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1.
Artigo em Inglês | MEDLINE | ID: mdl-31411335

RESUMO

Objectives The number of dinucleotide repeats (GT) nmodulate expression of heme oxygenase 1 (HMOX1), a stress response gene. Multiple repeats might affect chronic obstructive pulmonary disease (COPD) susceptibility. We aimed to investigate the association of this polymorphism with COPD and its interaction with occupational exposures (vapor, gas, dust, or fumes). Methods This population-based cross-sectional study included 4703 Danes, aged 45-84 years. HMOX1 (GT) nwas genotyped and grouped as short: ≤26, medium: 27-32 and long: ≥33 alleles. COPD was defined by the lower limit of normal (2.5 thFEV 1/FVC and FEV 1centiles). Occupational exposure was defined as ever exposed to vapor, gas, dust, or fume in expert-selected jobs. Associations were analyzed by adjusted mixed logistic regression. Results The population included 6% with COPD, 48% who had smoked ≥10 pack-years, and 46% with occupational exposure. HMOX1 was genotyped in 4423 participants. The adjusted odds ratio (OR) for the association between HMOX1 long allele and COPD was 1.75 [95% confidence interval (CI) 1.18-2.60]. An interaction was evident between HMOX1 long allele and occupational exposure, OR 2.38 (95% CI 1.04-5.46), versus HMOX1 short/medium without exposure. Analyses were replicated in another cohort, aged 20-44 years, N=1168, including 3% with COPD, 25% who had smoked ≥10 pack-years and 20% with occupational exposure. No associations were seen between COPD and HMOX1 long allele here. Conclusions Long alleles in HMOX1 alone and in interaction with occupational exposure seem to be associated with COPD. Failure to replicate data may be due to premature age for COPD development and low occupational exposure prevalence. We propose this long allele may be a genetic contributor to the COPD pathogenesis.

2.
J Med Genet ; 56(10): 701-710, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451536

RESUMO

BACKGROUND: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders. METHODS: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant. RESULTS: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias. CONCLUSIONS: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

3.
Eur J Hum Genet ; 27(4): 631-636, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659261

RESUMO

Genetic interaction is a crucial issue in the understanding of functional pathways underlying complex diseases. However, detecting such interaction effects is challenging in terms of both methodology and statistical power. We address this issue by introducing a disease-concordant twin-case-only design, which applies to both monozygotic and dizygotic twins. To investigate the power, we conducted a computer simulation study by setting a series of parameter schemes with different minor allele frequencies and relative risks. Results from the simulation study reveals that the disease-concordant twin-case-only design largely reduces sample size required for sufficient power compared to the ordinary case-only design for detecting gene-gene interaction using unrelated individuals. Sample sizes for dizygotic and monozygotic twins were roughly 1/2 and 1/4 of sample sizes in the ordinary case-only design. Since dizygotic twins are genetically similar as siblings, the enriched power for dizygotic twins also applies to affected siblings, which could help to largely extend the application of the powerful twin-case-only design. In summary, our simulation reveals high value of disease-concordant twins and siblings in efficiently detecting gene-by-gene interactions.

5.
Eur J Med Genet ; 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29959045

RESUMO

INTRODUCTION: MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients. MATERIALS AND METHODS: In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing. RESULTS: All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations. CONCLUSIONS: Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance.

8.
Pflugers Arch ; 470(2): 355-365, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29082441

RESUMO

Impairment of endothelial function with aging is accompanied by reduced nitric oxide (NO) production. T-type Cav3.1 channels augment nitric oxide and co-localize with eNOS. Therefore, the hypothesis was that T-type channels contribute to the endothelial dysfunction of aging. Endothelial function was determined in mesenteric arteries (perfusion) and aortae (isometric contraction) of young and old wild-type (WT), Cav3.1, and Cav3.2 knockout mice. NO production was measured by fluorescence imaging in mesenteric arteries. With age, endothelium-dependent subsequent dilatation (following depolarization with KCl) of mesenteric arteries was diminished in the arteries of WT mice, unchanged in Cav3.2-/- preparations but increased in those of Cav3.1-/- mice. NO synthase inhibition abolished the subsequent dilatation in mesenteric arteries and acetylcholine-induced relaxations in aortae. NO levels were significantly reduced in mesenteric arteries of old compared to young WT mice. In Cav3.1-/- and Cav3.2-/- preparations, NO levels increased significantly with age. Relaxations to acetylcholine were significantly smaller in the aortae of old compared to young WT mice, while such responses were comparable in preparations of young and old Cav3.1-/- and Cav3.2-/- mice. The expression of Cav3.1 was significantly reduced in aortae from aged compared to young WT mice. The level of phosphorylated eNOS was significantly increased in aortae from aged Cav3.1-/- mice. In conclusion, T-type calcium channel-deficient mice develop less age-dependent endothelial dysfunction. Changes in NO levels are involved in this phenomenon in WT and Cav3.1-/- mice. These findings suggest that T-type channels play an important role in age-induced endothelial dysfunction.

