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1.
Genome Res ; 29(9): 1555-1565, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31439692

RESUMO

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

2.
Blood Adv ; 3(7): 1039-1046, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30940639

RESUMO

Recent studies have identified germline mutations in TP53, PAX5, ETV6, and IKZF1 in kindreds with familial acute lymphoblastic leukemia (ALL), but the genetic basis of ALL in many kindreds is unknown despite mutational analysis of the exome. Here, we report a germline deletion of ETV6 identified by linkage and structural variant analysis of whole-genome sequencing data segregating in a kindred with thrombocytopenia, B-progenitor acute lymphoblastic leukemia, and diffuse large B-cell lymphoma. The 75-nt deletion removed the ETV6 exon 7 splice acceptor, resulting in exon skipping and protein truncation. The ETV6 deletion was also identified by optimal structural variant analysis of exome sequencing data. These findings identify a new mechanism of germline predisposition in ALL and implicate ETV6 germline variation in predisposition to lymphoma. Importantly, these data highlight the importance of germline structural variant analysis in the search for germline variants predisposing to familial leukemia.

4.
J Clin Oncol ; 36(20): 2078-2087, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-29847298

RESUMO

Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.

5.
Artigo em Inglês | MEDLINE | ID: mdl-29558868

RESUMO

Homozygous loss-of-function mutations in optineurin (OPTN) are a rare cause of amyotrophic lateral sclerosis (ALS), whereas heterozygous loss-of-function mutations have been suggested to increase ALS disease risk. We report a patient with ALS and frontotemporal dementia (FTD) from the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium carrying compound heterozygous loss-of-function variants in OPTN. Quantitative real-time mRNA expression analyses revealed a 75-80% reduction in OPTN expression in blood in the OPTN carrier as compared to controls, suggesting at least partial nonsense-mediated decay of the mutant transcripts. This case report illustrates the diverse inheritance patterns and variable clinical presentations associated with OPTN mutations, and underscores the importance of complete OPTN gene screening in patients with ALS and related disorders, especially in the context of clinical genetic testing.

6.
Clin Transl Gastroenterol ; 8(4): e87, 2017 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-28406493

RESUMO

OBJECTIVES: Hispanics represent an understudied inflammatory bowel disease (IBD) population. Prior studies examining genetic predisposition to IBD in Hispanics are limited. In this study, we examined whether European-derived IBD variants confer risk in Hispanics and their influence on IBD phenotype in Hispanics compared to non-Hispanic whites (NHW). METHODS: Self-identified Hispanics and NHWs with IBD were included. Hispanic controls were included for our genetic analyses. We performed single-variant testing at previously identified Crohn's disease (CD) and ulcerative colitis (UC) IBD variants in Hispanic cases and controls. These risk variants were used to compute individual genetic risk scores. Genetic risk scores and phenotype associations were compared between Hispanic and NHW. RESULTS: A total of 1,115 participants were included: 698 controls and 417 IBD patients (230 Hispanics). We found evidence of association within our Hispanic cohort at 22 IBD risk loci, with ~76% of the risk loci demonstrating over-representation of the European risk allele; these included loci corresponding to IL23R and NOD2 genes. CD genetic risk score for Hispanics (199.67) was similar to the score for NHW (200.33), P=0.51; the same was true in UC. Genetic risk scores did not predict IBD phenotype or complications in Hispanics or NHW except for a younger age of CD onset in Hispanics (P=0.04). CONCLUSIONS: This study highlights the fundamental importance of these loci in IBD pathogenesis including in our diverse Hispanic population. Future studies looking at non-genetic mechanisms of disease are needed to explain differences in age of presentation and phenotype between Hispanics and NHW.

7.
Nat Commun ; 7: 12353, 2016 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-27507172

RESUMO

Hereditary porphyrias are caused by mutations in genes that encode haem biosynthetic enzymes with resultant buildup of cytotoxic metabolic porphyrin intermediates. A long-standing open question is why the same causal porphyria mutations exhibit widely variable penetrance and expressivity in different individuals. Here we show that severely affected porphyria patients harbour variant alleles in the ABCB6 gene, also known as Lan, which encodes an ATP-binding cassette (ABC) transporter. Plasma membrane ABCB6 exports a variety of disease-related porphyrins. Functional studies show that most of these ABCB6 variants are expressed poorly and/or have impaired function. Accordingly, homozygous disruption of the Abcb6 gene in mice exacerbates porphyria phenotypes in the Fech(m1Pas) mouse model, as evidenced by increased porphyrin accumulation, and marked liver injury. Collectively, these studies support ABCB6 role as a genetic modifier of porphyria and suggest that porphyrin-inducing drugs may produce excessive toxicities in individuals with the rare Lan(-) blood type.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Isoantígenos/genética , Porfirias/genética , Porfirinas/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Alelos , Animais , Transporte Biológico/genética , Membrana Celular/metabolismo , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Heme/biossíntese , Heme/metabolismo , Humanos , Isoantígenos/sangue , Isoantígenos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mutação , Porfirias/metabolismo , Porfirias/urina , Porfirinas/urina , Homologia de Sequência de Aminoácidos , Índice de Gravidade de Doença , Sequenciamento Completo do Exoma
8.
Cartilage ; 7(2): 163-73, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27047639

