RESUMO
We investigated outcomes according to a new clinical grading system for chronic graft-versus-host disease (chronic GVHD) in 38 patients who developed chronic GVHD after an allogeneic hematopoietic stem cell transplantation. We categorized the patients into three grade groups, namely, grade I, grade II and grade III, according to the presence of three risk factors: extensive skin involvement, thrombocytopenia (TP) and progressive type of onset. Sixteen patients were classified into grade 1, 19 into grade II and three into grade III. The probability of withdrawal of systemic immunosuppression (IST) at 1, 2 and 3 years was 61, 76 and 87%, respectively. Patients with grades 2 or 3 chronic GVHD had prolonged duration of systemic IST compared to grade 1 (P=0.043). The probability of GVHD-specific survival (GSS) at 5 years was 52%. Twenty-two of 38 patients with chronic GVHD were still alive and the estimated 3-year overall survival (OS) rate was 60%, whereas that for the group with chronic GVHD grade I and grade II+III was 64 and 48% (P<0.05). Multivariate analysis showed that prior occurrence of acute GVHD, chronic GVHD grade, serum bilirubin over 1.5 mg/dl, date of diagnosis of chronic GVHD (
Assuntos
Doença Enxerto-Hospedeiro/patologia , Imunossupressores/administração & dosagem , Adulto , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Dermatopatias/etiologia , Análise de Sobrevida , Trombocitopenia/etiologiaRESUMO
Frontotemporal dementia accounts for a significant fraction of dementia cases. Frontotemporal dementia with parkinsonism linked to chromosome 17 is associated with either exonic or intronic mutations in the tau gene. This highlights the involvement of aberrant pre-mRNA splicing in the pathogenesis of neurodegenerative disorders. Little is known about the molecular mechanisms of the splicing defects underlying these diseases. To establish a model system for studying the role of pre-mRNA splicing in neurodegenerative diseases, we have constructed a tau minigene that reproduces tau alternative splicing in both cultured cells and in vitro biochemical assays. We demonstrate that mutations in a nonconserved intronic region of the human tau gene lead to increased splicing between exon 10 and exon 11. Systematic biochemical analyses indicate the importance of U1 snRNP and, to a lesser extent, U6 snRNP in differentially recognizing wild-type versus intron mutant tau pre-mRNAs. Gel mobility shift assays with purified U1 snRNP and oligonucleotide-directed RNase H cleavage experiments support the idea that the intronic mutations destabilize a stem-loop structure that sequesters the 5' splice site downstream of exon 10 in tau pre-mRNA, leading to increases in U1 snRNP binding and in splicing between exon 10 and exon 11. Thus, mutations in nonconserved intronic regions that increase rather than decrease alternative splicing can be an important pathogenic mechanism for the development of human diseases.
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Processamento Alternativo , Cromossomos Humanos Par 17 , Demência/genética , Ligação Genética , Íntrons , Mutação , Transtornos Parkinsonianos/genética , Precursores de RNA , Ribonucleoproteína Nuclear Pequena U1/metabolismo , Proteínas tau/genética , Adulto , Sequência de Bases , Sítios de Ligação , Éxons , Lobo Frontal , Células HeLa , Humanos , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Oligonucleotídeos , Ribonuclease H/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6/metabolismo , Lobo TemporalRESUMO
The analysis of complex human diseases has been spurred by the number of published genomic sequence variants - many identified in the course of sequencing the human genome. But, to be useful for genetic analysis, variants have to be mapped accurately, their frequencies in various populations determined, and automated high-throughput assay techniques developed. Recently proposed methods address these issues: the use of 'reduced representation shotgun' methods for more efficient detection of single nucleotide polymorphisms (SNPs), the employment of high-throughput genotyping techniques, the development of SNP maps that incorporate information about linkage disequilibrium, and the use of SNPs in identifying susceptibility genes for common illnesses.
