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1.
Artigo em Inglês | MEDLINE | ID: mdl-33409738

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause profound immune-related adverse events (irAEs). The host genetic background is likely to play a role in irAE susceptibility because the presentation of toxicity varies among patients and many do not develop irAEs despite continued ICI use. We sought to identify potential genetic markers conferring risk for irAEs. METHODS: We conducted a pilot exploratory study in 89 melanoma patients who received ICIs (44 with irAEs, and 45 without irAEs after at least 1 year from starting treatment). Genotyping was performed using the Infinium Multi-Ethnic Global-8 v1.0 Bead Chip. The genotype data were extracted using PLINK (v1.90b3.34) and processed for quality control. Population structure-based clustering was carried out using IBS matrix, pairwise population concordance test (p < 1 × 10-3), and phenotype distribution for all study participants, resulting in seven population structure-based clusters. In the analytical stage, 599,931 variants in autosomal chromosomes were included for the association study. The association test was performed using an additive genetic model with exact logistic regression, adjusted for age, sex, and population cluster. RESULTS: A total of 30 variants or single-nucleotide polymorphisms with p < 1 × 10-4 were identified; 12 were associated with an increased risk of irAEs, and the remaining 18 were associated with a decreased risk. Overall, nine of the identified single-nucleotide polymorphisms mapped to eight unique genes that have been associated with autoimmunity or inflammatory diseases. CONCLUSION: Several genetic variants associated with irAEs were identified. Additional larger studies are needed to validate these findings and establish their potential functional relevance.

2.
Int J Cancer ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32914876

RESUMO

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.

3.
Cancer Cytopathol ; 128(8): 553-562, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32320527

RESUMO

BACKGROUND: Approximately one third of needle biopsies that are performed to rule out malignancy of indeterminate pulmonary nodules detected radiologically during lung cancer screening are negative, thus exposing cancer-free patients to risks of pneumothorax, bleeding, and infection. A noninvasive confirmatory tool (eg, liquid biopsy) is urgently needed in the lung cancer diagnosis setting to stratify patients who should receive biopsy versus those who should be monitored. METHODS: A novel antigen-independent, 4-color fluorescence in situ hybridization (FISH)-based method was developed to detect circulating tumor cells (CTCs) with abnormalities in gene copy numbers in mononuclear cell-enriched peripheral blood samples from patients with (n = 107) and without (n = 100) lung cancer. RESULTS: Identification of CTCs using FISH probes at 10q22.3/CEP10 and 3p22.1/3q29 detected lung cancer cases with 94.2% accuracy, 89% sensitivity, and 100% specificity compared with biopsy. CONCLUSION: The high accuracy of this liquid biopsy method suggests that it may be used as a noninvasive decision tool to reduce the frequency of unnecessary needle biopsy in patients with benign pulmonary lesions.


Assuntos
Pneumopatias/diagnóstico , Neoplasias Pulmonares/diagnóstico , Células Neoplásicas Circulantes , Tomografia Computadorizada por Raios X/métodos , Células A549 , Idoso , Aneuploidia , Diagnóstico Diferencial , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Biópsia Líquida , Pneumopatias/diagnóstico por imagem , Pneumopatias/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sensibilidade e Especificidade
4.
Nat Commun ; 11(1): 27, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911640

RESUMO

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.


Assuntos
Neoplasias Pulmonares/genética , Pulmão/fisiopatologia , Adulto , Idoso , Feminino , Volume Expiratório Forçado , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/fisiopatologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Testes de Função Respiratória , Capacidade Vital
5.
Head Neck ; 39(6): 1195-1204, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28346771

RESUMO

BACKGROUND: Treatments for head and neck squamous cell carcinoma (HNSCC) are associated with toxicities that lead to emergency department presentation. METHODS: We utilized data from an ongoing prospective cohort of newly diagnosed, previously untreated patients (N = 298) with HNSCC to evaluate the association between clinical and epidemiologic factors and risk for and frequency of emergency department presentation. Time to event was calculated from the date of treatment initiation to emergency department presentation, date of death, or current date. Frequency of emergency department presentation was the sum of emergency department visits during the follow-up time. RESULTS: History of hypertension, normal/underweight body mass index (BMI), and probable depression predicted increased risk for emergency department presentation. BMI and severe pain were associated with higher frequency of emergency department presentations. CONCLUSION: Clinical and epidemiologic factors can help predict patients with HNSCC who will present to the emergency department. Such knowledge may improve treatment-related patient outcomes and quality of life. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1195-1204, 2017.


