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1.
Cells ; 8(8)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426340

RESUMO

Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable and prevalent neurodevelopmental disorder that frequently persists into adulthood. Strong evidence from genetic studies indicates that single nucleotide polymorphisms (SNPs) harboured in the ADGRL3 (LPHN3), SNAP25, FGF1, DRD4, and SLC6A2 genes are associated with ADHD. We genotyped 26 SNPs harboured in genes previously reported to be associated with ADHD and evaluated their potential association in 386 individuals belonging to 113 nuclear families from a Caribbean community in Barranquilla, Colombia, using family-based association tests. SNPs rs362990-SNAP25 (T allele; p = 2.46 × 10-4), rs2282794-FGF1 (A allele; p = 1.33 × 10-2), rs2122642-ADGRL3 (C allele, p = 3.5 × 10-2), and ADGRL3 haplotype CCC (markers rs1565902-rs10001410-rs2122642, OR = 1.74, Ppermuted = 0.021) were significantly associated with ADHD. Our results confirm the susceptibility to ADHD conferred by SNAP25, FGF1, and ADGRL3 variants in a community with a significant African American component, and provide evidence supporting the existence of specific patterns of genetic stratification underpinning the susceptibility to ADHD. Knowledge of population genetics is crucial to define risk and predict susceptibility to disease.

2.
Mol Neurobiol ; 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31161422

RESUMO

Uveitis, defined as inflammation of the uveal tract of the eye, is a leading cause of blindness and visual impairment throughout the world. The etiology of uveitis is complex, and autoimmunity plays a major role in its pathogenesis. Intermediate uveitis (IU), a subtype of ocular inflammation, has been associated with systemic autoimmune disorders, specifically with multiple sclerosis (MS). This article reports a rare three-generation family with several members affected by IU (four siblings) and comorbid MS (two siblings fulfilling MS diagnostic criteria and a third sibling presenting some neurological symptoms). Based on the clinical findings, we captured and sequenced whole exomes of seven pedigree members (affected and unaffected). Using a recessive model of transmission with full penetrance, we applied genetic linkage analysis to define minimal critical regions (MCRs) in suggestive or nominal regions of linkage. In these MCRs, we defined functional (some pathogenic), novel, and rare mutations that segregated as homozygous in affected and heterozygous in unaffected family members. The genes harboring these mutations, including DGKI, TNFRSF10A, GNGT1, CPAMD8, and BAFF, which are expressed in both eye and brain tissues and/or are related to autoimmune diseases, provide new avenues to evaluate the inherited causes of these devastating autoimmune conditions.

4.
Genes (Basel) ; 10(5)2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067764

RESUMO

BACKGROUND: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. METHODS: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. RESULTS: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. CONCLUSIONS: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.

5.
Stem Cell Res ; 37: 101440, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31026686

RESUMO

The mutation E280A in PSEN1 (presenilin-1) is the most common cause of early-onset familial Alzheimer's Disease (fAD). It presents autosomal dominant inheritance and frequently leads to the manifestation of the disease in relatively young individuals. Here we report the generation of one PSEN1 E280A iPSC line derived from an early-onset patient. OriP/EBNA1-based episomal plasmids containing OCT3/4, SOX2, KLF4, L-MYC, LIN28, BCL-xL and shp53 were used to reprogram oral mucosa fibroblasts. The iPSC line generated has normal karyotype, carry the E280A mutation, is free of plasmid integration, express high levels of pluripotency markers and can differentiate into all three germ layers.

6.
Transl Psychiatry ; 9(1): 42, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696812

RESUMO

Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.


Assuntos
Predisposição Genética para Doença , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto Jovem
7.
Mol Neurobiol ; 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30112632

RESUMO

The identification of novel genetic variants contributing to the widespread in the age of onset (AOO) of Alzheimer's disease (AD) could aid in the prognosis and/or development of new therapeutic strategies focused on early interventions. We recruited 78 individuals with AD from the Paisa genetic isolate in Antioquia, Colombia. These individuals belong to the world largest multigenerational and extended pedigree segregating AD as a consequence of a dominant fully penetrant mutation in the PSEN1 gene and exhibit an AOO ranging from the early 1930s to the late 1970s. To shed light on the genetic underpinning that could explain the large spread of the age of onset (AOO) of AD, 64 single nucleotide polymorphisms (SNP) associated with neuroanatomical, cardiovascular, and cognitive measures in AD were genotyped. Standard quality control and filtering procedures were applied, and single- and multi-locus linear mixed-effects models were used to identify AOO-associated SNPs. A full two-locus interaction model was fitted to define how identified SNPs interact to modulate AOO. We identified two key epistatic interactions between the APOE*E2 allele and SNPs ASTN2-rs7852878 and SNTG1-rs16914781 that delay AOO by up to ~ 8 years (95% CI 3.2-12.7, P = 1.83 × 10-3) and ~ 7.6 years (95% CI 3.3-11.8, P = 8.69 × 10-4), respectively, and validated our previous finding indicating that APOE*E2 delays AOO of AD in PSEN1 E280 mutation carriers. This new evidence involving APOE*E2 as an AOO delayer could be used for developing precision medicine approaches and predictive genomics models to potentially determine AOO in individuals genetically predisposed to AD.