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Mapeamento Cromossômico/métodos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Humanos , FarmacogenéticaRESUMO
To determine the role of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in extranodal NK/T-cell lymphoma patients, we conducted a retrospective analysis. In our previous study, we searched for patients who had received HDC/ASCT and identified 16 eligible patients and compared the treatment outcome with historical control group (n=246). Nine patients received HDC/ASCT in the first (CR1) or second complete remission (CR2), while seven patients received HDC/ASCT as salvage. Twelve of 16 patients achieved or maintained CR after HDC/ASCT. Among the 12 patients, five patients relapsed. Estimated 2-year overall survival (OS) and relapse-free survival (RFS) rates were 71.3+/-12.4% and 25.8+/-14.3%, respectively. There was a tendency of better survival in patients who received HDC/ASCT as compared to those who did not (P=0.091). In subset analysis, patients who underwent HDC/ASCT at CR (P=0.049) and patients with stage III or IV (P=0.001) had a favorable outcome. Patients with NKIPI 3,4 or EUNKTL, who underwent HDC/ASCT had more prolonged survival without statistical significance (P=0.055 and 0.056). In conclusion, HDC/ASCT may be considered as a treatment option for patients with extranodal NK/T-cell lymphoma, especially those in CR, with advanced disease (stage III/IV or EUNKTL) and high NKIPI scores.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células T/terapia , Transplante de Células-Tronco/métodos , Adolescente , Adulto , Terapia Combinada , Feminino , Humanos , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Sobreviventes , Fatores de Tempo , Transplante Autólogo , Resultado do TratamentoRESUMO
The efficacy of mobilizing peripheral blood progenitor cells (PBPC) with continuous intravenous (c.i.v.) administration of rhG-CSF was randomly compared to subcutaneous (s.c.) administration, in 15 normal donors in each arm of the study for 6 days. The percentage and absolute numbers of CD34+ cells in the c.i.v. and s.c. groups increased maximally at day 3 and 5, respectively, when compared with the steady-state (day 0) level. Peak CD34+ cell levels were achieved on day 3 in the c.i.v. group, with more rapid results than in the s.c. group (49.3/microl vs 35.9/microl, P=0.043). Plasma rhG-CSF levels declined progressively during mobilization in each group as the WBC increased. The serum level of rhG-CSF did not correlate with CD34+ cell counts in the peripheral blood. Toxicity profiles in the c.i.v. and s.c. groups were similar. Each regimen was effective in successfully mobilizing the target CD34 cell number.
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Antígenos CD34/biossíntese , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Infusões Intravenosas/métodos , Injeções Subcutâneas/métodos , Adolescente , Adulto , Separação Celular , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Cinética , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Fenótipo , Estudos Prospectivos , Proteínas Recombinantes , Fatores de TempoRESUMO
OBJECTIVE: To verify the association between APOE gene promoter polymorphisms and the development of AD and to determine whether the effect of promoter polymorphisms on AD is independent of the APOE epsilon4 allele. BACKGROUND: Three polymorphisms in the APOE promoter have been shown to modify APOE expression in vitro. Several studies have suggested that these polymorphisms may also modulate risk for AD, either independently or by modifying the effect of the APOE coding polymorphism. METHODS: The authors analyzed allele and genotype distributions for APOE and all three known APOE promoter polymorphisms (-491 A/T, -427 T/C, and -219 G/T) in a study group consisting of 237 subjects with AD and 274 age-matched controls. They then used log-linear and logistic regression analyses to test for possible interactions between APOE genotype and the promoter polymorphisms on risk of AD. CONCLUSION: A strong association between the APOE epsilon 4 allele and AD was detected regardless of promoter polymorphism status. In addition, the -491 AA genotype appears to be an independent genetic risk factor for AD. The -427 T/C polymorphism and the -219 T/G polymorphism were not directly associated with AD.
