RESUMO
This study examined whether coffee consumption is causally associated with osteoarthritis. A two-sample Mendelian randomization (MR) analysis using inverse-variance weighted (IVW) and weighted median estimates, and the MR-Egger regression method were performed. The publicly available summary statistical datasets of coffee consumption genome-wide association studies (GWASs) meta-analyses on coffee intake from eight Caucasian cohorts (n = 18,176), GWAS meta-analyses of predominately regular-type coffee consumers of European ancestry (n = up to 91,462), and a GWAS in 7410 patients with osteoarthritis in the arcOGEN study with 11,009 controls of European ancestry were evaluated. Four single-nucleotide polymorphisms (SNPs) from GWASs of coffee consumption as instrumental variables (IVs) to improve inference were selected. These SNPs were located at neurocalcin delta (NCALD) (rs16868941), cytochrome p450 oxidoreductase (POR) (rs17685), cytochrome p450 family 1 subfamily A member 1 (CYP1A1) (rs2470893), and neuronal cell adhesion molecule (NRCAM) (rs382140). The IVW method (beta = 0.381, SE = 0.170, p = 0.025) and the weighted median approach (beta = 0.419, SE = 0.206, p = 0.047) showed evidence to support a causal association between coffee consumption and osteoarthritis. MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept = 0.064; p = 0.549), but showed no causal association between coffee consumption and osteoarthritis (beta = - 0.518, SE = 1.270, p = 0.723). Cochran's Q test and the funnel plot indicated no evidence of heterogeneity between IV estimates based on the individual variants. The results of MR analysis support the observation that coffee consumption is causally associated with an increased risk of osteoarthritis.
Assuntos
Café/efeitos adversos , Osteoartrite/epidemiologia , População Branca/genética , Moléculas de Adesão Celular/genética , Citocromo P-450 CYP1A1/genética , Sistema Enzimático do Citocromo P-450/genética , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Metanálise como Assunto , Neurocalcina/genética , Osteoartrite/genética , Polimorfismo de Nucleotídeo Único , Análise de RegressãoRESUMO
INTRODUCTION: Decompression sickness (DCS) may cause a wide variety of symptoms, including central nervous system (CNS) manifestations. The main objective of this study was to examine whether DCS is associated with neuronal injury, and whether DCS could result in altered amyloid metabolism. METHODS: Seven, male divers with DCS and seven age-matched controls were included in the study. All the divers were treated by recompression but the controls did not receive hyperbaric oxygen. Cerebrospinal fluid (CSF) samples were collected 7-10 days after the diving injury and at three months follow-up. CSF biomarkers of neuronal injury, astroglial Injury/activation, and a range of markers of amyloid ß (Aß) metabolism, as well as two proinflammatory interleukins, were analysed using immunochemical methods. RESULTS: There were no significant differences in the best-established CSF markers of neuronal injury, total tau (T-tau) and neurofilament light, between DCS patients and controls or between the two sampling time points. Also, there were no significant changes in the astroglial or amyloid (Aß)-related markers between DCS patients and controls. However, the only diver with CNS symptoms had the highest levels of CSF T-tau, Aß38, Aß40 and Aß42. CONCLUSION: The results of our study speak against subclinical CNS injury or induction of inflammation or amyloid build-up in the brain among the six DCS patients without neurological symptoms. Further research, including on divers with CNS DCS, is justified.
Assuntos
Biomarcadores/líquido cefalorraquidiano , Sistema Nervoso Central/lesões , Doença da Descompressão/líquido cefalorraquidiano , Mergulho/lesões , Adulto , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Astrócitos , Estudos de Casos e Controles , Descompressão , Doença da Descompressão/terapia , Humanos , Oxigenoterapia Hiperbárica , Interleucina-6/líquido cefalorraquidiano , Interleucina-8/líquido cefalorraquidiano , Masculino , Neurocalcina/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Neurônios , Adulto Jovem , Proteínas tau/líquido cefalorraquidianoRESUMO
Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, Pâ=â1.3×10⻹°) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (Pâ=â1.7×10â»4, 1.8×10â»4, and 2.2×10â»4 respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates.
Assuntos
Dor/genética , Estudos de Coortes , Temperatura Baixa/efeitos adversos , Biologia Computacional , Bases de Dados Genéticas , Doença/genética , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Medicina Integrativa , Proteínas com Domínio LIM/genética , Masculino , Modelos Genéticos , Neurocalcina/genética , Dor/etiologia , Biologia de SistemasRESUMO
Visinin-like protein-1 (VILIP-1), a myristoylated calcium sensor protein with three EF-hand motifs, modulates adenylyl cyclase activity. It translocates to membranes when a postulated "calcium-myristoyl switch" is triggered by calcium-binding to expose its sequestered myristoyl moiety. We investigated the contributions of the EF-hand motifs to the translocation of VILIP-1 to membranes and to the modulation of adenylyl cyclase activity. Mutation of residues crucial for binding calcium within each one of the EF-hand motifs indicated that they all contributed to binding calcium. Simultaneous mutations of all of the three EF-hand motifs completely abolished VILIP-1's ability to bind calcium, attenuated but did not eliminate its modulation of adenylyl cyclase activity, and abolished its calcium-dependence for association with cellular membranes. These results show that the calcium-binding EF-hand motifs of VILIP-1 do not have an essential role in modulating adenylyl cyclase activity but instead have a structural role in activating the "calcium-myristoyl switch" of VILIP-1.