Assuntos
Carcinoma de Células Escamosas/terapia , Emergências/epidemiologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Tratamento de Emergência/métodos , Neoplasias de Cabeça e Pescoço/terapia , Adulto , Fatores Etários , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Tratamento de Emergência/estatística & dados numéricos , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores Sexuais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida
6.
Sex Transm Dis ; 44(3): 166-172, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28178115

RESUMO

BACKGROUND: This study investigated the prevalence of and risk factors for oral human papillomavirus (HPV) infection with multiple genotypes in the United States. METHODS: Data were from the nationally representative 2009-2012 National Health and Nutrition Examination Survey. This analysis comprised 9257 participants for whom data on oral HPV (37 genotypes) and associated risk factors were available. RESULTS: The weighted prevalence of multitype (2-6 types) oral HPV infection was 1.5% (2.5% for men, 0.4% for women) in the whole sample and 19.7% (22.0% for men, 12.1% for women) in those who had any type of oral HPV positivity. Most multitype oral HPV cases (83.8%) harbored one or more oncogenic types. In the adjusted multinominal logistic regression model, being male (relative risk ratio [RRR] = 3.69; 95% confidence interval [CI], 1.57-8.65), being a current cigarette smoker (RRR = 2.57; 95% CI, 1.23-5.36), and having a new sex partner in the past year (RRR = 2.10; 95% CI, 1.03-4.28) were associated with an increased risk of multitype oral HPV infection over single-type HPV infection. CONCLUSIONS: Men, smokers, and those who had new sexual partners were at a significantly higher risk for multitype oral HPV infection.


Assuntos
Genótipo , Doenças da Boca/epidemiologia , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Adolescente , Adulto , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doenças da Boca/virologia , Inquéritos Nutricionais , Infecções por Papillomavirus/virologia , Prevalência , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
7.
J Infect Dis ; 214(9): 1370-1375, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27553042

RESUMO

The very few studies that have examined the association between vaginal douching and genital human papillomavirus (HPV) infection have found contrary results. We investigated the associations between douching and numbers of HPV genotypes infecting 1271 participants aged 20-49 years in the 2003-2004 US National Health and Nutrition Examination Survey. After controlling for relevant covariates, douching in the past 6 months was significantly associated with infection by higher numbers of all genital HPV types (relative risk ratio, 1.26; 95% confidence interval, 1.03-1.54) and HPV high-risk types (1.40; 1.09-1.80).


Assuntos
Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/etiologia , Ducha Vaginal/efeitos adversos , Adulto , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Inquéritos Nutricionais , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Estados Unidos , Adulto Jovem
8.
Am J Prev Med ; 51(3): e77-85, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27067306

RESUMO

INTRODUCTION: Sunburns during childhood increase melanoma risk. Children of melanoma survivors are at higher risk, but little is known about their sunburn and sun protection. One study showed that almost half of melanoma survivors' children experienced sunburn in the past year. This study evaluated sunburn and sun protection in melanoma survivors' children, and relevant survivor characteristics from Social Cognitive Theory and the Health Belief Model. METHODS: Melanoma survivors (N=340) were recruited from a comprehensive cancer center. Survivors completed a baseline questionnaire administered by telephone to report on the behavior of their children (N=340) as part of an RCT of a sun protection intervention. Data were collected in 2008 and analyzed in 2015. RESULTS: In the prior 6 months, 28% of children experienced sunburn. "Always" or "frequent" sun protection varied by behavior: sunscreen, 69%; lip balm, 15%; wide-brimmed hats, 9%; sleeved shirts, 28%; pants, 48%; sunglasses, 10%; shade, 33%; and limiting time outdoors, 45%. Survivors' sunburn and sun protection were positively associated with these outcomes in children. Correlates of sunburn also included older child age and higher risk perceptions. Correlates of sun protection behaviors included younger child age; stronger intentions, higher self-efficacy, and more positive outcome expectations about sun protection; and greater number of melanomas in survivors. CONCLUSIONS: Melanoma survivors may have a heightened awareness of the importance of their children's sun protection, but their children are not routinely protected. Correlates of children's sunburn and sun protection suggest subgroups of survivors to target with interventions to improve sun protection.