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Doença de Alzheimer/genética , Apolipoproteínas E/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , RiscoRESUMO
Axonal forms of autosomal dominant hereditary motor and sensory neuropathies (HMSNs) represent a heterogeneous group of disorders based on genetic linkage studies. We recently identified one large family with axonal HMSN exhibiting linkage to chromosome 3q, designated HMSN IIB, and report here the clinical and electrodiagnostic features. We clinically evaluated 10 individuals with HMSN IIB and performed detailed electrophysiologic studies in 5 of these patients. HMSN IIB is characterized clinically by the presence of distal symmetric motor weakness and prominent sensory loss affecting the lower extremities with preserved ankle reflexes. Symptomatic age at onset is in the second or early third decade of life. Six patients with HMSN IIB had distal trophic ulcerations in the feet, leading to eventual toe amputations in four cases. Electrodiagnostic studies confirmed a distal sensorimotor axonopathy involving the lower limbs with normal motor conduction velocities. Tibial H-reflexes were preserved in HMSN IIB, despite the uniform loss of sural nerve potentials. Overall, individuals with HMSN IIB demonstrated a consistent clinical and electrodiagnostic phenotype that had no overlap with genetically unaffected family members. The identification of specific clinical and electrodiagnostic features of HMSN IIB may prove useful in the diagnosis and differentiation between various subtypes of HMSN II.
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Cromossomos Humanos Par 3 , Eletrodiagnóstico , Ligação Genética , Neuropatia Hereditária Motora e Sensorial/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Reflexo H/fisiologia , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Humanos , Perna (Membro) , Masculino , Músculos/fisiopatologia , Condução Nervosa , Linhagem , Fenótipo , Sensação , Nervo Sural/fisiopatologia , Nervo Tibial/fisiopatologiaRESUMO
OBJECTIVE: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele. BACKGROUND: Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. METHODS: Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification. RESULTS: The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population. CONCLUSION: The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.
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Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4 , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Fatores de RiscoRESUMO
The Collaborative Study on the Genetics of Alcoholism (COGA) is a multicenter research program to detect and map susceptibility genes for alcohol dependence and related phenotypes. The measure M of "maximum number of drinks consumed in a 24-hour period" is closely related to alcoholism diagnosis in this dataset and provides a quantitative measure to grade nonalcoholic individuals. Twin studies have shown log(M) to have a heritability of approximately 50%. Genome screens for this trait were performed in two distinct genotyped samples (wave 1 and wave 2), and in the combined sample. MAPMAKER/SIBS was used to carry out Haseman-Elston based regression analyses. On chromosome 4, an unweighted all-pairs multipoint LOD of 2.2 was obtained between D4S2407 and D4S1628 in wave 1; in wave 2, the region flanked by D4S2404 and D4S2407 gave a LOD of 1.5. In the combined sample, the maximal LOD was 3.5 very close to D4S2407. This evidence for linkage is in the region of the alcohol dehydrogenase gene cluster on chromosome 4. These findings on chromosome 4 are consistent with a prior report from COGA in which strictly defined nonalcoholic subjects in wave 1 were analyzed. The present analysis on log(M) allows more individuals to be included and thus is potentially more powerful.
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Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Genoma Humano , Mapeamento Cromossômico , Saúde da Família , Feminino , Genótipo , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Fenótipo , Distribuição AleatóriaRESUMO
The release of amyloid-beta peptide (Abeta) from beta-amyloid precursor protein (APP) requires cleavage by beta- and gamma-secretases. Several groups have identified a candidate for the beta-site APP-cleaving enzyme, BACE1, and its homologue BACE2. We sequenced the genes for BACE1 and BACE2 and found several polymorphisms in both genes. Genotyping a large cohort of AD cases and controls has shown no association between AD and the intronic polymorphism in BACE2 while there was a weak association between the BACE1 polymorphism in exon 5 and AD in those carrying the APOE epsilon4 allele.
