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1.
Kidney Int ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34619231

RESUMO

The human kidney is composed of many cell types that vary in their abundance and distribution from normal to diseased organ. As these cell types perform unique and essential functions, it is important to confidently label each within a single tissue to accurately assess tissue architecture and microenvironments. Towards this goal, we demonstrate the use of co-detection by indexing (CODEX) multiplexed immunofluorescence for visualizing 23 antigens within the human kidney. Using CODEX, many of the major cell types and substructures, such as collecting ducts, glomeruli, and thick ascending limb, were visualized within a single tissue section. Of these antibodies, 19 were conjugated in-house, demonstrating the flexibility and utility of this approach for studying the human kidney using custom and commercially available antibodies. We performed a pilot study that compared both fresh frozen and formalin-fixed paraffin-embedded healthy non-neoplastic and diabetic nephropathy kidney tissues. The largest cellular differences between the two groups was observed in cells labeled with aquaporin 1, cytokeratin 7, and α-smooth muscle actin. Thus, our data show the power of CODEX multiplexed immunofluorescence for surveying the cellular diversity of the human kidney and the potential for applications within pathology, histology, and building anatomical atlases.

2.
J Genet Couns ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34251069

RESUMO

State-based genetic counseling licensure creates standardization, ensures high-quality care, and supports the credentialing of genetic counselors (GCs) in the United States. However, it also has the unintended consequence of requiring substantial time and resources from genetic counselors who need to obtain licensure in multiple states. There is a wide range of variability among state licensure applications, required supporting documentation, verification processes, and cost-all of which are barriers for genetic counselors. New licensure laws are being passed on a regular basis, further complicating this process. Resources may be available to some genetic counselors such as employer reimbursement and administrative support; however, access to this support is not universal. This paper reviews the current condition of genetic counseling multi-state licensure, including barriers, unique challenges, and possible solutions for increased efficiencies, based on the authors' experiences and examples found in other healthcare fields.

4.
N Engl J Med ; 384(5): 428-439, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33471991

RESUMO

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Variação Genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Risco , Análise de Sequência de DNA , Adulto Jovem
5.
Nucleic Acids Res ; 49(D1): D884-D891, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33137190

RESUMO

The Ensembl project (https://www.ensembl.org) annotates genomes and disseminates genomic data for vertebrate species. We create detailed and comprehensive annotation of gene structures, regulatory elements and variants, and enable comparative genomics by inferring the evolutionary history of genes and genomes. Our integrated genomic data are made available in a variety of ways, including genome browsers, search interfaces, specialist tools such as the Ensembl Variant Effect Predictor, download files and programmatic interfaces. Here, we present recent Ensembl developments including two new website portals. Ensembl Rapid Release (http://rapid.ensembl.org) is designed to provide core tools and services for genomes as soon as possible and has been deployed to support large biodiversity sequencing projects. Our SARS-CoV-2 genome browser (https://covid-19.ensembl.org) integrates our own annotation with publicly available genomic data from numerous sources to facilitate the use of genomics in the international scientific response to the COVID-19 pandemic. We also report on other updates to our annotation resources, tools and services. All Ensembl data and software are freely available without restriction.


Assuntos
Biologia Computacional/métodos , Bases de Dados de Ácidos Nucleicos , Genômica/métodos , SARS-CoV-2/genética , Vertebrados/genética , Animais , COVID-19/epidemiologia , COVID-19/virologia , Humanos , Internet , Anotação de Sequência Molecular/métodos , Pandemias , Vertebrados/classificação
6.
J Med Toxicol ; 17(2): 176-184, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33146875