Assuntos
Melanoma/prevenção & controle , Neoplasias Cutâneas/prevenção & controle , Queimadura Solar/prevenção & controle , Sobreviventes , Adulto , Criança , Feminino , Humanos , Masculino , Protetores Solares/uso terapêutico , Inquéritos e Questionários
9.
Birth Defects Res A Clin Mol Teratol ; 103(8): 680-91, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26033863

RESUMO

Birth defects are a major cause of morbidity and mortality worldwide. There has been much progress in understanding the genetic basis of familial and syndromic forms of birth defects. However, the etiology of nonsydromic birth defects is not well-understood. Although there is still much work to be done, we have many of the tools needed to accomplish the task. Advances in next-generation sequencing have introduced a sea of possibilities, from disease-gene discovery to clinical screening and diagnosis. These advances have been fruitful in identifying a host of candidate disease genes, spanning the spectrum of birth defects. With the advent of CRISPR-Cas9 gene editing, researchers now have a precise tool for characterizing this genetic variation in model systems. Work in model organisms has also illustrated the importance of epigenetics in human development and birth defects etiology. Here we review past and current knowledge in birth defects genetics. We describe genotyping and sequencing methods for the detection and analysis of rare and common variants. We remark on the utility of model organisms and explore epigenetics in the context of structural malformation. We conclude by highlighting approaches that may provide insight into the complex genetics of birth defects.


Assuntos
Anormalidades Congênitas/genética , Marcadores Genéticos , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
10.
J Pain ; 15(10): 1015-22, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25043982

RESUMO

UNLABELLED: Survival outcomes in patients with squamous cell carcinoma of the head and neck (HNSCC) vary by extent of disease, behavioral factors, and socioeconomic factors. We assessed the extent to which pretreatment pain influences survival in 2,340 newly diagnosed patients with HNSCC, adjusting for disease stage, symptoms, pain medications, comorbidities, smoking, alcohol consumption, age, sex, and race/ethnicity. Patients rated their pain at presentation to the cancer center (0 = "no pain" and 10 = "pain as bad as you can imagine"). Survival time was calculated from the date of diagnosis to the date of death of any cause or last follow-up. Five-year overall survival was calculated for all the variables assessed in the study. Severe pain (≥7) was most prevalent among those with oral cancer (20.4%; pharynx = 18.8%; larynx = 16.1%) and significantly varied by tumor stage, fatigue severity, smoking status, comorbid lung disease, and race (all P < .05) across cancer diagnoses. Overall 5-year survival varied by pain for oral (severe pain = 31% vs nonsevere pain = 52%; P < .001) and pharyngeal cancer (severe pain = 33% vs nonsevere pain = 53%; P < .001). Multivariable analyses showed that pain persisted as an independent prognostic factor for survival. Pain reported prior to treatment should be considered in understanding survival outcomes in HNSCC patients. PERSPECTIVE: Pretreatment pain was an independent predictor of survival in a large sample of HNSCC patients even after accounting for tumor node metastasis stage, fatigue, age, race/ethnicity, smoking, and alcohol intake. Therefore, symptoms at presentation and before cancer treatment are important factors to be considered in understanding survival outcomes in HNSCC patients.


Assuntos
Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/fisiopatologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/fisiopatologia , Dor/fisiopatologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Comorbidade , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/diagnóstico , Neoplasias Laríngeas/epidemiologia , Neoplasias Laríngeas/fisiopatologia , Neoplasias Laríngeas/terapia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/fisiopatologia , Neoplasias Bucais/terapia , Análise Multivariada , Dor/epidemiologia , Medição da Dor , Neoplasias Faríngeas/diagnóstico , Neoplasias Faríngeas/epidemiologia , Neoplasias Faríngeas/fisiopatologia , Neoplasias Faríngeas/terapia , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço
11.
Cancer Epidemiol Biomarkers Prev ; 22(10): 1813-24, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24097199