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Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Polimorfismo Genético/genética , Idoso , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/biossíntese , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Apolipoproteína E4 , Apolipoproteínas E/genética , Endopeptidases , Éxons/genética , Feminino , Regulação Enzimológica da Expressão Gênica/genética , Frequência do Gene/genética , Testes Genéticos , Genótipo , Humanos , Masculino , Mutação/genéticaRESUMO
Alzheimer's disease (AD) is one of a number of neurodegenerative conditions including frontotemporal dementia and progressive supranuclear palsy that are associated with abnormal tau protein aggregates in neurons. Mutations in the tau gene cause familial forms of frontotemporal dementia and alleles of the tau gene have been associated with risk for progressive supranuclear palsy. However, studies evaluating whether polymorphic variation in tau is associated with AD have produced conflicting results. We investigated the role of the tau exon 2 polymorphism in a large sample of AD cases and controls and found no evidence that polymorphic variation in tau is associated AD.
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Doença de Alzheimer/genética , Polimorfismo Genético/genética , Proteínas tau/genética , Idoso , Éxons/genética , Feminino , Genótipo , Humanos , MasculinoRESUMO
OBJECTIVE: To use the Unified Batten Disease Rating Scale (UBDRS) to measure the rate of decline in physical and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) or Batten disease, a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002; during that time, the scale has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in quantitatively assessing clinical outcomes in research trials. METHODS: We administered the UBDRS to 82 subjects with JNCL genetically confirmed by CLN3 mutational analysis. Forty-four subjects were seen for more than one annual visit. From these data, the rate of physical impairment over time was quantified using multivariate linear regression and repeated-measures analysis. RESULTS: The UBDRS Physical Impairment subscale shows worsening over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This deterioration correlates with functional capability and is not influenced by CLN3 genotype. CONCLUSION: The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to quantify the rate of progression of physical impairment in subjects with JNCL in clinical trials.
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Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Adolescente , Adulto , Análise de Variância , Criança , Pré-Escolar , Estudos Transversais , Pessoas com Deficiência , Progressão da Doença , Genótipo , Homozigoto , Humanos , Glicoproteínas de Membrana , Chaperonas Moleculares , Mutação/genética , Lipofuscinoses Ceroides Neuronais/genética , Testes Neuropsicológicos , Estudos Prospectivos , Análise de Regressão , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: This nonrandomized open label phase II study evaluated the efficacy and safety of FOLFOXIRI in metastatic or recurrent gastric cancer patients. PATIENTS AND METHODS: Patients with histologically proven, metastatic gastric adenocarcinoma, aged 18-70 years, performance status zero to two, no prior chemotherapy, and with signed written informed consent were eligible. Treatment consisted of irinotecan 150 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 100 mg/m2 day 1, and 5-fluorouracil 2000 mg/m2 as a 48-h continuous infusion starting on day 1, which was repeated every 2 weeks. RESULTS: From August 2004 to August 2005, 48 patients were prospectively enrolled. The median age was 54 years (24-69). In total, 386 cycles were administered with a median of nine cycles per patient (range 1-12 cycles) and 45 of 48 patients were assessable for treatment response. An independent review of tumor responses resulted in overall response rate of 66.7% (95% confidence interval=53.4% to 80.0%) by intent-to-treat analysis with one complete response and 31 partial responses. The median survival of all patients was 14.8 months and the median time to progression was 9.6 months. Most common grade 3/4 toxic effects were neutropenia (12% of all cycles) and emesis (8% of all cycles). Grade 2 peripheral neuropathy occurred in five patients. One (2%) patient had severe tumor bleeding and five (10%) patients experienced grade 3 diarrhea. CONCLUSIONS: The modified FOLFOXIRI combination chemotherapy showed a very promising preliminary antitumor activity and was generally well tolerated as a first-line treatment of patients with metastatic gastric cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Carcinoma de Células em Anel de Sinete/secundário , Progressão da Doença , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Estudos Prospectivos , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
