Genética , Feminino , Triagem de Portadores Genéticos , Humanos , Masculino , Mutação , Linhagem , Fenótipo
14.
J Mol Neurosci ; 39(3): 346-53, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19757205

RESUMO

Familial idiopathic basal ganglia calcification (FIBGC) is an inherited neurodegenerative disorder characterized by the accumulation of calcium deposits in different brain regions, particularly in the basal ganglia. FIBGC usually follows an autosomal dominant pattern of inheritance. Despite the mapping to chromosome 14q of a susceptibility locus for IBGC (IBCG1) in one family, this locus has been excluded in several others, demonstrating genetic heterogeneity in this disorder. The etiology of this disorder thus remains largely unknown. Using a large extended multigenerational Italian family from South Tyrol with 17 affected in a total of 56 members, we performed a genome-wide linkage analysis in which we were able to exclude linkage to the IBCG1 locus on chromosome 14q and obtain evidence of a novel locus on chromosome 2q37. Electronic supplementary material. The online version of this article (doi:10.1007/s12031-009-9287-3) contains supplementary material, which is available to authorized users.


Assuntos
Doenças dos Gânglios da Base/genética , Calcinose/genética , Cromossomos Humanos Par 2/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Gânglios da Base/fisiopatologia , Doenças dos Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/fisiopatologia , Calcinose/metabolismo , Calcinose/fisiopatologia , Transtornos Cromossômicos/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 14/genética , Análise Mutacional de DNA , Feminino , Genes Dominantes/genética , Ligação Genética/genética , Marcadores Genéticos/genética , Testes Genéticos , Variação Genética/genética , Humanos , Padrões de Herança/genética , Itália , Masculino , Pessoa de Meia-Idade , Linhagem
15.
J Mol Neurosci ; 39(1-2): 235-41, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19319700

RESUMO

A genetic marker screening panel, ParkScreen, optimized for simultaneous marker amplification, was constructed to test or exclude linkage in families with parkinsonism or Parkinson's disease, using only a few affected individuals per family. ParkScreen functionality was proven by detection of linkage to PARK2 in a family with known Parkin mutations, exclusion of linkage to several of the known loci, and detection of suggestive linkage to PARK8, PARK3, and PARK11 in some families. In a novel approach, we also tested the ability of ParkScreen to screen patients originating from isolated populations. Using apparently sporadic patients from geographically isolated Alpine villages, suggestive linkage to PARK11 was found in one village. ParkScreen is a useful and inexpensive tool that allows the rapid screening of patients in families suitable for clinical follow-up and further characterization in order to identify specific mutations or novel genes.


Assuntos
Ligação Genética , Marcadores Genéticos , Testes Genéticos , Doença de Parkinson , Feminino , Predisposição Genética para Doença , Testes Genéticos/economia , Testes Genéticos/métodos , Humanos , Escore Lod , Masculino , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Linhagem , Ubiquitina-Proteína Ligases
17.
Cancer Res ; 68(21): 8986-92, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18974143

RESUMO

Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia and thyroid cancer. It has been known for a long time that exposure of cells to radiation results in extensive DNA damage; however, a small number of studies have tried to explain the mechanisms of radiation-induced carcinogenesis. The high prevalence of RET/PTC rearrangements in patients who have received external radiation, and the evidence of in vitro induction of RET rearrangements in human cells, suggest an enhanced sensitivity of the RET genomic region to damage by ionizing radiation. To assess whether RET is indeed more sensitive to radiations than other genomic regions, we used a COMET assay coupled with fluorescence in situ hybridization, which allows the measurement of DNA fragmentation in defined genomic regions of single cells. We compared the initial DNA damage of the genomic regions of RET, CXCL12/SDF1, ABL, MYC, PLA2G2A, p53, and JAK2 induced by ionizing radiation in both a lymphoblastoid and a fetal thyroid cell line. In both cell lines, RET fragmentation was significantly higher than in other genomic regions. Moreover, a differential distribution of signals within the COMET was associated with a higher percentage of RET fragments in the tail. RET was more susceptible to fragmentation in the thyroid-derived cells than in lymphoblasts. This enhanced susceptibility of RET to ionizing radiation suggests the possibility of using it as a radiation exposure marker.