RESUMO

INTRODUCTION: Implementing a hospital medication for addiction treatment (MAT) and a linkage program can improve care for patients with substance use disorder (SUD); however, lack of hospital funding and brick and mortar SUD resources are potential barriers to feasibility. METHODS: This study assesses the feasibility of implementation of a SUD linkage program. Components of the program include a county-funded hospital opioid support team (HOST), a hospital-employed addiction recovery specialist (ARS), and a medical toxicology MAT induction service and maintenance program. Data for linkage by HOST, ARS, and MAT program were tracked from July 2018 to December 2019. RESULTS: From July 2018 through December 2019, 1834 patients were linked to treatment: 1536 by HOST and 298 by the ARS. The most common disposition categories for patients linked by HOST were 16.73% to medically monitored detoxification, 9.38% to intensive outpatient, and 8.59% to short-term residential treatment. Among patients linked by the ARS, 65.66% were linked to outpatient treatment and 9.43% were linked directly to inpatient treatment. A total of 223 patients managed by the ARS were started on MAT by medical toxicology and linked to outpatient MAT clinic: 72.68% on buprenorphine/naloxone, 24.59% on naltrexone, 1.09% buprenorphine, and 0.55% acamprosate. CONCLUSION: Implementing a MAT and linkage program in the ED and hospital setting was feasible. Leveraging medical toxicology expertise as well as community and funding partnerships was crucial to successful implementation.

7.
Radiol Case Rep ; 15(12): 2617-2620, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33072235

RESUMO

Emergency physicians often rely on heuristics to facilitate clinical decisions due to the large volume of patients they see daily. Consequently, they are vulnerable to error and bias. We report the case of a 69-year-old male that presented to the emergency department (ED) with shortness of breath, productive cough, and dyspnea on exertion. One day prior to ED admission, he was diagnosed with bronchitis; however, point-of-care ultrasound (POCUS) in the ED identified acute pulmonary embolism. This case illustrates the potential dangers of anchoring bias and shows the benefits of using point-of-care ultrasound of the lungs and heart to assist in the diagnosis of acute pulmonary embolism.

8.
Anal Chem ; 92(19): 13084-13091, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32668145

RESUMO

Low molecular weight metabolites are essential for defining the molecular phenotypes of cells. However, spatial metabolomics tools often lack the sensitivity, specify, and spatial resolution to provide comprehensive descriptions of these species in tissue. MALDI imaging mass spectrometry (IMS) of low molecular weight ions is particularly challenging as MALDI matrix clusters are often nominally isobaric with multiple metabolite ions, requiring high resolving power instrumentation or derivatization to circumvent this issue. An alternative to this is to perform ion mobility separation before ion detection, enabling the visualization of metabolites without the interference of matrix ions. Additional difficulties surrounding low weight metabolite visualization include high resolution imaging, while maintaining sufficient ion numbers for broad and representative analysis of the tissue chemical complement. Here, we use MALDI timsTOF IMS to image low molecular weight metabolites at higher spatial resolution than most metabolite MALDI IMS experiments (20 µm) while maintaining broad coverage within the human kidney. We demonstrate that trapped ion mobility spectrometry (TIMS) can resolve matrix peaks from metabolite signal and separate both isobaric and isomeric metabolites with different distributions within the kidney. The added ion mobility data dimension dramatically increased the peak capacity for spatial metabolomics experiments. Through this improved sensitivity, we have found >40 low molecular weight metabolites in human kidney tissue, such as argininic acid, acetylcarnitine, and choline that localize to the cortex, medulla, and renal pelvis, respectively. Future work will involve further exploring metabolomic profiles of human kidneys as a function of age, sex, and race.


Assuntos
Acetilcarnitina/metabolismo , Arginina/análogos & derivados , Colina/metabolismo , Rim/metabolismo , Metabolômica , Acetilcarnitina/análise , Arginina/análise , Arginina/metabolismo , Colina/análise , Humanos , Espectrometria de Mobilidade Iônica , Rim/química , Peso Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
9.
Nat Genet ; 52(1): 56-73, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911677

RESUMO

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Mapeamento Cromossômico/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Teorema de Bayes , Feminino , Humanos , Desequilíbrio de Ligação , Sequências Reguladoras de Ácido Nucleico , Fatores de Risco
10.
J Clin Oncol ; 38(7): 674-685, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841383

RESUMO

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.


