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The use of radioisotopes in cancer therapy is becoming increasingly important. As a potential candidate for targeted alpha therapy, 230U (t1/2 = 20.8 d), the decay daughter of 230Pa (t1/2 = 17.4 d) is currently being investigated for cancer treatment. For radioisotopes to be used in biomedicine, they must be radiochemically pure and free from carrier interference. This can be challenging given their short half-life. Thus, radiological separation methods for harvesting isotopes for use in biomedicine must be simple, fast, and capable of obtaining the required purity levels. Herein, we demonstrate a new rapid method for the separation of 230U and 230Pa from a proton-irradiated 232Th metal target and from coproduced fission products with high recovery and purity. A dual-column approach was used, in which the first column was an anion exchange (AX) column and the second column was a DGA column. The MP-1 AX resin was used for the primary separation of the three major components (U, Pa, and Th, as well as fission products), and the DGA column was used for further purification of the separated 230U. The method is simple and allows for straightforward separation of U, Pa, Th, and fission products; also, the entire process from target dissolution to shipment of 230U could be completed in 3 days with an overall 230U recovery yield of 96 ± 3%. Additionally, separated 230Pa fractions can be used to harvest ingrown 230U after initial separation.
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Identity-by-descent (IBD) segments are a useful tool for applications ranging from demographic inference to relationship classification, but most detection methods rely on phasing information and therefore require substantial computation time. As genetic datasets grow, methods for inferring IBD segments that scale well will be critical. We developed IBIS, an IBD detector that locates long regions of allele sharing between unphased individuals, and benchmarked it with Refined IBD, GERMLINE, and TRUFFLE on 3,000 simulated individuals. Phasing these with Beagle 5 takes 4.3 CPU days, followed by either Refined IBD or GERMLINE segment detection in 2.9 or 1.1 h, respectively. By comparison, IBIS finishes in 6.8 min or 7.8 min with IBD2 functionality enabled: speedups of 805-946× including phasing time. TRUFFLE takes 2.6 h, corresponding to IBIS speedups of 20.2-23.3×. IBIS is also accurate, inferring ≥7 cM IBD segments at quality comparable to Refined IBD and GERMLINE. With these segments, IBIS classifies first through third degree relatives in real Mexican American samples at rates meeting or exceeding other methods tested and identifies fourth through sixth degree pairs at rates within 0.0%-2.0% of the top method. While allele frequency-based approaches that do not detect segments can infer relationship degrees faster than IBIS, the fastest are biased in admixed samples, with KING inferring 30.8% fewer fifth degree Mexican American relatives correctly compared with IBIS. Finally, we ran IBIS on chromosome 2 of the UK Biobank dataset and estimate its runtime on the autosomes to be 3.3 days parallelized across 128 cores.
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Análise de Sequência/métodos , Alelos , Cromossomos Humanos Par 2/genética , Frequência do Gene/genética , Genoma Humano/genética , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: The concept of healthcare acceptability is important for nursing staff spending most of their time with patients. Nevertheless, acceptability remains confusing without a collective definition in existing literature. OBJECTIVE: This study aimed to create a consensus among experts on definition and conceptual framework of healthcare acceptability. METHODS: We conducted two rounds of Delphi surveys to collect opinions from experts on definition and conceptual framework of healthcare acceptability proposed following thematic content analysis. We calculated the consensus among experts using the modified Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument and followed the guidance on conducting and reporting Delphi studies (CREDES) best practices. RESULTS: A total of 34 experts completed two rounds of Delphi survey. The definition was validated through consensus as: "a multi-construct concept describing the nonlinear cumulative combination in parts or in whole of experienced or anticipated specific healthcare from the relevant patients/participants, communities, providers/researchers or healthcare systems' managers and policy makers' perspectives in a given context." The overall quality rating was 92.6% and 95.1% for the proposed definition and conceptual framework respectively. CONCLUSION: Opinions collected from experts provided significant insights to build a consensus on healthcare acceptability advancing public health nursing.