The association of Epstein-Barr virus (EBV) with Hodgkin's lymphoma (HL) has been investigated over the last few years. The impact of EBV on clinical outcome is still controversial, however. In this study, we investigated the effect of EBV status on clinical outcome of HL patients. Between January 1986 and September 2004, fifty-six patients, diagnosed as having HL, were included in the analysis. Clinical data were reviewed retrospectively from the patients' records. Tissues from 56 patients were analyzed for the presence of EBV using the in situ hybridization (ISH) for EBV-encoded RNA (EBER) and immunohistochemistry for latent membrane protein (LMP)1. EBV infection was identified in 41.1% of cases by EBER ISH, 26.8% by LMP1 expression, and 26.8% by LMP1 and EBER ISH. EBER-positive HL were significantly more frequent in mixed cellularity (MC) subtype (P=0.014) and advanced stage (P=0.034). There was a trend toward shorter overall survival in EBER-positive patients without statistical significance (P=0.238). LMP1 expression also correlated with MC subtype (P=0.006) and advanced stage (P=0.007), although it did not significantly influence the survival outcome. In subgroup analysis, both EBER and LMP1 positivities were associated with longer progression-free survival in patients with age <25 years old (P=0.045). Reverse trends were shown in patients > or =25 years old. In this study, we demonstrated that the impact of tumor EBV status on prognosis may be age dependent and young patients with latent EBV infection have favorable prognosis.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/isolamento & purificação , Doença de Hodgkin/virologia , Adulto , Intervalo Livre de Doença , Feminino , Doença de Hodgkin/classificação , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive neurodegenerative disorder characterized by blindness, seizures, and relentless decline in cognitive, motor, and behavioral function. Onset is in the early school years, with progression to death typically by late adolescence. Development of a clinical instrument to quantify severity of illness is a prerequisite to eventual assessment of experimental therapeutic interventions. OBJECTIVE: To develop a clinical rating instrument to assess motor, behavioral, and functional capability in JNCL. METHODS: A clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), was developed by the authors to assess motor, behavioral, and functional capability in JNCL. Children with verified JNCL were evaluated independently by three neurologists. Intraclass correlation coefficients (ICCs) were used to estimate the interrater reliability for total scores in each domain. Interrater reliability for scale items was assessed with weighted kappa statistics. RESULTS: Thirty-one children with confirmed JNCL (10 boys, 21 girls) were evaluated. The mean age at symptom onset was 6.1 +/- 1.6 years, and the mean duration of illness was 9.0 +/- 4.4 years. The ICCs for the domains were as follows: motor = 0.83, behavioral = 0.68, and functional capability = 0.85. CONCLUSIONS: The Unified Batten Disease Rating Scale (UBDRS) is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form, the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.
Assuntos
Lipofuscinoses Ceroides Neuronais/diagnóstico , Testes Neuropsicológicos/normas , Testes de Personalidade/normas , Índice de Gravidade de Doença , Adolescente , Adulto , Criança , Pré-Escolar , Ensaios Clínicos como Assunto/normas , Progressão da Doença , Feminino , Humanos , Masculino , Exame Neurológico/métodos , Exame Neurológico/normas , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Lipofuscinoses Ceroides Neuronais/psicologia , Valor Preditivo dos Testes , Prognóstico , Resultado do TratamentoRESUMO
Alcoholism has a significant genetic basis, and identifying genes that confer a susceptibility to alcoholism will aid clinicians in preventing and effectively treating the disease. One commonly used technique to identify genetic risk factors for complex disorders such as alcoholism is the candidate gene approach, which directly tests the effects of genetic variants of a potentially contributing gene in an association study. These studies, which may include members of an affected family or unrelated cases and controls, can be performed relatively quickly and inexpensively and may allow identification of genes with small effects. However, the candidate gene approach is limited by how much is known of the biology of the disease being investigated. As researchers identify potential candidate genes using animal studies or linking them to DNA regions implicated through other analyses, the candidate gene approach will continue to be commonly used.