RESUMO

BACKGROUND: We studied whether a melanoma survivor-centered intervention was more effective than materials available to the general public in increasing children's sun protection. METHODS: In a randomized controlled trial, melanoma survivors (n = 340) who had a child ≤ 12 years received a targeted sun protection intervention (DVD and booklets) or standard education. Primary outcomes were children's sunburns, children's sun protection, and survivors' psychosocial factors at baseline and postintervention (1 and 4 months). RESULTS: The intervention increased children's sunscreen reapplication at 1 month (P = 0.002) and use of wide-brimmed hats at 4 months (P = 0.045). There were no effects on other behaviors or sunburns. The intervention improved survivors' hats/clothing self-efficacy at both follow-up assessments (P = 0.026, 0.009). At 4 months, the intervention improved survivors' clothing intentions (P = 0.029), knowledge (P = 0.010), and outcome expectations for hats (P = 0.002) and clothing (P = 0.037). Children's sun protection increased with survivors' intervention use. The intervention was less effective in survivors who were female or who had a family history, older children, or children with higher baseline sun protection scores. CONCLUSIONS: A melanoma survivor-centered sun protection intervention can improve some child and survivor outcomes. The intervention may be more effective in survivors who have younger children or less experience with sun protection. Intervention delivery must be enhanced to maximize use. IMPACT: This is the first study to examine a sun protection intervention for children of melanoma survivors. Findings will guide interventions for this important population at increased melanoma risk.


Assuntos
Melanoma/prevenção & controle , Neoplasias Cutâneas/prevenção & controle , Queimadura Solar/prevenção & controle , Protetores Solares/administração & dosagem , Adulto , Criança , Feminino , Humanos , Masculino , Sobreviventes
12.
Front Psychiatry ; 4: 114, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24065931

RESUMO

A compromised brain reward system has been postulated as a key feature of drug dependence. We examined whether several polymorphisms of genes found to regulate nicotinic acetylcholine receptor (nAChR) and dopamine expression were related to an intrinsic reward sensitivity (IRS) deficit we previously identified among a subgroup of smokers using event-related potentials (ERPs). We examined genetic polymorphisms within the CHRNA5-A3-B4 gene cluster (CHRNA3 rs578776, CHRNA5 rs16969968, LOC123688 rs8034191, and CHRNA3 rs1051730), the ANKK1 gene (rs1800497), and the D2 dopamine receptor gene (DRD2 rs1079597, DRD2 rs1799732) from 104 smokers of European ancestry in a smoking cessation trial. Prior to treatment, we recorded ERPs evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related pictures. Smokers were assigned to two groups (IRS+/IRS-) based on the amplitude of the late positive potential (LPP) component to the pictures, a neural marker of motivational salience. Smokers (n = 42) with blunted brain responses to intrinsically rewarding (pleasant) pictures and enhanced responses to cigarette pictures were assigned to the IRS- group, while smokers (n = 62) with the opposite pattern of LPP responding were assigned to the IRS+ group. Carriers of the protective minor T allele (T/T, C/T) of the CHRNA3 rs578776 were less likely to be members of the IRS- group than those homozygous for the at-risk C allele (C/C). The CHRNA3 rs578776 polymorphism did not differ on questionnaires of nicotine dependence, depressed mood, or trait affective disposition and did not predict abstinence at 6 months after the quit date. These results suggest that polymorphisms of genes influencing nAChR expression are related to an endophenotype of reward sensitivity in smokers.

13.
Genet Epidemiol ; 36(4): 340-51, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22539395

RESUMO

Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.


Assuntos
Cromossomos Humanos Par 15 , Variação Genética , Fumar/efeitos adversos , Adolescente , Adulto , Afro-Americanos , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência do Gene , Genética Populacional , Humanos , Pneumopatias/etiologia , Pneumopatias/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Risco
14.
Circ Cardiovasc Genet ; 4(1): 36-42, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21163914