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Recursos Humanos de Enfermagem , Aceitação pelo Paciente de Cuidados de Saúde , Humanos , Consenso , Técnica Delphi , Inquéritos e QuestionáriosRESUMO
In this work, an integrated liquid-crystal-based phase modulator operating at visible wavelengths was developed and experimentally demonstrated. A visible-light silicon-nitride-based 300-mm-wafer foundry platform and a liquid-crystal integration process were developed to leverage the birefringence of liquid crystal to actively tune the effective index of a section of silicon-nitride waveguide and induce a phase shift over its length. The device was experimentally shown to achieve a 41π phase shift within 4.8â Vpp for a 500-µm-long modulator, which means that a 2π phase shifter would need to be only 24.4â µm long. This device is a compact and low-power solution to the challenge of integrated phase modulation in silicon nitride and paves the way for future low-power small-form-factor integrated systems at visible wavelengths.
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Simulations of close relatives and identical by descent (IBD) segments are common in genetic studies, yet most past efforts have utilized sex averaged genetic maps and ignored crossover interference, thus omitting features known to affect the breakpoints of IBD segments. We developed Ped-sim, a method for simulating relatives that can utilize either sex-specific or sex averaged genetic maps and also either a model of crossover interference or the traditional Poisson model for inter-crossover distances. To characterize the impact of previously ignored mechanisms, we simulated data for all four combinations of these factors. We found that modeling crossover interference decreases the standard deviation of pairwise IBD proportions by 10.4% on average in full siblings through second cousins. By contrast, sex-specific maps increase this standard deviation by 4.2% on average, and also impact the number of segments relatives share. Most notably, using sex-specific maps, the number of segments half-siblings share is bimodal; and when combined with interference modeling, the probability that sixth cousins have non-zero IBD sharing ranges from 9.0 to 13.1%, depending on the sexes of the individuals through which they are related. We present new analytical results for the distributions of IBD segments under these models and show they match results from simulations. Finally, we compared IBD sharing rates between simulated and real relatives and find that the combination of sex-specific maps and interference modeling most accurately captures IBD rates in real data. Ped-sim is open source and available from https://github.com/williamslab/ped-sim.
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Mapeamento Cromossômico/métodos , Simulação por Computador , Caracteres Sexuais , Feminino , Variação Genética , Genética Populacional , Genoma Humano , Humanos , Masculino , Modelos Genéticos , Linhagem , Distribuição de PoissonRESUMO
As genetic datasets increase in size, the fraction of samples with one or more close relatives grows rapidly, resulting in sets of mutually related individuals. We present DRUID-deep relatedness utilizing identity by descent-a method that works by inferring the identical-by-descent (IBD) sharing profile of an ungenotyped ancestor of a set of close relatives. Using this IBD profile, DRUID infers relatedness between unobserved ancestors and more distant relatives, thereby combining information from multiple samples to remove one or more generations between the deep relationships to be identified. DRUID constructs sets of close relatives by detecting full siblings and also uses an approach to identify the aunts/uncles of two or more siblings, recovering 92.2% of real aunts/uncles with zero false positives. In real and simulated data, DRUID correctly infers up to 10.5% more relatives than PADRE when using data from two sets of distantly related siblings, and 10.7%-31.3% more relatives given two sets of siblings and their aunts/uncles. DRUID frequently infers relationships either correctly or within one degree of the truth, with PADRE classifying 43.3%-58.3% of tenth degree relatives in this way compared to 79.6%-96.7% using DRUID.
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Genoma Humano/genética , Polimorfismo de Nucleotídeo Único/genética , Feminino , Genética Populacional/métodos , Humanos , Masculino , Linhagem , IrmãosRESUMO
A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.