Assuntos
Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Neoplasias/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Internacionalidade , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/genética , Risco
11.
Nucleic Acids Res ; 48(D1): D682-D688, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31691826

RESUMO

The Ensembl (https://www.ensembl.org) is a system for generating and distributing genome annotation such as genes, variation, regulation and comparative genomics across the vertebrate subphylum and key model organisms. The Ensembl annotation pipeline is capable of integrating experimental and reference data from multiple providers into a single integrated resource. Here, we present 94 newly annotated and re-annotated genomes, bringing the total number of genomes offered by Ensembl to 227. This represents the single largest expansion of the resource since its inception. We also detail our continued efforts to improve human annotation, developments in our epigenome analysis and display, a new tool for imputing causal genes from genome-wide association studies and visualisation of variation within a 3D protein model. Finally, we present information on our new website. Both software and data are made available without restriction via our website, online tools platform and programmatic interfaces (available under an Apache 2.0 license) and data updates made available four times a year.


Assuntos
Biologia Computacional/métodos , Bases de Dados Genéticas , Epigenoma , Anotação de Sequência Molecular , Algoritmos , Animais , Gráficos por Computador , Bases de Dados de Proteínas , Variação Genética , Estudo de Associação Genômica Ampla , Genômica , Histonas/metabolismo , Humanos , Imageamento Tridimensional , Internet , Ligantes , Ferramenta de Busca , Software , Especificidade da Espécie , Transcriptoma , Interface Usuário-Computador , Navegador
13.
J Am Chem Soc ; 141(22): 8670-8674, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117643

RESUMO

The development of an intermolecular and enantioselective aza-Wacker reaction is described. Using indoles as the N-source and a selection of alkenols as the coupling partners selective ß-hydride elimination toward the alcohol was achieved. This strategy preserves the newly formed stereocenter by preventing the formation of traditionally observed enamine products. Allylic and homoallylic alcohols with a variety of functional groups are compatible with the reaction in high enantioselectivity. Isotopic-labeling experiments support a syn amino-palladation mechanism for this new class of aza-Wacker reactions.


Assuntos
Indóis/química , Alquilação , Estereoisomerismo
14.
J Am Chem Soc ; 141(22): 8708-8711, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31124676

RESUMO

Herein we describe the development of a Pd-catalyzed enantioselective Markovnikov addition of carbamates to allylic alcohols for the construction of α-tertiary and α-secondary amines. The reaction affords a range of ß-amino alcohols, after reduction of the aldehyde in situ, which contain a variety of functional groups in moderate yields and moderate to good enantioselectivities. These products can be readily oxidized to ß-amino acids, valuable building blocks for the synthesis of biologically active compounds. Mechanistic studies indicate that the C-N bond formation occurs via a syn amino-palladation mechanism, an insight which may guide future reaction development given the limited number of enantioselective syntheses of α-tertiary amines.


Assuntos
Álcoois/química , Alcenos/química , Aminas/química , Carbamatos/química , Estereoisomerismo
15.
Metallomics ; 11(5): 982-993, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-30968088

RESUMO

Zinc (Zn) is an essential trace metal required for all forms of life, but is toxic at high concentrations. While the toxic effects of high levels of Zn are well documented, the mechanism of cell death appears to vary based on the study and concentration of Zn. Zn has been proposed as an anti-cancer treatment against non-small cell lung cancer (NSCLC). The goal of this analysis was to determine the effects of Zn on metabolism and cell death in A549 cells. Here, high throughput multi-omics analysis identified the molecular effects of Zn intoxication on the proteome, metabolome, and transcriptome of A549 human NSCLC cells after 5 min to 24 h of Zn exposure. Multi-omics analysis combined with additional experimental evidence suggests Zn intoxication induces ferroptosis, an iron and lipid peroxidation-dependent programmed cell death, demonstrating the utility of multi-omics analysis to identify cellular response to intoxicants.