Assuntos
Proteínas de Ligação ao Cálcio/química , Proteínas do Tecido Nervoso/química , Receptores de Detecção de Cálcio , Adenilil Ciclases/metabolismo , Motivos de Aminoácidos , Cálcio/metabolismo , Linhagem Celular , AMP Cíclico/metabolismo , Citosol/metabolismo , DNA Complementar/metabolismo , Motivos EF Hand , Humanos , Imuno-Histoquímica , Microscopia de Fluorescência , Mutação , Ácido Mirístico/metabolismo , Neurocalcina , Reação em Cadeia da Polimerase , Conformação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/metabolismo , Fatores de Tempo , TransfecçãoRESUMO
We identified a new human gene that encodes a cognate of the bovine neurocalcin delta from a human fetal brain cDNA library; hence we named it human neurocalcin delta (NCALD) gene. The deduced polypeptide product of the cDNA is 22 kDa in size, and its amino acid sequence is 100% and 99% identical to that of the bovine and chicken neurocalcin, respectively. Northern blots showed that the NCALD gene is more abundantly expressed in brain, testis, ovary and small intestine. Tissue in situ hybridization confirmed the existence of the NCALD mRNA in the adult human testis. Radiation hybrid panel mapping localized the gene to chromosome 8 between molecular markers D8S270 and D8S257.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Cromossomos Humanos Par 8 , Proteínas do Tecido Nervoso/genética , Receptores de Detecção de Cálcio , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Bovinos , Mapeamento Cromossômico , Clonagem Molecular , DNA Complementar , Perfilação da Expressão Gênica , Humanos , Masculino , Dados de Sequência Molecular , Neurocalcina , Fases de Leitura Aberta , Testículo/metabolismo , Testículo/patologia , Distribuição TecidualRESUMO
The neuronal calcium sensor (NCS) proteins belong to a subfamily of the EF-hand calcium binding proteins. These proteins are primarily expressed in the nervous system and currently include more than 20 members across species [Nakayama et al., J Mol Evol 34:416-448, 1992]. Two homologues of the ncs genes, Ce-ncs-1 and Ce-ncs-2, have recently been identified in the nematode C. elegans. Here we report the cDNA sequence of a third C. elegans ncs homologue, Ce-ncs-3. We demonstrate that a null mutation in this gene caused by a large deletion in the locus does not confer a visible phenotype in C. elegans. This, in addition to the strong homology between Ce-NCS-3 and the other C. elegans NCS proteins, may indicate functional redundancy between the three genes.
Assuntos
Caenorhabditis elegans/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas do Tecido Nervoso/genética , Receptores de Detecção de Cálcio , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA Complementar/genética , Dados de Sequência Molecular , Neurocalcina , Alinhamento de SequênciaRESUMO
We have cloned and sequenced two types of human cDNA, HLP3 and HLP4, encoding a protein of 191 amino acid residues with four EF-hand calcium-binding motifs. The HLP3 and HLP4 proteins are homologous to the neuron-specific calcium-binding proteins and are likely human counterparts of the neural visinin-like protein(NVP) 1 and NVP2 identified in the rat brain (Kajimoto et al. 1993), displaying 98% and 99% amino acid identities with these sequences, respectively. The human HLP3 and 4 mRNAs are detected only in the brain and found at high amount in the cerebral cortex and cerebellum by Northern blot analysis.
Assuntos
Proteínas de Ligação ao Cálcio/genética , DNA Complementar/genética , Proteínas do Tecido Nervoso/genética , Receptores de Detecção de Cálcio , Sequência de Aminoácidos , Animais , Sequência de Bases , Encéfalo/metabolismo , Clonagem Molecular , DNA Complementar/isolamento & purificação , Motivos EF Hand/genética , Expressão Gênica , Humanos , Dados de Sequência Molecular , Neurocalcina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Distribuição TecidualRESUMO
In the course of isolation and sequence analysis of microsatellite repeat containing human cDNAs, we have isolated the human homologue of the rat visinin-like peptide gene. The human gene shows a high degree of conservation at both the amino acid and the DNA sequence level. The (CA)n microsatellite repeat embedded in the 3' untranslated region of the gene is conserved between rat and human, along with the flanking DNA sequences. We have mapped the VSNL1 gene to the short arm of chromosome 2.