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Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Variação Genética , Americanos Mexicanos/genética , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/patologia , Saúde da Família , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Locos de Características Quantitativas/genética , Sequenciamento Completo do Genoma/métodosRESUMO
The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.
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Ceramidas/biossíntese , Ácidos Graxos Dessaturases/genética , Western Blotting , Sistemas CRISPR-Cas/genética , Ceramidas/metabolismo , Feminino , Genótipo , Células Hep G2 , Humanos , Masculino , Americanos MexicanosRESUMO
Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. Finally, many pedigrees are available as an important legacy from the era of linkage analysis. Unfortunately, pedigree likelihoods are notoriously hard to compute. In this paper, we reexamine the computational bottlenecks and implement ultra-fast pedigree-based GWAS analysis. Kinship coefficients can either be based on explicitly provided pedigrees or automatically estimated from dense markers. Our strategy (a) works for random sample data, pedigree data, or a mix of both; (b) entails no loss of power; (c) allows for any number of covariate adjustments, including correction for population stratification; (d) allows for testing SNPs under additive, dominant, and recessive models; and (e) accommodates both univariate and multivariate quantitative traits. On a typical personal computer (six CPU cores at 2.67 GHz), analyzing a univariate HDL (high-density lipoprotein) trait from the San Antonio Family Heart Study (935,392 SNPs on 1,388 individuals in 124 pedigrees) takes less than 2 min and 1.5 GB of memory. Complete multivariate QTL analysis of the three time-points of the longitudinal HDL multivariate trait takes less than 5 min and 1.5 GB of memory. The algorithm is implemented as the Ped-GWAS Analysis (Option 29) in the Mendel statistical genetics package, which is freely available for Macintosh, Linux, and Windows platforms from http://genetics.ucla.edu/software/mendel.
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Ligação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas , Humanos , Modelos Genéticos , Modelos Estatísticos , SoftwareRESUMO
Aims: The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Methods and results: Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion: We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies.
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Transportador 1 de Cassete de Ligação de ATP/genética , Aterosclerose/genética , Proteínas de Transporte/genética , HDL-Colesterol/metabolismo , Regulação da Expressão Gênica , Proteínas do Tecido Nervoso/genética , Transportador 1 de Cassete de Ligação de ATP/biossíntese , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Proteínas de Transporte/biossíntese , Linhagem Celular , Colesterol/metabolismo , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Macrófagos/metabolismo , Camundongos Knockout , Proteínas do Tecido Nervoso/biossíntese , RNA/genéticaRESUMO
Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.
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Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Americanos Mexicanos/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Mapeamento Cromossômico , Ilhas de CpG , Metilação de DNA , Diabetes Mellitus Tipo 2/epidemiologia , Epigenômica , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Padrões de Herança , Resistência à Insulina/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável , Fatores de Risco , Fatores Sexuais , Texas/epidemiologia , Texas/etnologia , Adulto JovemRESUMO
BACKGROUND: Differential plasma concentrations of circulating lipid species are associated with pathogenesis of type 2 diabetes (T2D). Whether the wide inter-individual variability in the plasma lipidome contributes to the genetic basis of T2D is unknown. Here, we investigated the potential overlap in the genetic basis of the plasma lipidome and T2D-related traits. RESULTS: We used plasma lipidomic data (1202 pedigreed individuals, 319 lipid species representing 23 lipid classes) from San Antonio Family Heart Study in Mexican Americans. Bivariate trait analyses were used to estimate the genetic and environmental correlation of all lipid species with three T2D-related traits: risk of T2D, presence of prediabetes and homeostatic model of assessment - insulin resistance. We found that 44 lipid species were significantly genetically correlated with one or more of the three T2D-related traits. Majority of these lipid species belonged to the diacylglycerol (DAG, 17 species) and triacylglycerol (TAG, 17 species) classes. Six lipid species (all belonging to the triacylglycerol class and containing palmitate at the first position) were significantly genetically correlated with all the T2D-related traits. CONCLUSIONS: Our results imply that: a) not all plasma lipid species are genetically informative for T2D pathogenesis; b) the DAG and TAG lipid classes partially share genetic basis of T2D; and c) 1-palmitate containing TAGs may provide additional insights into the genetic basis of T2D.
