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1.
Sci Rep ; 11(1): 748, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436952

RESUMO

The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) in 8091 genes on multi-dimensional facial shape phenotypes in a European cohort of 2329 healthy individuals. Using three-dimensional images, we partitioned the full face into 31 hierarchically arranged segments to model facial morphology at multiple levels, and generated multi-dimensional phenotypes representing the shape variation within each segment. We used MultiSKAT, a multivariate kernel regression approach to scan the exome for face-associated low-frequency variants in a gene-based manner. After accounting for multiple tests, seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 in NECTIN1 had a significant effect on chin morphology and was predicted bioinformatically to have a deleterious effect on protein function. Notably, NECTIN1 is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed that nectin1a mutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. Findings from this study expanded our understanding of the genetic basis of normal-range facial shape by highlighting the role of low-frequency coding variants in several novel genes.

2.
Nat Genet ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288918

RESUMO

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants. In summary, our analyses provide insights into the understanding of how complex morphological traits are shaped by both individual and coordinated genetic actions.

3.
Ann Lab Med ; 40(1): 63-67, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31432641

RESUMO

As 16S ribosomal RNA (rRNA)-targeted sequencing can detect DNA from non-viable bacteria, it can be used to identify pathogens from clinical samples even in patients pretreated with antibiotics. We compared the results of 16S rRNA-targeted sequencing and culture for identifying bacterial species in normally sterile body fluid (NSBF): cerebrospinal, pericardial, peritoneal and pleural fluids. Over a 10-year period, a total of 312 NSBF samples were evaluated simultaneously using 16S rRNA-targeted sequencing and culture. Results were concordant in 287/312 (92.0%) samples, including 277 (88.8%) negative and 10 (3.2%) positive samples. Of the 16 sequencing-positive, culture-negative samples, eight showed clinically relevant isolates that included Fusobacterium nucleatum subsp. nucleatum, Streptococcus pneumoniae, and Staphylococcus spp. All these samples were obtained from the patients pretreated with antibiotics. The diagnostic yield of 16S rRNA-targeted sequencing combined with culture was 11.2%, while that of culture alone was 6.1%. 16S rRNA-targeted sequencing in conjunction with culture could be useful for identifying bacteria in NSBF samples, especially when patients have been pretreated with antibiotics and when anaerobic infection is suspected.


Assuntos
Bactérias/isolamento & purificação , RNA Ribossômico 16S/metabolismo , Antibacterianos/farmacologia , Líquido Ascítico/microbiologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Líquido Cefalorraquidiano/microbiologia , Técnicas de Laboratório Clínico , Humanos , RNA Ribossômico 16S/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
4.
Elife ; 82019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31763980

RESUMO

The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.


Assuntos
Face/anatomia & histologia , Loci Gênicos/genética , Desenvolvimento Maxilofacial/genética , Fenótipo , Adolescente , Adulto , Pontos de Referência Anatômicos , Padronização Corporal/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ontologia Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
5.
Front Genet ; 9: 497, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405702

RESUMO

Many factors influence human facial morphology, including genetics, age, nutrition, biomechanical forces, and endocrine factors. Moreover, facial features clearly differ between males and females, and these differences are driven primarily by the influence of sex hormones during growth and development. Specific genetic variants are known to influence circulating sex hormone levels in humans, which we hypothesize, in turn, affect facial features. In this study, we investigated the effects of testosterone-related genetic variants on facial morphology. We tested 32 genetic variants across 22 candidate genes related to levels of testosterone, sex hormone-binding globulin (SHGB) and dehydroepiandrosterone sulfate (DHEAS) in three cohorts of healthy individuals for which 3D facial surface images were available (Pittsburgh 3DFN, Penn State and ALSPAC cohorts; total n = 7418). Facial shape was described using a recently developed extension of the dense-surface correspondence approach, in which the 3D facial surface was partitioned into a set of 63 hierarchically organized modules. Each variant was tested against each of the facial surface modules in a multivariate genetic association-testing framework and meta-analyzed. Additionally, the association between these candidate SNPs and five facial ratios was investigated in the Pittsburgh 3DFN cohort. Two significant associations involving intronic variants of SHBG were found: both rs12150660 (p = 1.07E-07) and rs1799941 (p = 6.15E-06) showed an effect on mandible shape. Rs8023580 (an intronic variant of NR2F2-AS1) showed an association with the total and upper facial width to height ratios (p = 9.61E-04 and p = 7.35E-04, respectively). These results indicate that testosterone-related genetic variants affect normal-range facial morphology, and in particular, facial features known to exhibit strong sexual dimorphism in humans.