9.
Am J Hum Genet ; 100(6): 907-925, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575647

RESUMO

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.


Assuntos
Cromatina/metabolismo , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transcrição Genética , Fator de Transcrição YY1/genética , Acetilação , Adolescente , Sequência de Bases , Pré-Escolar , Imunoprecipitação da Cromatina , Estudos de Coortes , Elementos Facilitadores Genéticos/genética , Feminino , Ontologia Genética , Haplótipos/genética , Hemizigoto , Histonas/metabolismo , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Ligação Proteica/genética , Domínios Proteicos , Fator de Transcrição YY1/química
10.
Sci Rep ; 7: 43813, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28276460

RESUMO

A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis.


Assuntos
Neoplasias Ósseas/genética , Neoplasias da Mama/genética , Neoplasias Hepáticas/genética , Mutação , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Proteínas do Citoesqueleto/genética , Progressão da Doença , Feminino , Genômica , Humanos , Proteínas com Domínio LIM/genética , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Sequenciamento Completo do Exoma/métodos
11.
Ugeskr Laeger ; 178(34)2016 Aug 22.
Artigo em Dinamarquês | MEDLINE | ID: mdl-27549007

RESUMO

Neuralgic amyotrophy (NA) is characterized by sudden onset of severe pain in the shoulder/upper arm and muscle amyotrophy. Up to 60% of patients with NA are misdiagnosed as having shoulder joint pathology or cervical pathology. We report a case of a 13-year-old girl diagnosed with the hereditary form of NA (HNA). Array comparative genomic hybridization showed a maternally inherited duplication of 1.5 Mb including the entire SEPT9-gene. The girl was treated with non-steroidal anti-inflammatory drugs, corticosteroids and physiotherapy. Individuals with HNA should avoid extreme muscle activity and severe cold, as this may trigger attacks.


Assuntos
Neurite do Plexo Braquial/diagnóstico , Adolescente , Neurite do Plexo Braquial/complicações , Neurite do Plexo Braquial/genética , Neurite do Plexo Braquial/terapia , Feminino , Humanos , Dor de Ombro/etiologia
12.
Am J Med Genet A ; 170(11): 2934-2942, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27409573

RESUMO

17q12 deletions and duplications are two distinct, recurrent chromosomal aberrations usually diagnosed by chromosomal microarray analysis (CMA). The aberrations encompass the genes, HNF1B, LHX1, and ACACA, among others. We here describe a large national cohort of 12 phenotyped patients with 17q12 deletions and 26 phenotyped patients with 17q12 duplications. The total cohort includes 19 index patients and 19 family members. We also reviewed the literature in order to further improve the basis for the counseling. We emphasize that renal disease, learning disability, behavioral abnormalities, epilepsy, autism, schizophrenia, structural brain abnormalities, facial dysmorphism, and joint laxity are features seen in both the 17q12 deletion syndrome and the reciprocal 17q12 duplication syndrome; and we extend the list of features seen in both patient categories to include strabismus, esophageal defects, and duodenal atresia. Delayed language development, learning disability, kidney involvement, and eye dysmorphism and strabismus were the most consistently shared features among patients with 17q12 deletion. Patients with 17q12 duplications were characterized by an extremely wide phenotypic spectrum, including a variable degree of learning disabilities, delayed language development, delayed motor milestones, and a broad range of psychiatric and neurological features. This patient group also included adults achieving an academic degree. Assessing index patients and non-index patients separately, our observations illustrate that an overall milder disease burden is seen, in particular in patients with 17q12 duplications who are ascertained on the duplication rather than the phenotype. This evidence may be useful in prenatal counseling. © 2016 Wiley Periodicals, Inc.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Duplicação Cromossômica , Cromossomos Humanos Par 17 , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Dinamarca , Facies , Humanos , Lactente , Recém-Nascido , Padrões de Herança , Fenótipo , Polimorfismo de Nucleotídeo Único , Sistema de Registros , Síndrome , Adulto Jovem
13.
Basic Clin Pharmacol Toxicol ; 119(4): 381-8, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27061230