RESUMO

OBJECTIVE: Normal physiological movement creates different weightbearing zones within a human knee: the medial condyle bearing the highest and the trochlea bearing the lowest weight. Adaptation to different physiological loading conditions results in different tissue and cellular properties within a knee. The objective of this study was to use microarray analysis to examine gene expression differences among three anatomical regions of human knee articular cartilage at baseline and following induction of an acute impact injury. DESIGN: Cartilage explants were harvested from 7 cadaveric knees (12 plugs per knee). A drop tower was utilized to introduce injury. Plugs were examined 24 hours after impact for gene expression using microarray. The primary analysis is the comparison of baseline versus impacted samples within each region separately. In addition, pairwise comparisons among the three regions were performed at baseline and after impact. False discovery rate (FDR) was used to evaluate significance of differential gene expression. RESULTS: In the comparison of before and after injury, the trochlear had 130 differentially expressed genes (FDR ≤ 0.05) while the condyles had none. In the comparison among regions, smaller sets of differentially expressed genes (n ≤ 21) were found, with trochlea being more different than the condyles. Most of more frequently expressed genes in trochlea are developmental genes. CONCLUSIONS: Within the experimental setup of this study, only the trochlea was displaying an acute genetic response on injury. Our data demonstrated the regional-specific response to injury in human articular cartilage.

9.
Blood ; 126(5): 640-50, 2015 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-26084673

RESUMO

Transcriptional regulators are recurrently altered through translocations, deletions, or aberrant expression in acute myeloid leukemia (AML). Although critically important in leukemogenesis, the underlying pathogenetic mechanisms they trigger remain largely unknown. Here, we identified that Id1 (inhibitor of DNA binding 1) plays a pivotal role in acute myeloid leukemogenesis. Using genetically modified mice, we found that loss of Id1 inhibited t(8;21) leukemia initiation and progression in vivo by abrogating protein kinase B (AKT)1 activation, and that Id1 interacted with AKT1 through its C terminus. An Id1 inhibitor impaired the in vitro growth of AML cells and, when combined with an AKT inhibitor, triggered even greater apoptosis and growth inhibition, whereas normal hematopoietic stem/progenitor cells were largely spared. We then performed in vivo experiments and found that the Id1 inhibitor significantly prolonged the survival of t(8;21)(+) leukemic mice, whereas overexpression of activated AKT1 promoted leukemogenesis. Thus, our results establish Id1/Akt1 signaling as a potential therapeutic target in t(8;21) leukemia.


Assuntos
Proteína 1 Inibidora de Diferenciação/metabolismo , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Carcinogênese , Linhagem Celular Tumoral , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Proteína 1 Inibidora de Diferenciação/deficiência , Proteína 1 Inibidora de Diferenciação/genética , Proteínas Inibidoras de Diferenciação/antagonistas & inibidores , Proteínas Inibidoras de Diferenciação/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Domínios e Motivos de Interação entre Proteínas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais , Translocação Genética
10.
Arch Med Res ; 45(8): 744-52, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25446617

RESUMO

BACKGROUND AND AIMS: Increased amyloid deposition in HIV-infected brains may contribute to the pathogenesis of neurocognitive dysfunction in infected patients. We have previously shown that exposure to HIV results in enhanced amyloid ß (Aß) levels in human brain microvascular endothelial cells, suggesting that brain endothelial cells contribute to accumulation of Aß in HIV-infected brains. Importantly, Aß not only accumulates in the cytoplasm of HIV-exposed cells but also enters the nuclei of brain endothelial cells. METHODS: cDNA microarray analysis was performed in order to examine changes in the transcriptional profile associated with Aß nuclear entry in the presence of HIV-1. RESULTS: Gene network analysis indicated that inhibition of nuclear entry of Aß resulted in enrichment in gene sets involved in apoptosis and survival, endoplasmic reticulum stress response, immune response, cell cycle, DNA damage, oxidative stress, cytoskeleton remodeling and transforming growth factor ß (TGFß) receptor signaling. CONCLUSIONS: The obtained data indicate that HIV-induced Aß nuclear uptake affects several cellular stress-related pathways relevant for HIV-induced Aß pathology.