8.
Transl Psychiatry ; 8(1): 70, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29581422

RESUMO

Major depressive disorder (MDD) is a common but serious psychiatric disorder with significant levels of morbidity and mortality. Recent genome-wide association studies (GWAS) on common variants increase our understanding of MDD; however, the underlying genetic basis remains largely unknown. Many studies have been proposed to explore the genetics of complex diseases from a viewpoint of the "missing heritability" by considering low-frequency and rare variants, copy-number variations, and other types of genetic variants. Here we developed a novel computational and statistical strategy to investigate the "missing heritability" of MDD. We applied Hamming distance on common, low-frequency, and rare single-nucleotide polymorphism (SNP) sets to measure genetic distance between two individuals, and then built the multi-dimensional scaling (MDS) pictures. Whole-exome genotyping data from a Los Angeles Mexican-American cohort (203 MDD and 196 controls) and a European-ancestry cohort (473 MDD and 497 controls) were examined using our proposed methodology. MDS plots showed very significant separations between MDD cases and healthy controls for low-frequency SNP set (P value < 2.2e-16) and rare SNP set (P value = 7.681e-12). Our results suggested that low-frequency and rare variants may play more significant roles in the genetics of MDD.

9.
J Diabetes Complications ; 31(10): 1549-1561, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28735903

RESUMO

BACKGROUND: Childhood obesity is a serious public health problem associated with the development of several chronic diseases, such as type 2 diabetes mellitus, dyslipidemia, and hypertension. The elevated prevalence of obesity is mostly due to inadequate diet and lifestyle, but it is also influenced by genetic factors. OBJECTIVES: To review recent advances in the field of the genetics of obesity. We summarize the list of genes associated with the rare non-syndromic forms of obesity, and explain their function. Furthermore, we discuss the technologies that are available for the genetic diagnosis of obesity. RESULTS: Several studies reported that single gene variants cause Mendelian forms of obesity, determined by mutations of major effect in single genes. Rare, non-syndromic forms of obesity are a result of loss-of-function mutations in genes that act on the development and function of the hypothalamus or the leptin-melanocortin pathway. These variants disrupt enzymes and receptors that play a role in energy homeostasis, resulting in severe early-onset obesity and endocrine dysfunctions. Different approaches and technologies have been used to understand the genetic background of obesity. Currently, whole genome and whole exome sequencing are important diagnostic tools to identify new genes and variants associated with severe obesity, but other approaches are also useful at individual or population levels, such as linkage analysis, candidate gene sequencing, chromosomal microarray analysis, and genome-wide association studies. CONCLUSIONS: The understanding of the genetic causes of obesity and the usefulness and limitations of the genetic diagnostic approaches can contribute to the development of new personalized therapeutic targets against obesity.


Assuntos
Ligação Genética , Predisposição Genética para Doença , Modelos Genéticos , Mutação , Obesidade Pediátrica/genética , Polimorfismo Genético , Criança , DNA/química , DNA/metabolismo , Estudos de Associação Genética/métodos , Estudos de Associação Genética/tendências , Testes Genéticos/tendências , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/tendências , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Obesidade Pediátrica/diagnóstico , Obesidade Pediátrica/metabolismo
10.
J Child Psychol Psychiatry ; 58(6): 663-678, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28295312