RESUMO

Sudden death due to acute intoxication occurs frequently in patients with opioid addiction (OA). To examine whether certain genotypes were associated with this, we examined the frequencies of 29 SNPs located in candidate genes related to opioid pharmacology: ABCB1, OPRM1, UGT2B7, CYP3A5, CYP2B6, CYP2C19, CYP2D6, COMT, KCNJ6 and SCN9A in 274 deceased patients with OA (DOA), 309 living patients with OA (LOA) and in 394 healthy volunteers (HV). The main hypothesis of the study was that subjects homozygous for the variant 3435T in ABCB1 (rs1045642) occur more frequently in DOA than in LOA and HV because morphine and methadone more readily cross the blood barrier in these subjects due to a lower efflux transporter activity of the ABCB1 (p-glycoprotein) transporter. Our results did not support this hypothesis, because no statistically significant difference (p = 0.506) in the frequency of the TT genotype of rs1045642 was observed between the DOA, LOA and HV cohorts. However, for another ABCB1 variant, rs9282564, we found that the frequencies of the AG and TT genotypes were 13, 21 and 25% in DOA, LOA and HV, respectively, and after correcting for age, sex and multiple testing, the differences between DOA and LOA were statistically significantly different (p = 0.027). The COMT rs4680 AA genotype frequencies were 25%, 35% and 31% in DOA, LOA and HV, respectively, and the difference between DOA and LOA was also statistically significant (p = 0.0028). In conclusion, this study generated two hypotheses suggesting possible associations of a reduced risk of death and carrying, respectively, the ABCB1 rs9282564 AG and TT genotypes and the COMT rs4680 AA genotype among patients with OA. These findings should be confirmed in independent cohorts, and if a causal relationship between these variants and fatal poisoning in OA is confirmed, then it may be possible at least in theory to personalize prevention of sudden death in this patient group.


Assuntos
Catecol O-Metiltransferase/genética , Morte Súbita/etiologia , Dependência de Morfina/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Idoso , Catecol O-Metiltransferase/metabolismo , Estudos de Coortes , Dinamarca , Feminino , Estudos de Associação Genética , Heterozigoto , Homozigoto , Humanos , Masculino , Metadona/sangue , Metadona/toxicidade , Pessoa de Meia-Idade , Morfina/sangue , Morfina/toxicidade , Dependência de Morfina/metabolismo , Dependência de Morfina/mortalidade , Dependência de Morfina/fisiopatologia , Entorpecentes/sangue , Entorpecentes/toxicidade , Adulto Jovem
14.
Int J Cancer ; 137(9): 2093-103, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25912829

RESUMO

Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup with generally poor outcome and lack of an effective targeted therapy. Prognostic or predictive biomarkers to guide treatment decisions for this group of patients are needed. To evaluate the potential of S100A14 protein as a novel biomarker in TNBC, the protein expression of S100A14 was correlated with clinical outcomes in a Pilot Sample set and a Danish cohort of predominantly TNBC patients. Kaplan-Meier analysis identified a prognostic impact of S100A14 on disease-free survival and overall survival, showing that tumors with high S100A14 protein expression levels were significantly correlated with poor outcome in TNBC patients (p = 0.017; p = 0.038), particularly those in the basal-like subgroup (p = 0.006; p = 0.037). Importantly, TNBC patients with high S100A14 expression, but tumor-negative axillary lymph nodes (N-), had equally poor outcomes as those with tumor-positive axillary lymph nodes (N+), while TNBC/N- patients with low S100A14 expression had a significantly better disease free survival (p = 0.013). Multivariate analysis revealed that S100A14 is an independent prognostic factor for TNBC patients (p = 0.024; p = 0.05). At the cellular level, S100A14 was found to be expressed in epithelial-like, but not in mesenchymal-like, TNBC cells in vitro. S100A14 is an independent prognostic factor in TNBC and a novel potential therapeutic target in TNBC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma Ductal de Mama/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
15.
Forensic Sci Med Pathol ; 11(2): 193-201, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25801127