Assuntos
Alcoolismo/genética , Modelos Animais de Doenças , Polimorfismo Genético/genética , Alcoolismo/epidemiologia , Animais , Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Variação Genética/genética , Humanos , Camundongos , Mutação/genética , Linhagem , Característica Quantitativa HerdávelRESUMO
Commingling analysis is commonly used to provide preliminary evidence for a single genetic locus with a major effect on the quantitative trait of interest. In this paper, the effectiveness of commingling analysis as a screening technique to identify samples for segregation analysis is assessed by applying both commingling and segregation analyses to samples of simulated pedigree data in which a major locus is segregating in the presence of polygenes and an individual-specific environmental effect. Under the circumstances simulated here, there is evidence for a single locus from segregation analysis but not from commingling analysis in at least 20% of the samples. No more than 2% of the samples provided evidence for commingling but not for segregation of a single locus. Comparisons of the samples that give evidence for both commingling and segregation, evidence for one but not the other, and no evidence for either show that evidence for commingling depends on the distributional characteristics of the trait in the sample, while support for the single locus from segregation analysis depends on both the distributional characteristics as well as the transmission of the rarer allele from parents to offspring. Since lack of commingling does not rule out the existence of a single locus in the realistic situations considered here, commingling analysis has limited usefulness as a screening technique for the presence for a single locus. In contrast, evidence for commingling does suggest the possibility that a single locus has a major effect on the trait and commingling analysis can provide guidance in the choice of initial parameter estimates for segregation analysis.
Assuntos
Técnicas Genéticas , Modelos Genéticos , Distribuição de Qui-Quadrado , Interpretação Estatística de Dados , Estudos de Avaliação como Assunto , Feminino , Humanos , Masculino , Linhagem , Análise de RegressãoRESUMO
Kifafa is the Swahili name for an epileptic seizure disorder, first reported in the early 1960s, that is prevalent in the Wapogoro tribe of the Mahenge region of Tanzania in eastern Africa. A 1990 epidemiological survey of seizure disorders in this region reported a prevalence in the range of 19/1,000-36/1,000, with a mean age at onset of 11.6 years; 80% of those affected had onset prior to 20 years of age. A team of investigators returned to Tanzania in 1992 and collected data on > 1,600 relatives of 26 probands in 20 kifafa families. We have undertaken a genetic analysis of these data in order to detect the presence of familial clustering and whether such aggregation could be attributed to genetic factors. Of the 127 affected individuals in these pedigrees, 23 are first-degree relatives (parent, full sibling, or offspring) of the 26 probands; 20 are second-degree relatives (half-sibling, grandparent, uncle, or aunt). When corrected for age, the risk to first-degree relatives is .15; the risk to second-degree relatives is .063. These risks are significantly higher than would be expected if there were no familial clustering. Segregation analysis, using PAP (rev.4.0), was undertaken to clarify the mode of inheritance. Among the Mendelian single-locus models, an additive model was favored over either a dominant, recessive, or codominant model. The single-locus model could be rejected when compared with the mixed Mendelian model (inclusion of a polygenic background), although the major-gene component tends to be recessive.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Epilepsia/genética , Adolescente , Adulto , Distribuição por Idade , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Linhagem , PrevalênciaRESUMO
Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. The neuronal form of this disorder is referred to as Charcot-Marie-Tooth type II disease (CMT2). CMT2 is usually inherited as an autosomal dominant trait with a variable age at onset of symptoms associated with progressive axonal neuropathy. In some families, the locus that predisposes to CMT2 has been demonstrated to map to the distal portion of the short arm of chromosome 1. Other families with CMT2 do not show linkage with 1p markers, suggesting genetic heterogeneity in CMT2. We investigated linkage in a single large kindred with autosomal dominant CMT2. The gene responsible for CMT2 in this kindred (CMT2B) was mapped to the interval between the microsatellite markers D3S1769 and D3S1744 in the 3q13-22 region. Study of additional CMT2 kindreds should serve to further refine the disease gene region and may ultimately lead to the identification of a gene defect that underlies the CMT2 phenotype.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 3 , Mapeamento Cromossômico , Feminino , Ligação Genética , Marcadores Genéticos , Humanos , Escore Lod , Masculino , LinhagemRESUMO
Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.