6.
PLoS Genet ; 14(10): e1007675, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30286078

RESUMO

The mechanisms that regulate post-natal growth of the craniofacial complex and that ultimately determine the size and shape of our faces are not well understood. Hippo signaling is a general mechanism to control tissue growth and organ size, and although it is known that Hippo signaling functions in neural crest specification and patterning during embryogenesis and before birth, its specific role in postnatal craniofacial growth remains elusive. We have identified the transcription factor FoxO6 as an activator of Hippo signaling regulating neonatal growth of the face. During late stages of mouse development, FoxO6 is expressed specifically in craniofacial tissues and FoxO6-/- mice undergo expansion of the face, frontal cortex, olfactory component and skull. Enlargement of the mandible and maxilla and lengthening of the incisors in FoxO6-/- mice are associated with increases in cell proliferation. In vitro and in vivo studies demonstrated that FoxO6 activates Lats1 expression, thereby increasing Yap phosphorylation and activation of Hippo signaling. FoxO6-/- mice have significantly reduced Hippo Signaling caused by a decrease in Lats1 expression and decreases in Shh and Runx2 expression, suggesting that Shh and Runx2 are also linked to Hippo signaling. In vitro, FoxO6 activates Hippo reporter constructs and regulates cell proliferation. Furthermore PITX2, a regulator of Hippo signaling is associated with Axenfeld-Rieger Syndrome causing a flattened midface and we show that PITX2 activates FoxO6 expression. Craniofacial specific expression of FoxO6 postnatally regulates Hippo signaling and cell proliferation. Together, these results identify a FoxO6-Hippo regulatory pathway that controls skull growth, odontogenesis and face morphology.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Desenvolvimento Maxilofacial/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Crânio/crescimento & desenvolvimento , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Proteínas de Homeodomínio/metabolismo , Desenvolvimento Maxilofacial/genética , Camundongos , Crista Neural/citologia , Tamanho do Órgão , Fosforilação , Transdução de Sinais , Crânio/metabolismo , Fatores de Transcrição/metabolismo
7.
PLoS Genet ; 14(8): e1007501, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30067744

RESUMO

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Lábio/anormalidades , Adolescente , Adulto , Criança , Pré-Escolar , Grupos de Populações Continentais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Estudos Longitudinais , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
8.
Sci Rep ; 8(1): 8470, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855589

RESUMO

Velopharyngeal dysfunction (VPD) occurs when the muscular soft palate (velum) and lateral pharyngeal walls are physically unable to separate the oral and nasal cavities during speech production leading to hypernasality and abnormal speech reduction. Because VPD is often associated with overt or submucous cleft palate, it could be present as a subclinical phenotype in families with a history of orofacial clefting. A key assumption to this model is that the overt and subclinical manifestations of the orofacial cleft phenotype exist on a continuum and therefore share common etiological factors. We performed a genome-wide association study in 976 unaffected relatives of isolated CP probands, 54 of whom had VPD. Five loci were significantly (p < 5 × 10-8) associated with VPD: 3q29, 9p21.1, 12q21.31, 16p12.3 and 16p13.3. An additional 15 loci showing suggestive evidence of association with VPD were observed. Several genes known to be involved in orofacial clefting and craniofacial development are located in these regions, such as TFRC, PCYT1A, BNC2 and FREM1. Although further research is necessary, this could be an indication for a potential shared genetic architecture between VPD and cleft palate, and supporting the hypothesis that VPD is a subclinical phenotype of orofacial clefting.