RESUMO

PURPOSE: Deaths among drug addicts are frequently caused by intoxication with methadone and/or morphine. These drugs are often used in combination with other drugs, such as buprenorphine. In addition, methadone is generally used as a mixture of R- and S-enantiomers. To date, a method for separation and quantitation of these specific drugs has not been developed. The aim of this study was to develop a sensitive enantioselective method for quantitation of morphine, its active metabolite morphine 6-glucuronide, buprenorphine, and R- and S-methadone, in a single analytical run. METHODS: Whole blood samples were diluted with 0.5 mol/L ammonium carbonate buffer and extracted on a Bond Elut C18 solid-phase extraction column with an automatic solid-phase extraction system. Chromatographic separation was performed on a chiral alpha-1-acid glycoprotein column with an acetonitrile/ammonium acetate buffer (10 mmol/L, pH 7.0, 22:78 v/v) mobile phase. The whole blood concentrations of the drugs were quantified by mass spectrometry using their stable isotope-labeled compounds as internal standards. RESULTS: The method was validated with respect to specificity, linearity, precision, limits of detection, and quantification and matrix effects. The precision (coefficient of variation) was below 15%, and the accuracy was between 90 and 115%. CONCLUSIONS: This method will be useful for routine analyses in forensic laboratories where blood samples are frequently analyzed for drugs of abuse. In some cases, sudden death from methadone overdose is caused by the enantiomeric form of the methadone, which makes the enantiomer separation capability of this method important.


Assuntos
Buprenorfina/sangue , Metadona/sangue , Derivados da Morfina/sangue , Morfina/sangue , Entorpecentes/sangue , Buprenorfina/química , Cromatografia Líquida , Toxicologia Forense , Humanos , Espectrometria de Massas , Metadona/química , Estrutura Molecular , Morfina/química , Derivados da Morfina/química , Entorpecentes/química , Extração em Fase Sólida , Estereoisomerismo , Transtornos Relacionados ao Uso de Substâncias/sangue
16.
Pharmacogenet Genomics ; 23(10): 526-34, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23873119

RESUMO

OBJECTIVE: The aim of this study was to determine the association between the renal clearance (CL(renal)) of metformin in healthy Caucasian volunteers and the single-nucleotide polymorphism (SNP) c.808G>T (rs316019) in OCT2 as well as the relevance of the gene-gene interactions between this SNP and (a) the promoter SNP g.-66T>C (rs2252281) in MATE1 and (b) the OCT1 reduced-function diplotypes. METHODS: Fifty healthy volunteers genotyped for the c.808G>T were enrolled in the study. The distribution was 25 GG, 20 GT, and 5 TT volunteers. The pharmacokinetics of a 500 mg single oral dose of metformin was studied. RESULTS: When analyzed alone, the c.808 (G>T) affected neither the CL(renal) nor the secretory clearance (CL(sec)) of metformin. However, both CL(renal) and CL(sec) were increased for the volunteers with minor alleles in c.808 (G>T) who were also homozygous for the reference variant g.-66T>C: CL(renal): GG, GT, and TT: 28.1, 34.5, and 44.8 l/h (P = 0.004), respectively and CL(sec): GG, GT, and TT: 21.4, 27.8, and 37.6 l/h (P = 0.005), respectively. In the volunteers with minor alleles in c.808 (G>T) who were also heterozygous for g.-66T>C, both CL(renal) and CL(sec) were found to be reduced (P < 0.028) when compared with volunteers with minor alleles in c.808 (G>T) carrying the g.-66T>C reference genotype. CONCLUSION: We report counteracting effects of the c.808 (G>T) and g.-66T>C on the renal elimination of metformin. When adjusted for the genetic variation g.-66T>C, our results suggest that c.808 (G>T) could have a dominant genotype to phenotype correlation.