Assuntos
Ferroptose/efeitos dos fármacos , Pulmão/patologia , Zinco/toxicidade , Células A549 , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Genômica , Humanos , NAD/biossíntese , Necrose , Ligação Proteica/efeitos dos fármacos , Fatores de Tempo
16.
Cancer Epidemiol Biomarkers Prev ; 28(4): 822-825, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30642840

RESUMO

BACKGROUND: Genes regulated by breast cancer risk alleles identified through genome-wide association studies (GWAS) may harbor rare coding risk alleles. METHODS: We sequenced the coding regions for 38 genes within 500 kb of 38 lead GWAS SNPs in 13,538 breast cancer cases and 5,518 controls. RESULTS: Truncating variants in these genes were rare, and were not associated with breast cancer risk. Burden testing of rare missense variants highlighted 5 genes with some suggestion of an association with breast cancer, although none met the multiple testing thresholds: MKL1, FTO, NEK10, MDM4, and COX11. Six common alleles in COX11, MAP3K1 (two), and NEK10 (three) were associated at the P < 0.0001 significance level, but these likely reflect linkage disequilibrium with causal regulatory variants. CONCLUSIONS: There was no evidence that rare coding variants in these genes confer substantial breast cancer risks. However, more modest effect sizes could not be ruled out. IMPACT: We tested the hypothesis that rare variants in 38 genes near breast cancer GWAS loci may mediate risk. These variants do not appear to play a major role in breast cancer heritability.


Assuntos
Neoplasias da Mama/genética , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos
17.
Int J Cancer ; 144(5): 1195-1204, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30175445

RESUMO

Breast cancer patients with BRCA1/2-driven tumors may benefit from targeted therapy. It is not clear whether current BRCA screening guidelines are effective at identifying these patients. The purpose of our study was to evaluate the prevalence of inherited BRCA1/2 pathogenic variants in a large, clinically representative breast cancer cohort and to estimate the proportion of BRCA1/2 carriers not detected by selectively screening individuals with the highest probability of being carriers according to current clinical guidelines. The study included 5,122 unselected Swedish breast cancer patients diagnosed from 2001 to 2008. Target sequence enrichment (48.48 Fluidigm Access Arrays) and sequencing were performed (Illumina Hi-Seq 2,500 instrument, v4 chemistry). Differences in patient and tumor characteristics of BRCA1/2 carriers who were already identified as part of clinical BRCA1/2 testing routines and additional BRCA1/2 carriers found by sequencing the entire study population were compared using logistic regression models. Ninety-two of 5,099 patients with valid variant calls were identified as BRCA1/2 carriers by screening all study participants (1.8%). Only 416 study participants (8.2%) were screened as part of clinical practice, but this identified 35 out of 92 carriers (38.0%). Clinically identified carriers were younger, less likely postmenopausal and more likely to be associated with familiar ovarian cancer compared to the additional carriers identified by screening all patients. More BRCA2 (34/42, 81.0%) than BRCA1 carriers (23/50, 46%) were missed by clinical screening. In conclusion, BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%. Six in ten BRCA carriers were not detected by selective clinical screening of individuals.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Mutação/genética , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Prevalência
18.
Am J Hum Genet ; 104(1): 21-34, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554720

RESUMO

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Predisposição Genética para Doença , Herança Multifatorial/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Feminino , Humanos , Anamnese , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores de Estrogênio/metabolismo , Reprodutibilidade dos Testes , Medição de Risco
19.
J Anim Sci ; 97(1): 90-100, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30481306