Assuntos
Estudo de Associação Genômica Ampla , Insuficiência Velofaríngea/patologia , Adolescente , Adulto , Antígenos CD/genética , Criança , Colina-Fosfato Citidililtransferase/genética , Fissura Palatina/genética , Fissura Palatina/patologia , Proteínas de Ligação a DNA/genética , Feminino , Loci Gênicos , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores da Transferrina/genética , Insuficiência Velofaríngea/genética , Adulto Jovem
9.
Hum Mol Genet ; 27(17): 3113-3127, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931343

RESUMO

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Biomarcadores/análise , Cárie Dentária/genética , Dentição Permanente , Estudo de Associação Genômica Ampla/métodos , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fenótipo
10.
PLoS One ; 13(4): e0196148, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29698431

RESUMO

The shape of the cranial vault, a region comprising interlocking flat bones surrounding the cerebral cortex, varies considerably in humans. Strongly influenced by brain size and shape, cranial vault morphology has both clinical and evolutionary relevance. However, little is known about the genetic basis of normal vault shape in humans. We performed a genome-wide association study (GWAS) on three vault measures (maximum cranial width [MCW], maximum cranial length [MCL], and cephalic index [CI]) in a sample of 4419 healthy individuals of European ancestry. All measures were adjusted by sex, age, and body size, then tested for association with genetic variants spanning the genome. GWAS results for the two cohorts were combined via meta-analysis. Significant associations were observed at two loci: 15p11.2 (lead SNP rs2924767, p = 2.107 × 10-8) for MCW and 17q11.2 (lead SNP rs72841279, p = 5.29 × 10-9) for MCL. Additionally, 32 suggestive loci (p < 5x10-6) were observed. Several candidate genes were located in these loci, such as NLK, MEF2A, SOX9 and SOX11. Genome-wide linkage analysis of cranial vault shape in mice (N = 433) was performed to follow-up the associated candidate loci identified in the human GWAS. Two loci, 17q11.2 (c11.loc44 in mice) and 17q25.1 (c11.loc74 in mice), associated with cranial vault size in humans, were also linked with cranial vault size in mice (LOD scores: 3.37 and 3.79 respectively). These results provide further insight into genetic pathways and mechanisms underlying normal variation in human craniofacial morphology.


Assuntos
Estudo de Associação Genômica Ampla , Crânio/metabolismo , Adulto , Animais , Proteínas de Transporte de Cátions/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Ligação Genética , Loci Gênicos , Genótipo , Humanos , Fatores de Transcrição MEF2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXC/genética , Crânio/anatomia & histologia , Adulto Jovem
11.
Nat Genet ; 50(3): 414-423, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29459680

RESUMO

Genome-wide association scans of complex multipartite traits like the human face typically use preselected phenotypic measures. Here we report a data-driven approach to phenotyping facial shape at multiple levels of organization, allowing for an open-ended description of facial variation while preserving statistical power. In a sample of 2,329 persons of European ancestry, we identified 38 loci, 15 of which replicated in an independent European sample (n = 1,719). Four loci were completely new. For the others, additional support (n = 9) or pleiotropic effects (n = 2) were found in the literature, but the results reported here were further refined. All 15 replicated loci highlighted distinctive patterns of global-to-local genetic effects on facial shape and showed enrichment for active chromatin elements in human cranial neural crest cells, suggesting an early developmental origin of the facial variation captured. These results have implications for studies of facial genetics and other complex morphological traits.


Assuntos
Mapeamento Cromossômico , Face/anatomia & histologia , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Adulto , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Genótipo , Humanos , Desenvolvimento Maxilofacial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estados Unidos , Adulto Jovem
12.
Am J Hum Genet ; 101(6): 913-924, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198719

RESUMO

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10-8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.


Assuntos
Orelha/anatomia & histologia , Herança Multifatorial/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Animais , Região Branquial/anatomia & histologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Receptor Edar/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Camundongos , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Fator de Transcrição PAX9/genética , Proteínas/genética , Receptores Acoplados a Proteínas-G/genética , Proteínas Ribossômicas/genética , Fatores de Transcrição/genética , Adulto Jovem
13.
Ann Lab Med ; 37(6): 494-498, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28840986