Assuntos
Hipoglicemiantes/farmacocinética , Rim/metabolismo , Metformina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Genótipo , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/urina , Rim/efeitos dos fármacos , Desequilíbrio de Ligação , Masculino , Metformina/administração & dosagem , Metformina/urina , Transportador 2 de Cátion Orgânico , Polimorfismo de Nucleotídeo Único
17.
Genet Test Mol Biomarkers ; 16(12): 1419-23, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23046070

RESUMO

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder with three disease-causing genes identified to date: ENG, ACVRL1, and SMAD4. We report an HHT patient with allelic dropout that on routine sequence analysis for a known mutation in the family (c.817-3T>G in ENG) initially seemed to be homozygous for the mutation. AIM: To explore the possibility of allelic dropout causing a false result in this patient. METHODS: Mutation analysis of additional family members was performed and haplotype analysis carried out. New primers were designed to reveal the presence of a possible sequence variant, which could explain the presumed allelic dropout. RESULTS: Allelic dropout caused by a six-nucleotide duplication close to the standard reverse primer was the assumed cause of a false homozygous diagnosis. CONCLUSION: Sequence variants outside of the primer regions can be the cause of allelic dropout, creating unforeseen errors in genotyping. Our finding emphasizes the need for careful quality control in all molecular genetic studies.


Assuntos
Antígenos CD/genética , Testes Genéticos , Receptores de Superfície Celular/genética , Telangiectasia Hemorrágica Hereditária/genética , Receptores de Activinas Tipo II/genética , Adolescente , Sequência de Bases , Endoglina , Feminino , Genótipo , Humanos , Perda de Heterozigosidade , Masculino , Dados de Sequência Molecular , Proteína Smad4/genética
18.
Eur J Med Genet ; 55(10): 564-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22750323

RESUMO

We present a de novo 1.4 Mb deletion of chromosome 19p13.11-p13.12 in a 16 year old boy with intellectual disability, autistic features, microcephaly, hearing impairment, hypertrichosis, synophrys, protruding front teeth, and other dysmorphic features. By comparing our patient to reported cases with overlapping deletions, we have refined the minimal critical region of hypertrichosis, synophrys, and protruding front teeth to 305 kb, a region containing seven genes. CASP14, which is considered a good candidate gene for hypertrichosis, is not included in this region, questioning the causal relationship.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 19/genética , Sobrancelhas/anormalidades , Hipertricose/genética , Deficiência Intelectual/genética , Anormalidades Dentárias/genética , Adolescente , Caspases/genética , Loci Gênicos , Humanos , Masculino
20.
Clin Respir J ; 6(3): 175-85, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21651749

RESUMO

INTRODUCTION: Exposure to particulate matter (PM) may induce inflammation and oxidative stress in the airways. Carriers of null polymorphisms of glutathione S-transferases (GSTs), which detoxify reactive oxygen species, may be particularly susceptible to the effects of PM. OBJECTIVES: To investigate whether deletions of GSTM1 and GSTT1 modify the potential effects of exposure to indoor sources of PM on symptoms and objective markers of respiratory disease. METHODS: We conducted a population-based, cross-sectional study of 3471 persons aged 18-69 years. Information about exposure to indoor sources of PM and respiratory symptoms was obtained by a self-administered questionnaire. In addition, measurements of lung function (spirometry) and fractional exhaled nitric oxide were performed. Copy number variation of GSTM1 and GSTT1 was determined by polymerase chain reaction-based assays. RESULTS: We found that none of the symptoms and objective markers of respiratory disease were significantly associated with the GST null polymorphisms. An increasing number of positive alleles of the GSTM1 polymorphism tended to be associated lower prevalence of wheeze, cough, and high forced expiratory volume in 1 s (FEV(1) ), but these trends were not statistically significant. Furthermore, we did not observe any statistically significant interactions between GST copy number variation and exposure to indoor sources of PM in relation to respiratory symptoms and markers. CONCLUSIONS: In this adult population, GST copy number variations were not significantly associated with respiratory outcomes and did not modify the effects of self-reported exposure to indoor sources of PM on respiratory outcomes.


Assuntos
Poluição do Ar em Ambientes Fechados/estatística & dados numéricos , Dosagem de Genes/genética , Glutationa Transferase/genética , Pneumopatias/epidemiologia , Pneumopatias/genética , Adolescente , Adulto , Idoso , Asma/epidemiologia , Asma/genética , Biomarcadores , Culinária/estatística & dados numéricos , Exposição Ambiental , Feminino , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Pneumonia/genética , Sons Respiratórios/genética , Rinite Alérgica Sazonal/epidemiologia , Rinite Alérgica Sazonal/genética , Fatores de Risco , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Adulto Jovem
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