Assuntos
Proteínas Proto-Oncogênicas c-ret/genética , Radiação Ionizante , Linhagem Celular , Ensaio Cometa , Humanos , Hibridização in Situ Fluorescente , Técnicas In Vitro , Leucemia Induzida por Radiação/genética , Neoplasias Induzidas por Radiação/genética , Fatores de Risco , Neoplasias da Glândula Tireoide/etiologia , Neoplasias da Glândula Tireoide/genética
18.
Am J Med Genet B Neuropsychiatr Genet ; 147B(7): 1319-22, 2008 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-18361429

RESUMO

Familial Idiopathic Basal Ganglia Calcification (FIBGC) is a neurodegenerative syndrome that usually follows an autosomal dominant pattern of inheritance. Linkage to only one locus on chromosome 14q (IBCG1) has been described so far. We identified and characterized a large multigenerational Italian family from a population isolate with 14 FIBGC affected members. Linkage analysis excluded the IBCG1 locus, thus demonstrating further locus heterogeneity for this disease.


Assuntos
Doenças dos Gânglios da Base/genética , Calcinose/genética , Cromossomos Humanos Par 14/genética , Ligação Genética , Adulto , Idoso , Saúde da Família , Feminino , Humanos , Padrões de Herança , Itália , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem
19.
BMC Med Genet ; 8: 29, 2007 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-17550581

RESUMO

BACKGROUND: There is increasing evidence of the important role that small, isolated populations could play in finding genes involved in the etiology of diseases. For historical and political reasons, South Tyrol, the northern most Italian region, includes several villages of small dimensions which remained isolated over the centuries. METHODS: The MICROS study is a population-based survey on three small, isolated villages, characterized by: old settlement; small number of founders; high endogamy rates; slow/null population expansion. During the stage-1 (2002/03) genealogical data, screening questionnaires, clinical measurements, blood and urine samples, and DNA were collected for 1175 adult volunteers. Stage-2, concerning trait diagnoses, linkage analysis and association studies, is ongoing. The selection of the traits is being driven by expert clinicians. Preliminary, descriptive statistics were obtained. Power simulations for finding linkage on a quantitative trait locus (QTL) were undertaken. RESULTS: Starting from participants, genealogies were reconstructed for 50,037 subjects, going back to the early 1600s. Within the last five generations, subjects were clustered in one pedigree of 7049 subjects plus 178 smaller pedigrees (3 to 85 subjects each). A significant probability of familial clustering was assessed for many traits, especially among the cardiovascular, neurological and respiratory traits. Simulations showed that the MICROS pedigree has a substantial power to detect a LOD score > or = 3 when the QTL specific heritability is > or = 20%. CONCLUSION: The MICROS study is an extensive, ongoing, two-stage survey aimed at characterizing the genetic epidemiology of Mendelian and complex diseases. Our approach, involving different scientific disciplines, is an advantageous strategy to define and to study population isolates. The isolation of the Alpine populations, together with the extensive data collected so far, make the MICROS study a powerful resource for the study of diseases in many fields of medicine. Recent successes and simulation studies give us confidence that our pedigrees can be valuable both in finding new candidates loci and to confirm existing candidate genes.


Assuntos
Projetos de Pesquisa Epidemiológica , Doenças Genéticas Inatas/epidemiologia , Ligação Genética , Predisposição Genética para Doença/genética , Genética Populacional , Locos de Características Quantitativas , Análise por Conglomerados , Simulação por Computador , Coleta de Dados/métodos , Feminino , Doenças Genéticas Inatas/genética , Humanos , Itália/epidemiologia , Escore Lod , Masculino , Linhagem
20.
Am J Hum Genet ; 79(4): 716-23, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16960808

RESUMO

Restless legs syndrome (RLS) is a common neurological condition with three loci (12q, 14q, and 9p) described so far, although none of these genes has yet been identified. We report a genomewide linkage scan of patients with RLS (n=37) assessed in a population isolate (n=530) of South Tyrol (Italy). Using both nonparametric and parametric analyses, we initially obtained suggestive evidence of a novel locus on chromosome 2q, with nominal evidence of linkage on chromosomes 5p and 17p. Follow-up genotyping yielded significant evidence of linkage (nonparametric LOD score 5.5, P

Assuntos
Cromossomos Humanos Par 2/genética , Predisposição Genética para Doença , Síndrome das Pernas Inquietas/genética , Adolescente , Adulto , Criança , Mapeamento Cromossômico , Família , Feminino , Ligação Genética , Genoma Humano , Humanos , Itália , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem
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