RESUMO

BACKGROUND: Molecular detection of Middle East respiratory syndrome coronavirus (MERS-CoV) using real-time reverse transcription (rRT)-PCR assays is the method of choice for diagnosis of MERS. We evaluated the performance of the PowerChek MERS (upE & ORF1a) real-time PCR Kit (PowerChek MERS assay; Kogene Biotech, Korea) a one-step rRT-PCR assay for the qualitative detection of MERS-CoV. METHODS: We evaluated PowerChek MERS assay performance in comparison with nested RT-PCR and sequencing of the RNA-dependent RNA polymerase (RdRp) and N genes. To evaluate diagnostic sensitivity and specificity, 100 clinical specimens (50 positive and 50 negative for MERS-CoV) were simultaneously tested by using the PowerChek MERS and sequencing assays. Assay performance, including limit of detection and precision, was evaluated in vitro by using MERS-CoV RNA transcripts. Analytical specificity was evaluated with a diverse collection of 16 respiratory virus-positive clinical specimens and 14 respiratory bacterial isolates. RESULTS: The 95% limits of detection of the PowerChek MERS assay for the upE and the open rading frame (ORF)1a were 16.2 copies/µL and 8.2 copies/µL, respectively. No cross-reactivity was observed. The diagnostic sensitivity and specificity of the PowerChek MERS assay were both 100% (95% confidence interval, 91.1-100%). CONCLUSIONS: The PowerChek MERS assay is a straightforward and accurate assay for detecting MERS-CoV RNA. The assay will be a useful tool for the rapid diagnosis of MERS and could prove especially important for MERS outbreak control.


Assuntos
Infecções por Coronavirus/diagnóstico , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , RNA Viral/análise , Infecções por Coronavirus/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Nasofaringe/virologia , Fases de Leitura Aberta/genética , RNA Viral/metabolismo , Kit de Reagentes para Diagnóstico , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Análise de Sequência de RNA , Escarro/virologia
14.
Environ Health ; 16(1): 35, 2017 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-28381288

RESUMO

BACKGROUND: Prenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life. Placental biomarkers and outcomes at birth may offer biologic insight into these associations. This is the first study to address these associations with candidate genes from the phthalate and placenta literature, accounting for sex differences, and using absolute quantitation methods for mRNA levels. METHODS: We measured candidate mRNAs in 180 placentas sampled at birth (HSD17B1, AHR, CGA, CYP19A1, SLC27A4, PTGS2, PPARG, CYP11A1) by quantitative PCR and an absolute standard curve. We estimated associations of loge mRNA with quartiles of urinary phthalate monoesters using linear mixed models. Phthalate metabolites (N = 358) and mRNAs (N = 180) were transformed to a z-score and modeled as independent, correlated vectors in relation to large for gestational age (LGA) and gestational diabetes mellitus (GDM). RESULTS: CGA was associated with 4 out of 6 urinary phthalates. CGA was 2.0 loge units lower at the 3rd vs. 1st quartile of mono-n-butyl phthalate (MnBP) (95% confidence interval (CI): -3.5, -0.5) in male placentas, but 0.6 loge units higher (95% CI: -0.8, 1.9) in female placentas (sex interaction p = 0.01). There was an inverse association of MnBP with PPARG in male placentas (-1.1 loge units at highest vs. lowest quartile, 95% CI: -2.0, -0.1). CY19A1, CYP11A1, CGA were associated with one or more of the following in a sex-specific manner: monobenzyl phthalate (MBzP), MnBP, mono-iso-butyl phthalate (MiBP). These 3 mRNAs were lower by 1.4-fold (95% CI: -2.4, -1.0) in male GDM placentas vs. female and non-GDM placentas (p-value for interaction = 0.04). The metabolites MnBP/MiBP were 16% higher (95% CI: 0, 22) in GDM pregnancies. CONCLUSIONS: Prenatal concentrations of certain phthalates and outcomes at birth were modestly associated with molecular changes in fetal placental tissue during pregnancy. Associations were stronger in male vs. female placentas, and associations with MnBP and MiBP were stronger than other metabolites. Placental mRNAs are being pursued further as potential mediators of exposure-induced risks to the health of the child.