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Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Lipídeos/sangue , Americanos Mexicanos/genética , Estado Pré-Diabético/genética , Característica Quantitativa Herdável , Adulto , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Feminino , Interação Gene-Ambiente , Humanos , Resistência à Insulina/etnologia , Masculino , Estado Pré-Diabético/sangue , Estado Pré-Diabético/etnologiaRESUMO
Maternal-offspring gene interactions, aka maternal-fetal genotype (MFG) incompatibilities, are neglected in complex diseases and quantitative trait studies. They are implicated in birth to adult onset diseases but there are limited ways to investigate their influence on quantitative traits. We present the quantitative-MFG (QMFG) test, a linear mixed model where maternal and offspring genotypes are fixed effects and residual correlations between family members are random effects. The QMFG handles families of any size, common or general scenarios of MFG incompatibility, and additional covariates. We develop likelihood ratio tests (LRTs) and rapid score tests and show they provide correct inference. In addition, the LRT's alternative model provides unbiased parameter estimates. We show that testing the association of SNPs by fitting a standard model, which only considers the offspring genotypes, has very low power or can lead to incorrect conclusions. We also show that offspring genetic effects are missed if the MFG modeling assumptions are too restrictive. With genome-wide association study data from the San Antonio Family Heart Study, we demonstrate that the QMFG score test is an effective and rapid screening tool. The QMFG test therefore has important potential to identify pathways of complex diseases for which the genetic etiology remains to be discovered.
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Predisposição Genética para Doença , Genótipo , Modelos Lineares , Modelos Genéticos , Simulação por Computador , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Funções Verossimilhança , Linhagem , Polimorfismo de Nucleotídeo Único , Gravidez , Característica Quantitativa HerdávelRESUMO
Previous work has shown that the hippocampus is smaller in the brains of individuals suffering from major depressive disorder (MDD) than those of healthy controls. Moreover, right hippocampal volume specifically has been found to predict the probability of subsequent depressive episodes. This study explored the utility of right hippocampal volume as an endophenotype of recurrent MDD (rMDD). We observed a significant genetic correlation between the two traits in a large sample of Mexican American individuals from extended pedigrees (ρg = -0.34, p = 0.013). A bivariate linkage scan revealed a significant pleiotropic quantitative trait locus on chromosome 18p11.31-32 (LOD = 3.61). Bivariate association analysis conducted under the linkage peak revealed a variant (rs574972) within an intron of the gene SMCHD1 meeting the corrected significance level (χ(2) = 19.0, p = 7.4 × 10(-5)). Univariate association analyses of each phenotype separately revealed that the same variant was significant for right hippocampal volume alone, and also revealed a suggestively significant variant (rs12455524) within the gene DLGAP1 for rMDD alone. The results implicate right-hemisphere hippocampal volume as a possible endophenotype of rMDD, and in so doing highlight a potential gene of interest for rMDD risk.
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Proteínas Cromossômicas não Histona/genética , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Hipocampo/patologia , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Endofenótipos , Saúde da Família , Feminino , Lateralidade Funcional/genética , Ligação Genética , Predisposição Genética para Doença , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Americanos Mexicanos , Pessoa de Meia-Idade , Recidiva , Proteínas Associadas SAP90-PSD95 , Adulto JovemRESUMO
Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution (18)F-labelled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression.