RESUMO

Heifers that have an earlier age at puberty often have greater lifetime productivity. Age at puberty is moderately heritable so selection should effectively reduce the number of days to puberty, and improve heifer productivity and profitability as a result. However, recording age at puberty is intensive, requiring repeat ovarian scanning to determine age at first corpus luteum (AGECL). Genomic selection has been proposed as a strategy to select for earlier age at puberty; however, large reference populations of cows with AGECL records and genotypes would be required to generate accurate GEBV for this trait. Reproductive maturity score (RMS) is a proxy trait for age at puberty for implementation in northern Australia beef herds, where large scale recording of AGECL is not feasible. RMS assigns a score of 0 to 5 from a single ovarian scan to describe ovarian maturity at ~600 d. Here we use multivariate genomic prediction to evaluate the value of a large RMS data set to improve accuracy of GEBV for age at puberty (AGECL). There were 882 Brahman and 990 Tropical Composite heifers with AGECL phenotypes, and an independent set of 974 Brahman, 1,798 Santa Gertrudis, and 910 Droughtmaster heifers with RMS phenotypes. All animals had 728,785 real or imputed SNP genotypes. The correlation of AGECL and RMS (h2 = 0.23) was estimated as -0.83 using the genomic information. This result also demonstrates that using genomic information it is possible to estimate genetic correlations between traits collected on different animals in different herds, with minimal or unknown pedigree linkage between them. Inclusion of heifers with RMS in the multi-trait model improved the accuracy of genomic evaluations for AGECL. Accuracy of RMS GEBV generally did not improve by adding heifers with AGECL phenotypes into the reference population. These results suggest that RMS and AGECL may be used together in a multi-trait prediction model to increase the accuracy of prediction for age at puberty in tropically adapted beef cattle.


Assuntos
Bovinos/genética , Genoma/genética , Genômica , Reprodução/genética , Maturidade Sexual/genética , Animais , Austrália , Cruzamento , Bovinos/fisiologia , Feminino , Genótipo , Análise Multivariada , Linhagem , Fenótipo
20.
Cancer Res ; 78(21): 6329-6338, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385609

RESUMO

Genetic variants that increase breast cancer risk can be rare or common. This study tests whether the genetic risk stratification of breast cancer by rare and common variants in established loci can discriminate tumors with different biology, patient survival, and mode of detection. Multinomial logistic regression tested associations between genetic risk load [protein-truncating variant (PTV) carriership in 31 breast cancer predisposition genes-or polygenic risk score (PRS) using 162 single-nucleotide polymorphisms], tumor characteristics, and mode of detection (OR). Ten-year breast cancer-specific survival (HR) was estimated using Cox regression models. In this unselected cohort of 5,099 patients with breast cancer diagnosed in Sweden between 2001 and 2008, PTV carriers (n = 597) were younger and associated with more aggressive tumor phenotypes (ER-negative, large size, high grade, high proliferation, luminal B, and basal-like subtype) and worse outcome (HR, 1.65; 1.16-2.36) than noncarriers. After excluding 92 BRCA1/2 carriers, PTV carriership remained associated with high grade and worse survival (HR, 1.76; 1.21-2.56). In 5,007 BRCA1/2 noncarriers, higher PRS was associated with less aggressive tumor characteristics (ER-positive, PR-positive, small size, low grade, low proliferation, and luminal A subtype). Among patients with low mammographic density (<25%), non-BRCA1/2 PTV carriers were more often interval than screen-detected breast cancer (OR, 1.89; 1.12-3.21) than noncarriers. In contrast, higher PRS was associated with lower risk of interval compared with screen-detected cancer (OR, 0.77; 0.64-0.93) in women with low mammographic density. These findings suggest that rare and common breast cancer susceptibility loci are differentially associated with tumor characteristics, survival, and mode of detection.Significance: These findings offer the potential to improve screening practices for breast cancer by providing a deeper understanding of how risk variants affect disease progression and mode of detection. Cancer Res; 78(21); 6329-38. ©2018 AACR.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Detecção Precoce de Câncer/métodos , Variação Genética , Adulto , Idoso , Proteína BRCA1/genética , Densidade da Mama , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Sobrevivência Celular , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Metástase Linfática , Mamografia , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Risco , Resultado do Tratamento
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