Assuntos
Poluentes Ambientais/urina , Exposição Materna , Ácidos Ftálicos/urina , Placenta/metabolismo , RNA Mensageiro/metabolismo , Adulto , Aromatase/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Estradiol Desidrogenases/genética , Proteínas de Transporte de Ácido Graxo/genética , Feminino , Expressão Gênica , Subunidade alfa de Hormônios Glicoproteicos/genética , Humanos , Masculino , PPAR gama/genética , Gravidez , Receptores de Hidrocarboneto Arílico/genética , Caracteres Sexuais , População Urbana , Adulto Jovem
15.
PLoS One ; 12(4): e0176566, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28441456

RESUMO

Several studies have now shown evidence of association between common genetic variants and quantitative facial traits in humans. The reported associations generally involve simple univariate measures and likely represent only a small fraction of the genetic loci influencing facial morphology. In this study, we applied factor analysis to a set of 276 facial linear distances derived from 3D facial surface images of 2187 unrelated individuals of European ancestry. We retained 23 facial factors, which we then tested for genetic associations using a genome-wide panel of 10,677,593 single nucleotide polymorphisms (SNPs). In total, we identified genome-wide significant (p < 5 × 10-8) associations in three regions, including two that are novel: one involving measures of midface height at 6q26 within an intron of PARK2 (lead SNP rs9456748; p = 4.99 × 10-8) and another involving measures of central upper lip height at 9p22 within FREM1 (lead SNP rs72713618; p = 2.02 × 10-8). In both cases, the genetic association was stronger with the composite facial factor phenotype than with any of the individual linear distances that comprise those factors. While the biological role of PARK2 in the craniofacial complex is currently unclear, there is evidence from both mouse models and Mendelian syndromes that FREM1 may influence facial variation. These results highlight the potential value of data-driven multivariate phenotyping for genetic studies of human facial morphology.


Assuntos
Face/anatomia & histologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Antropometria , Criança , Pré-Escolar , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Adulto Jovem
16.
Ann Lab Med ; 37(2): 147-150, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28029001

RESUMO

There has been increasing interest in standardized and quantitative Epstein-Barr virus (EBV) DNA testing for the management of EBV disease. We evaluated the performance of the Real-Q EBV Quantification Kit (BioSewoom, Korea) in whole blood (WB). Nucleic acid extraction and real-time PCR were performed by using the MagNA Pure 96 (Roche Diagnostics, Germany) and 7500 Fast real-time PCR system (Applied Biosystems, USA), respectively. Assay sensitivity, linearity, and conversion factor were determined by using the World Health Organization international standard diluted in EBV-negative WB. We used 81 WB clinical specimens to compare performance of the Real-Q EBV Quantification Kit and artus EBV RG PCR Kit (Qiagen, Germany). The limit of detection (LOD) and limit of quantification (LOQ) for the Real-Q kit were 453 and 750 IU/mL, respectively. The conversion factor from EBV genomic copies to IU was 0.62. The linear range of the assay was from 750 to 106 IU/mL. Viral load values measured with the Real-Q assay were on average 0.54 log10 copies/mL higher than those measured with the artus assay. The Real-Q assay offered good analytical performance for EBV DNA quantification in WB.


Assuntos
DNA Viral/sangue , Herpesvirus Humano 4/genética , DNA Viral/metabolismo , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Limite de Detecção , Kit de Reagentes para Diagnóstico , Reação em Cadeia da Polimerase em Tempo Real
17.
J Clin Microbiol ; 55(2): 479-484, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27903601

RESUMO

The Allplex respiratory panels 1, 2, and 3 (Allplex) comprise a one-step real-time reverse transcription-PCR assay for the detection of respiratory viruses (RVs) and influenza A subtypes based on multiple detection temperature (MuDT) technology. The performance of the Allplex assay was compared with those of the AdvanSure RV real-time PCR kit (AdvanSure) and the PowerChek pandemic H1N1/H3N2/H5N1 real-time PCR kit (PowerChek) using 417 clinical respiratory specimens. In comparison with the AdvanSure assay for RV detection by each virus, the ranges of positive percent agreement, negative percent agreement, and kappa values with the Allplex assay were 82.8 to 100%, 95.5 to 100%, and 0.85 to 1.00, respectively. For influenza A virus (INF A) subtyping, the kappa values between the Allplex and PowerChek assays were 0.67 and 1.00 for the INF A H1N1-pdm09 and H3 subtypes, respectively. Uniplex PCR and sequencing for samples with discrepant results demonstrated that the majority of results were concordant with those from the Allplex assay. When testing 24 samples, the turnaround and hands-on time required to perform the Allplex assay were 4 h 15 min and 15 min, respectively. In conclusion, the Allplex assay produced results comparable to those from the AdvanSure and PowerChek assays.