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Tonsila do Cerebelo/metabolismo , Ansiedade/genética , Ansiedade/fisiopatologia , Predisposição Genética para Doença/genética , Hereditariedade , Hipocampo/metabolismo , Temperamento/fisiologia , Animais , Depressão/genética , Feminino , Reação de Congelamento Cataléptica , Glucose/metabolismo , Macaca mulatta/genética , Macaca mulatta/fisiologia , Masculino , Modelos Animais , Vias Neurais/fisiologia , Linhagem , Fenótipo , Tomografia por Emissão de Pósitrons , Estresse Psicológico , Lobo Temporal/metabolismo , Vocalização AnimalRESUMO
BACKGROUND: Detection of type 2 diabetes (T2D) is routinely based on the presence of dysglycemia. Although disturbed lipid metabolism is a hallmark of T2D, the potential of plasma lipidomics as a biomarker of future T2D is unknown. Our objective was to develop and validate a plasma lipidomic risk score (LRS) as a biomarker of future type 2 diabetes and to evaluate its cost-effectiveness for T2D screening. METHODS: Plasma LRS, based on significantly associated lipid species from an array of 319 lipid species, was developed in a cohort of initially T2D-free individuals from the San Antonio Family Heart Study (SAFHS). The LRS derived from SAFHS as well as its recalibrated version were validated in an independent cohort from Australia--the AusDiab cohort. The participants were T2D-free at baseline and followed for 9197 person-years in the SAFHS cohort (n = 771) and 5930 person-years in the AusDiab cohort (n = 644). Statistically and clinically improved T2D prediction was evaluated with established statistical parameters in both cohorts. Modeling studies were conducted to determine whether the use of LRS would be cost-effective for T2D screening. The main outcome measures included accuracy and incremental value of the LRS over routinely used clinical predictors of T2D risk; validation of these results in an independent cohort and cost-effectiveness of including LRS in screening/intervention programs for T2D. RESULTS: The LRS was based on plasma concentration of dihydroceramide 18:0, lysoalkylphosphatidylcholine 22:1 and triacyglycerol 16:0/18:0/18:1. The score predicted future T2D independently of prediabetes with an accuracy of 76%. Even in the subset of initially euglycemic individuals, the LRS improved T2D prediction. In the AusDiab cohort, the LRS continued to predict T2D significantly and independently. When combined with risk-stratification methods currently used in clinical practice, the LRS significantly improved the model fit (p < 0.001), information content (p < 0.001), discrimination (p < 0.001) and reclassification (p < 0.001) in both cohorts. Modeling studies demonstrated that LRS-based risk-stratification combined with metformin supplementation for high-risk individuals was the most cost-effective strategy for T2D prevention. CONCLUSIONS: Considering the novelty, incremental value and cost-effectiveness of LRS it should be used for risk-stratification of future T2D.
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Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/economia , Lipídeos/sangue , Biomarcadores/sangue , Estudos de Coortes , Análise Custo-Benefício , Diabetes Mellitus Tipo 2/etiologia , Humanos , Resistência à Insulina , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p-value in combined analysis of both datasets is 1.4×10(-15) for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen.
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Infecções por Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/sangue , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Herpesvirus Humano 4 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos/genética , Infecções por Vírus Epstein-Barr/sangue , Feminino , Ligação Genética , Estudo de Associação Genômica Ampla , Cadeias beta de HLA-DQ/imunologia , Cadeias HLA-DRB1/imunologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Doença de Hodgkin/genética , Doença de Hodgkin/virologia , Humanos , Imunoglobulina G/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/virologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Identification of genes associated with brain aging should markedly improve our understanding of the biological processes that govern normal age-related decline. However, challenges to identifying genes that facilitate successful brain aging are considerable, including a lack of established phenotypes and difficulties in modeling the effects of aging per se, rather than genes that influence the underlying trait. In a large cohort of randomly selected pedigrees (n = 1,129 subjects), we documented profound aging effects from young adulthood to old age (18-83 y) on neurocognitive ability and diffusion-based white-matter measures. Despite significant phenotypic correlation between white-matter integrity and tests of processing speed, working memory, declarative memory, and intelligence, no evidence for pleiotropy between these classes of phenotypes was observed. Applying an advanced quantitative gene-by-environment interaction analysis where age is treated as an environmental factor, we demonstrate a heritable basis for neurocognitive deterioration as a function of age. Furthermore, by decomposing gene-by-aging (G × A) interactions, we infer that different genes influence some neurocognitive traits as a function of age, whereas other neurocognitive traits are influenced by the same genes, but to differential levels, from young adulthood to old age. In contrast, increasing white-matter incoherence with age appears to be nongenetic. These results clearly demonstrate that traits sensitive to the genetic influences on brain aging can be identified, a critical first step in delineating the biological mechanisms of successful aging.
Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Cognição/fisiologia , Transtornos da Memória/fisiopatologia , Americanos Mexicanos/genética , Fibras Nervosas Mielinizadas/fisiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Análise de Variância , Anisotropia , Encéfalo/patologia , Imagem de Tensor de Difusão , Humanos , Transtornos da Memória/genética , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/patologia , Neuroimagem , LinhagemRESUMO
BACKGROUND: We report here the first genome-wide high-resolution polymorphism resource for non-human primate (NHP) association and linkage studies, constructed for the Caribbean-origin vervet monkey, or African green monkey (Chlorocebus aethiops sabaeus), one of the most widely used NHPs in biomedical research. We generated this resource by whole genome sequencing (WGS) of monkeys from the Vervet Research Colony (VRC), an NIH-supported research resource for which extensive phenotypic data are available. RESULTS: We identified genome-wide single nucleotide polymorphisms (SNPs) by WGS of 721 members of an extended pedigree from the VRC. From high-depth WGS data we identified more than 4 million polymorphic unequivocal segregating sites; by pruning these SNPs based on heterozygosity, quality control filters, and the degree of linkage disequilibrium (LD) between SNPs, we constructed genome-wide panels suitable for genetic association (about 500,000 SNPs) and linkage analysis (about 150,000 SNPs). To further enhance the utility of these resources for linkage analysis, we used a further pruned subset of the linkage panel to generate multipoint identity by descent matrices. CONCLUSIONS: The genetic and phenotypic resources now available for the VRC and other Caribbean-origin vervets enable their use for genetic investigation of traits relevant to human diseases.
Assuntos
Chlorocebus aethiops/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Animais , Mapeamento Cromossômico , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Fenótipo , Locos de Características Quantitativas , Análise de SequênciaRESUMO
Increased immunoglobulin G (IgG) response to dietary antigens can be associated with gastrointestinal dysfunction and autoimmunity. The underlying processes contributing to these adverse reactions remain largely unknown, and it is likely that genetic factors play a role. Here, we estimate heritability and attempt to localize genetic factors influencing IgG antibody levels against food-derived antigens using an integrative genomics approach. IgG antibody levels were determined by ELISA in >1,300 Mexican Americans for the following food antigens: wheat gliadin; bovine casein; and two forms of bovine serum albumin (BSA-a and BSA-b). Pedigree-based variance components methods were used to estimate additive genetic heritability (h(2) ), perform genome-wide association analyses, and identify transcriptional signatures (based on 19,858 transcripts from peripheral blood lymphocytes). Heritability estimates were significant for all traits (0.15-0.53), and shared environment (based on shared residency among study participants) was significant for casein (0.09) and BSA-a (0.33). Genome-wide significant evidence of association was obtained only for antibody to gliadin (P = 8.57 × 10(-8) ), mapping to the human leukocyte antigen II region, with HLA-DRA and BTNL2 as the best candidate genes. Lack of association of known celiac disease risk alleles HLA-DQ2.5 and -DQ8 with antigliadin antibodies in the studied population suggests a separate genetic etiology. Significant transcriptional signatures were found for all IgG levels except BSA-b. These results demonstrate that individual genetic differences contribute to food antigen antibody measures in this population. Further investigations may elucidate the underlying immunological processes involved.