RESUMO

BACKGROUND: The Multimodal Treatment Study (MTA) began as a 14-month randomized clinical trial of behavioral and pharmacological treatments of 579 children (7-10 years of age) diagnosed with attention-deficit/hyperactivity disorder (ADHD)-combined type. It transitioned into an observational long-term follow-up of 515 cases consented for continuation and 289 classmates (258 without ADHD) added as a local normative comparison group (LNCG), with assessments 2-16 years after baseline. METHODS: Primary (symptom severity) and secondary (adult height) outcomes in adulthood were specified. Treatment was monitored to age 18, and naturalistic subgroups were formed based on three patterns of long-term use of stimulant medication (Consistent, Inconsistent, and Negligible). For the follow-up, hypothesis-generating analyses were performed on outcomes in early adulthood (at 25 years of age). Planned comparisons were used to estimate ADHD-LNCG differences reflecting persistence of symptoms and naturalistic subgroup differences reflecting benefit (symptom reduction) and cost (height suppression) associated with extended use of medication. RESULTS: For ratings of symptom severity, the ADHD-LNCG comparison was statistically significant for the parent/self-report average (0.51 ± 0.04, p < .0001, d = 1.11), documenting symptom persistence, and for the parent/self-report difference (0.21 ± 0.04, p < .0001, d = .60), documenting source discrepancy, but the comparisons of naturalistic subgroups reflecting medication effects were not significant. For adult height, the ADHD group was 1.29 ± 0.55 cm shorter than the LNCG (p < .01, d = .21), and the comparisons of the naturalistic subgroups were significant: the treated group with the Consistent or Inconsistent pattern was 2.55 ± 0.73 cm shorter than the subgroup with the Negligible pattern (p < .0005, d = .42), and within the treated group, the subgroup with the Consistent pattern was 2.36 ± 1.13 cm shorter than the subgroup with the Inconsistent pattern (p < .04, d = .38). CONCLUSIONS: In the MTA follow-up into adulthood, the ADHD group showed symptom persistence compared to local norms from the LNCG. Within naturalistic subgroups of ADHD cases, extended use of medication was associated with suppression of adult height but not with reduction of symptom severity.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/terapia , Estatura/fisiologia , Avaliação de Resultados (Cuidados de Saúde) , Índice de Gravidade de Doença , Adolescente , Adulto , Assistência ao Convalescente , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Adulto Jovem
11.
Mol Neurobiol ; 54(6): 4486-4495, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27356916

RESUMO

Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1-/-)] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra-/-)] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra-/- mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1-/- mice. Casp1-/- mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra-/- mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1-/- mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Interleucina-1/metabolismo , Movimento , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Transdução de Sinais , Envelhecimento/patologia , Animais , Contagem de Células , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Atividade Motora , Degeneração Neural/patologia , Teste de Desempenho do Rota-Rod , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismo
12.
F1000Res ; 5: 870, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27990255

RESUMO

Kin and group interactions are important determinants of reproductive success in many species. Their optimization could, therefore, potentially improve the productivity and breeding success of managed populations used for agricultural and conservation purposes. Here we demonstrate this potential using a novel approach to measure and predict the effect of kin and group dynamics on reproductive output in a well-known species, the meerkat Suricata suricatta. Variation in social dynamics predicts 30% of the individual variation in reproductive success of this species in managed populations, and accurately forecasts reproductive output at least two years into the future. Optimization of social dynamics in captive meerkat populations doubles their projected reproductive output. These results demonstrate the utility of a quantitative approach to breeding programs informed by social and kinship dynamics. They suggest that this approach has great potential for improvements in the management of social endangered and agricultural species.

13.
Biol Psychiatry ; 80(12): 943-954, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27692237

RESUMO

BACKGROUND: Genetic factors predispose individuals to attention-deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3. In this study, we functionally analyzed noncoding variants in this gene as likely pathological contributors. METHODS: In silico, in vitro, and in vivo approaches were used to identify and characterize evolutionary conserved elements within the ADGRL3 linkage region (~207 Kb). Family-based genetic analyses of 838 individuals (372 affected and 466 unaffected patients) identified ADHD-associated single nucleotide polymorphisms harbored in some of these conserved elements. Luciferase assays and zebrafish green fluorescent protein transgenesis tested conserved elements for transcriptional enhancer activity. Electromobility shift assays were used to verify transcription factor-binding disruption by ADHD risk alleles. RESULTS: An ultraconserved element was discovered (evolutionary conserved region 47) that functions as a transcriptional enhancer. A three-variant ADHD risk haplotype in evolutionary conserved region 47, formed by rs17226398, rs56038622, and rs2271338, reduced enhancer activity by 40% in neuroblastoma and astrocytoma cells (pBonferroni < .0001). This enhancer also drove green fluorescent protein expression in the zebrafish brain in a tissue-specific manner, sharing aspects of endogenous ADGRL3 expression. The rs2271338 risk allele disrupts binding of YY1 transcription factor, an important factor in the development and function of the central nervous system. Expression quantitative trait loci analysis of postmortem human brain tissues revealed an association between rs2271338 and reduced ADGRL3 expression in the thalamus. CONCLUSIONS: These results uncover the first functional evidence of common noncoding variants with potential implications for the pathology of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Adulto Jovem
14.
Mol Genet Genomic Med ; 4(5): 540-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27652281