Assuntos
Transporte Ativo do Núcleo Celular/genética , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Infecções por HIV/metabolismo , HIV-1 , Transporte Proteico/genética , Apoptose/genética , Encéfalo/metabolismo , Linhagem Celular , Células Cultivadas , Dinaminas/antagonistas & inibidores , Estresse do Retículo Endoplasmático/genética , Células Endoteliais/metabolismo , Células HEK293 , Humanos , Estresse Oxidativo/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/metabolismo
11.
Fetal Pediatr Pathol ; 33(4): 226-33, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24833307

RESUMO

We aim to identify the link between placental histological findings and obstetric reports to determine possible risk factors of spontaneous preterm birth (SPTB). We prospectively ascertained birth records and outcomes from all deliveries in our hospital in 1 year. Records were used to determine and stratify for either full-term or preterm [spontaneous or indicated (I)] deliveries. We analyzed for risk factor association using χ(2) tests and common odds ratio estimates (SPSS v21.0). Our cohort totaled 6088 deliveries: 236 IPTB, 43 SPTB, and 5809 term births. Largely Hispanic, we determined race, parity, prenatal care access, preeclampsia, gestational diabetes, and BMI to be highly associated with SPTB (p < 0.01). Histologically, placentas of women with SPTB were twice as likely to have chronic villitis. We found that chronic villitis is associated with SPTB. Results of this study can be used in increasing the understanding of SPTB.


Assuntos
Nascimento Prematuro/etiologia , Nascimento Prematuro/patologia , Adulto , Estudos de Coortes , Demografia , Diabetes Gestacional/epidemiologia , Feminino , Florida/epidemiologia , Humanos , Recém-Nascido , Placenta/patologia , Doenças Placentárias/epidemiologia , Doenças Placentárias/patologia , Pré-Eclâmpsia/epidemiologia , Gravidez , Nascimento Prematuro/epidemiologia , Cuidado Pré-Natal , Estudos Prospectivos , Fatores de Risco , População Urbana , Adulto Jovem
12.
BMC Sports Sci Med Rehabil ; 6(1): 6, 2014 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-24552436

RESUMO

BACKGROUND: The mechanisms through which exercise reduces cardiovascular disease are not fully understood. We used echocardiograms, cardiac biomarkers and gene expression to investigate cardiovascular effects associated with exercise training. METHODS: Nineteen sedentary men (22-37 years) completed a 17-week half-marathon training program. Serial measurements of resting heart rate, blood pressure, maximum oxygen consumption, lipids, C-reactive protein, cardiac troponin T, echocardiograms and blood for gene expression were obtained from baseline to peak training. Controls included 22 sedentary men who did not exercise. RESULTS: Among the training group, VO2 max increased from 37.1 to 42.0 ml/kg/min (p < 0.001). Significant changes were seen in left ventricular wall thickness and mass, stroke volume, resting heart rate and blood pressure (p < 0.001). The control group demonstrated no significant changes. Expression profiling in the training group identified 10 significantly over-expressed and 53 significantly under-expressed loci involved in inflammatory pathways. Dividing the training group into high and low responders based on percent change in VO2 max identified loci that differentiated these two groups at baseline and after training. CONCLUSION: Intensive exercise training leads to significant increase in cardiac and hemodynamic performance, and significant changes in expression of genes involved in immune and inflammatory response.

13.
Environ Health Perspect ; 121(6): 725-30, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23632211

RESUMO

BACKGROUND: The gut microbiome, a dynamic bacterial community that interacts with the host, is integral to human health because it regulates energy metabolism and immune functions. The gut microbiome may also play a role in risks from environmental toxicants. OBJECTIVES: We investigated the effects of polychlorinated biphenyls (PCBs) and exercise on the composition and structure of the gut microbiome in mice. METHODS: After mice exercised voluntarily for 5 weeks, they were treated by oral gavage with a mixture of environmentally relevant PCB congeners (PCB153, PCB138, and PCB180; total PCB dose, 150 µmol/kg) for 2 days. We then assessed the microbiome by determination of 16S rRNA using microarray analysis. RESULTS: Oral exposure to PCBs significantly altered the abundance of the gut microbiome in mice primarily by decreasing the levels of Proteobacteria. The activity level of the mice correlated with a substantial shift in abundance, biodiversity, and composition of the microbiome. Importantly, exercise attenuated PCB-induced changes in the gut microbiome. CONCLUSIONS: Our results show that oral exposure to PCBs can induce substantial changes in the gut microbiome, which may then influence their systemic toxicity. These changes can be attenuated by behavioral factors, such as voluntary exercise.