RESUMO

BACKGROUND: Thoracic aortic aneurysms leading to acute aortic dissections are the major diseases that affect the thoracic aorta. Approximately 20% of patients with thoracic aortic aneurysms and dissections (TAAD) have a family history of TAAD, and these patients present younger with more rapidly enlarging aneurysms than patients without a family history of aortic disease. METHODS AND RESULTS: A large family with multiple members with TAAD inherited in an autosomal-dominant manner was identified. The ascending aortic aneurysms were associated with slow enlargement, a low risk of dissection, and decreased penetrance in women. Genome-wide linkage analysis was performed, and a novel locus on chromosome 12 was identified for the mutant gene causing disease in this family. Of the 12 male members who carry the disease-linked microsatellite haplotype, 9 had ascending aortic aneurysms with an average diameter of 4.7 cm at an average age of 52.4 years (range, 32 to 76 years) at the time of diagnosis; only 1 individual had progressed to acute aortic dissection, and no other members with aortic dissections were identified. Women harboring the disease-linked haplotype did not have thoracic aortic disease, including 1 aged 84 years. Sequencing of 9 genes within the critical interval at the chromosome 12 locus did not identify the mutant gene. CONCLUSIONS: Mapping a locus for ascending thoracic aortic aneurysms associated with a low risk of aortic dissection supports our hypothesis that genes leading to familial disease can be associated with less-aggressive thoracic aortic disease.


Assuntos
Aneurisma Dissecante/complicações , Aneurisma Dissecante/genética , Aorta/patologia , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/genética , Progressão da Doença , Loci Gênicos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 12/genética , Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genoma Humano/genética , Haplótipos/genética , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de Risco , Análise de Sequência de DNA
15.
Am J Hum Genet ; 84(5): 617-27, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19409525

RESUMO

The vascular smooth muscle cell (SMC)-specific isoform of alpha-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.


Assuntos
Actinas/genética , Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Doença da Artéria Coronariana/genética , Doença de Moyamoya/genética , Acidente Vascular Cerebral/genética , Actinas/metabolismo , Adolescente , Adulto , Aneurisma Dissecante/patologia , Aneurisma da Aorta Torácica/patologia , Proliferação de Células , Células Cultivadas , Doença da Artéria Coronariana/patologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Doença de Moyamoya/patologia , Mutação , Miócitos de Músculo Liso/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Adulto Jovem
16.
Nat Genet ; 39(12): 1488-93, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17994018

RESUMO

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.


Assuntos
Actinas/genética , Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Mutação de Sentido Incorreto , Aorta/metabolismo , Aorta/patologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Linhagem
17.
Circulation ; 107(25): 3184-90, 2003 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-12821554

RESUMO

BACKGROUND: Familial thoracic aortic aneurysms and dissections (TAAD) occur as part of known syndromes such as Marfan syndrome but can also be inherited in families in an autosomal dominant manner as an isolated condition. Previous studies have mapped genes causing nonsyndromic familial TAAD to 5q13-15 (TAAD1) and 11q23.2-q24 (FAA1). Further genetic heterogeneity for the condition was evident by the presence of TAAD in some families not linked to these known loci. METHODS AND RESULTS: A 4-generation family with dominant mode of inheritance of TAAD was studied. Affected status was determined by dilation of the ascending aorta, surgical repair of an aneurysm or dissection, or death as the result of aortic dissection. None of the family members evaluated met the diagnostic criteria for Marfan syndrome. After exclusion of known loci for familial TAAD, a genome-wide scan was carried out to map the defective gene causing the disease in the family. A locus was mapped to a 25-cM region on 3p24-25 with a maximum multipoint logarithm of the odds score of 4.28. CONCLUSIONS: A third locus for nonsyndromic TAAD was mapped to 3p24-25 and termed the TAAD2 locus. This locus overlaps a previously mapped second locus for Marfan syndrome, termed the MFS2 locus. Future characterization of the TAAD2 gene will determine if TAAD2 is allelic to MFS2. In addition, identification of the TAAD2 gene will improve the presymptomatic diagnosis of individuals with this life-threatening genetic syndrome and provide information concerning the pathogenesis of the disease.


Assuntos
Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 3/genética , Adolescente , Adulto , Aneurisma Dissecante/diagnóstico , Aneurisma Dissecante/epidemiologia , Aneurisma da Aorta Torácica/diagnóstico , Aneurisma da Aorta Torácica/epidemiologia , Proteínas de Ligação ao Cálcio/genética , Criança , Comorbidade , Análise Mutacional de DNA , Ecocardiografia , Proteínas da Matriz Extracelular/genética , Feminino , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Genótipo , Alemanha/epidemiologia , Haplótipos , Humanos , Escore Lod , Masculino , Síndrome de Marfan/epidemiologia , Síndrome de Marfan/genética , Pessoa de Meia-Idade , Linhagem , Penetrância , Suíça/epidemiologia
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