Assuntos
Técnicas de Genotipagem/métodos , Vírus da Influenza A/classificação , Vírus da Influenza A/isolamento & purificação , Técnicas de Diagnóstico Molecular/métodos , Infecções Respiratórias/diagnóstico , Viroses/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real/métodos , Infecções Respiratórias/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Viroses/virologia , Adulto Jovem
19.
J Clin Virol ; 85: 27-30, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27816021

RESUMO

BACKGROUND: Long-term nucleoside analogue (NA) treatment leads to selection for drug-resistant mutations in patients undergoing hepatitis B virus (HBV) therapy. The Abbott RealTime HBV Sequencing assay (Abbott assay; Abbott Molecular Inc., Des Plaines, IL, USA) targets the reverse transcriptase region of the polymerase gene and as such has the ability to detect NA resistance-associated mutations in HBV. OBJECTIVES: We evaluated the analytical performance of the Abbott assay and compared its diagnostic performance to that of a laboratory-developed nested-PCR and sequencing method. STUDY DESIGN: The analytical sensitivity of the Abbott assay was determined using a serially-diluted WHO International Standard. To validate the clinical performances of the Abbott assay and the laboratory-developed assay, 89 clinical plasma samples with various levels of HBV DNA were tested using both assays. RESULTS: The limit of detection of the Abbott assay, was 210IU/ml and it successfully detected mutations when the mutant types were present at levels ≥20%. Among 89 clinical specimens, 43 and 42 were amplification positive in the Abbott and laboratory-developed assays, respectively, with 87.6% overall agreement (78/89; 95% confidence interval [CI], 78.6-93.4). The Abbott assay failed to detect the minor mutant populations in two specimens, and therefore overall concordance was 85.3% (76/89), and the kappa value was 0.79 (95% CI, 0.67-0.90). CONCLUSIONS: The Abbott assay showed comparable diagnostic performance to laboratory-developed nested PCR followed by direct sequencing, and may be useful as a routine method for detecting HBV NA resistance-associated mutations in clinical laboratory settings.


Assuntos
Farmacorresistência Viral , Vírus da Hepatite B/genética , Testes de Sensibilidade Microbiana/métodos , DNA Polimerase Dirigida por RNA/genética , Análise de Sequência de DNA/métodos , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/enzimologia , Hepatite B Crônica/virologia , Humanos , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade
20.
Ann Lab Med ; 36(6): 603-6, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27578516

RESUMO

Standardized cytomegalovirus (CMV) DNA quantification is important for managing CMV disease. We evaluated the performance of the Real-Q CMV Quantification Kit (Real-Q assay; BioSewoom, Korea) using whole blood (WB), with nucleic acid extraction using MagNA Pure 96 (Roche Diagnostics, Germany). Real-time PCR was performed on two platforms: the 7500 Fast real-time PCR (7500 Fast; Applied Biosystems, USA) and CFX96 real-time PCR detection (CFX96; Bio-Rad, USA) systems. The WHO international standard, diluted with CMV-negative WB, was used to validate the analytical performance. We used 90 WB clinical samples for comparison with the artus CMV RG PCR kit (artus assay; Qiagen, Germany). Limits of detections (LODs) in 7500 Fast and CFX96 were 367 and 479 IU/mL, respectively. The assay was linear from the LOD to 106 IU/mL (R² ≥0.9886). The conversion factors from copies to IU in 7500 Fast and CFX96 were 0.95 and 1.06, respectively. Compared with the artus assay, for values <1,000 copies/mL, 100% of the samples had a variation <0.7 log10 copies/mL; >1,000 copies/mL, 73.3% and 80.6% of samples in 7500 Fast and CFX96, respectively, had <0.5 log10 copies/mL. The Real-Q assay is useful for quantifying CMV in WB with the two real-time PCR platforms.


Assuntos
Citomegalovirus/genética , DNA Viral/sangue , Reação em Cadeia da Polimerase em Tempo Real , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/virologia , DNA Viral/metabolismo , Humanos , Limite de Detecção , Kit de Reagentes para Diagnóstico
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