RESUMO

BACKGROUND: ADHD is the most common neuropsychiatric condition affecting individuals of all ages. Long-term outcomes of affected individuals and association with severe comorbidities as SUD or conduct disorders are the main concern. Genetic associations have been extensively described. Multiple studies show that intronic variants harbored in the ADGRL3 (LPHN3) gene are associated with ADHD, especially associated with poor outcomes. METHODS: In this study, we evaluated this association in the Multimodal Treatment Study of children with ADHD (MTA), initiated as a 14-month randomized clinical trial of 579 children diagnosed with DSM-IV ADHD-Combined Type (ADHD-C), that transitioned to a 16-year prospective observational follow-up, and 289 classmates added at the 2-year assessment to serve as a local normative comparison group (LNCG). Diagnostic evaluations at entry were based on the Diagnostic Interview Schedule for Children-Parent (DISC-P), which was repeated at several points over the years. For an add-on genetic study, blood samples were collected from 232 in the MTA group and 139 in the LNCG. RESULTS: For the 205 MTA participants, 14.6% retained the DISC-P diagnosis of ADHD-C in adolescence. For 127 LNCG participants, 88.2% remained undiagnosed by the DISC-P. We genotyped 15 polymorphic SNP markers harbored in the ADGRL3 gene, and compared allele frequencies for the 30 cases with continued diagnosis of ADHD-C in adolescence to the other participants. Replication of the association of rs2345039 ADGRL3 variant was observed (P value = 0.004, FDR corrected = 0.03; Odds ratio = 2.25, upper CI 1.28-3.97). CONCLUSION: The detection of susceptibility conferred by ADGRL3 variants in the extreme phenotype of continued diagnosis of ADHD-C from childhood to adolescence provides additional support that the association of ADGRL3 and ADHD is not spurious. Exploring genetic effects in longitudinal cohorts, in which refined, age-dependent phenotypes are documented, is crucial to understand the natural history of ADHD.

15.
Am J Med Genet B Neuropsychiatr Genet ; 171(8): 1116-1130, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27573710

RESUMO

The identification of mutations modifying the age of onset (AOO) in Alzheimer's disease (AD) is crucial for understanding the natural history of AD and, therefore, for early interventions. Patients with sporadic AD (sAD) from a genetic isolate in the extremes of the AOO distribution were whole-exome genotyped. Single- and multi-locus linear mixed-effects models were used to identify functional variants modifying AOO. A posteriori enrichment and bioinformatic analyses were applied to evaluate the non-random clustering of the associate variants to physiopathological pathways involved in AD. We identified more than 20 pathogenic, genome-wide statistically significant mutations of major modifier effect on the AOO. These variants are harbored in genes implicated in neuron apoptosis, neurogenesis, inflammatory processes linked to AD, oligodendrocyte differentiation, and memory processes. This set of new genes harboring these mutations could be of importance for prediction, follow-up and eventually as therapeutical targets of AD. © 2016 Wiley Periodicals, Inc.


Assuntos
Idade de Início , Doença de Alzheimer/genética , Idoso , Exoma , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
16.
Redox Biol ; 9: 124-133, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27479053

RESUMO

Many environmental and physiological stresses are chronic. Thus, cells are constantly exposed to diverse types of genotoxic insults that challenge genome stability, including those that induce oxidative DNA damage. However, most in vitro studies that model cellular response to oxidative stressors employ short exposures and/or acute stress models. In this study, we tested the hypothesis that chronic and repeated exposure to a micromolar concentration of hydrogen peroxide (H2O2) could activate DNA damage responses, resulting in cellular adaptations. For this purpose, we developed an in vitro model in which we incubated mouse myoblast cells with a steady concentration of ~50µM H2O2 for one hour daily for seven days, followed by a final challenge of a 10 or 20X higher dose of H2O2 (0.5 or 1mM). We report that intermittent long-term exposure to this oxidative stimulus nearly eliminated cell toxicity and significantly decreased genotoxicity (in particular, a >5-fold decreased in double-strand breaks) resulting from subsequent acute exposure to oxidative stress. This protection was associated with cell cycle arrest in G2/M and induction of expression of nine DNA repair genes. Together, this evidence supports an adaptive response to chronic, low-level oxidative stress that results in genomic protection and up-regulated maintenance of cellular homeostasis.


Assuntos
Adaptação Biológica/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Animais , Linhagem Celular , Dano ao DNA , Camundongos , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Espécies Reativas de Oxigênio/metabolismo
17.
Atten Defic Hyperact Disord ; 8(4): 215-223, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27510231

RESUMO

The Wender-Utah Rating Scale (WURS) is a widely used self-report instrument for retrospective assessment of childhood ADHD. However, many WURS items are not specific to ADHD. Here, we investigated the effect of excluding these items on the performance of the WURS in predicting adult ADHD based on previous diagnosis and current clinically significant symptoms. The study was conducted on a sample of adults (n = 1014; 48 % male) participating in a family-based investigation of ADHD. Participants completed the 61-item WURS questionnaire and the 66-item Conners Adult ADHD Rating Scale. Receiver operating characteristic (ROC) curves were used to compare the performance of the eight-item WURS (WURS-8) and the longer WURS-25 in predicting previous ADHD diagnosis and current clinically significant ADHD symptoms. WURS-8 and WURS-25 have approximately the same power to predict adult ADHD, based on either previous diagnosis or current symptoms (area under the ROC curves >0.8). WURS-8 performs at least as well as the longer WURS-25 in predicting adult ADHD. This 8-item questionnaire is thus a valid instrument and is especially useful for screening for ADHD in large epidemiological samples.


Assuntos
Envelhecimento/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica/normas , Curva ROC , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Psicometria , Estudos Retrospectivos , Fatores Sexuais , Adulto Jovem
18.
Rheum Dis Clin North Am ; 42(3): 457-72, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27431348

RESUMO

Polyautoimmunity is defined as the presence of more than one well-defined autoimmune disease (AD) in a single patient. Polyautoimmunity is a frequent condition in Sjögren syndrome (SS) and follows a grouping pattern. The most frequent ADs observed in SS are autoimmune thyroid disease, rheumatoid arthritis, and systemic lupus erythematosus. Main factors associated with polyautoimmunity in SS are tobacco smoking and some genetic variants. The study of polyautoimmunity provides important clues for elucidating the common mechanisms of autoimmne diseases (ie, the autoimmune tautology).


Assuntos
Doenças Autoimunes/epidemiologia , Síndrome de Sjogren/epidemiologia , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Comorbidade , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Fumar/epidemiologia , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/genética , Tireoidite Autoimune/imunologia
20.
J Autoimmun ; 72: 65-72, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27209085

RESUMO

OBJECTIVES: Familial autoimmunity and polyautoimmunity represent extreme phenotypes ideal for identifying major genomic variants contributing to autoimmunity. Whole exome sequencing (WES) and linkage analysis are well suited for this purpose due to its strong resolution upon familial segregation patterns of functional protein coding and splice variants. The primary objective of this study was to identify potentially autoimmune causative variants using WES data from extreme pedigrees segregating polyautoimmunity phenotypes. METHODS: DNA of 47 individuals across 10 extreme pedigrees, ascertained from probands affected with polyautoimmunity and familial autoimmunity, were selected for WES. Variant calls were obtained through Genome Analysis Toolkit. Filtration and prioritization framework to identify mutation(s) were applied, and later implemented for genetic linkage analysis. Sanger sequencing corroborated variants with significant linkage. RESULTS: Novel and mostly rare variants harbored in SRA1, MLL4, ABCB8, DHX34 and PLAUR showed significant linkage (LOD scores are >3.0). The strongest signal was in SRA1, with a LOD score of 5.48. Network analyses indicated that SRA1, PLAUR and ABCB8 contribute to regulation of apoptotic processes. CONCLUSIONS: Novel and rare variants in genetic linkage with polyautoimmunity were identified throughout WES. Genes harboring these variants might be major players of autoimmunity.


Assuntos
Autoimunidade/genética , Predisposição Genética para Doença/genética , Genômica/métodos , Mutação , Transportadores de Cassetes de Ligação de ATP/genética , Sequência de Bases , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Exoma/genética , Saúde da Família , Feminino , Redes Reguladoras de Genes , Humanos , Escore Lod , Masculino , Linhagem , Fenótipo , RNA Helicases/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Análise de Sequência de DNA
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