Assuntos
Poluentes Ambientais/toxicidade , Intestinos/microbiologia , Metagenoma/efeitos dos fármacos , Condicionamento Físico Animal , Bifenilos Policlorados/toxicidade , Animais , Ácido Cólico/farmacologia , Ácidos Graxos Voláteis/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
J Card Fail ; 19(4): 233-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23582089

RESUMO

BACKGROUND: LMNA cardiomyopathy presents with electrocardiogram (ECG) abnormalities, conduction system disease (CSD), and/or arrhythmias before the onset of dilated cardiomyopathy (DCM). Knowing the time interval between the onset of CSD and its progression to DCM would help to guide clinical care. METHODS AND RESULTS: We evaluated family members from 16 pedigrees previously identified to carry LMNA mutations for the ages of onset of ECG abnormalities, CSD, or arrhythmia and of left ventricular enlargement (LVE) and/or systolic dysfunction. Of 103 subjects, 64 carried their family LMNA mutation, and 51 (79%) had ECG abnormalities with a mean age of onset of 41.2 years (range 18-76). Ventricular dysfunction was observed in 26 with a mean age of onset of 47.6 years (range 28-82); at diagnosis 9 had systolic dysfunction but no LVE, 5 had LVE but no systolic dysfunction, and 11 had DCM. Of 16 subjects identified with ECG abnormalities who later developed ventricular dysfunction, the median ages of onset by log-rank analyses were 41 and 48 years, respectively. CONCLUSIONS: ECG abnormalities preceded DCM with a median difference of 7 years. Clinical surveillance should occur at least annually in those at risk for LMNA cardiomyopathy with any ECG findings.


Assuntos
Cardiomiopatia Dilatada/genética , Eletrocardiografia/tendências , Sistema de Condução Cardíaco/fisiologia , Lamina Tipo A/genética , Disfunção Ventricular/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/epidemiologia , Feminino , Seguimentos , Sistema de Condução Cardíaco/patologia , Humanos , Lipodistrofia/diagnóstico , Lipodistrofia/epidemiologia , Lipodistrofia/genética , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Disfunção Ventricular/diagnóstico , Disfunção Ventricular/epidemiologia , Adulto Jovem
15.
Circ Cardiovasc Genet ; 6(2): 144-53, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23418287

RESUMO

BACKGROUND- Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. METHODS AND RESULTS- We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. CONCLUSIONS- These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.


Assuntos
Cardiomiopatia Dilatada/genética , Exoma/genética , Genoma Humano , Proteínas Musculares/genética , Proteínas Quinases/genética , Adolescente , Adulto , Idoso , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Cromossomos Humanos Par 9 , Conectina , Feminino , Heterogeneidade Genética , Ligação Genética , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Razão de Chances , Linhagem , Análise de Sequência de DNA , Adulto Jovem
16.
Ann Hum Genet ; 77(2): 147-57, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23289938

RESUMO

The rates of obesity and sedentary lifestyle are on a dramatic incline, with associated detrimental health effects among women in particular. Although exercise prescriptions are useful for overcoming these problems, success can be hampered by differential responsiveness among individuals in cardiovascular fitness indices (i.e. improvements in strength, lipids, VO(2) max). Genomic factors appear to play an important role in determining this inter-individual variation. We performed microarray analyses on mRNA in whole blood from 60 sedentary women from a multi-ethnic cohort who underwent 12 weeks of exercise, to identify gene subsets that were differentially expressed between individuals who experienced the greatest and least improvements in fitness. We identified 43 transcripts in 39 unique genes (FDR<10%; FC>1.5) whose expression increased the most in "high" versus "low" pre-menopausal female responders. These 39 genes were enriched in six biological pathways, including oxidative phosphorylation (p = 8.08 × 10(-3)). Several of the 39 genes (i.e. TIGD7, UQCRH, PSMA6, WDR12, TFB2M, USP15) have previously reported associations with fitness-related phenotypes. In summary, we identified gene signatures based on mRNA analysis that define responsiveness to exercise in a largely minority-based female cohort. Importantly, this study validates several genes/pathways previously associated with exercise responsiveness and extends these findings with additional novel genes.


Assuntos
Exercício , Marcadores Genéticos , Obesidade/genética , Aptidão Física , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Terapia por Exercício , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genoma , Humanos , Pessoa de Meia-Idade , Consumo de Oxigênio , Comportamento Sedentário , Adulto Jovem
18.
Hum Genet ; 132(3): 323-36, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23192594

RESUMO

Genome-wide association studies (GWAS) of obesity measures have identified associations with single nucleotide polymorphisms (SNPs). However, no large-scale evaluation of gene-environment interactions has been performed. We conducted a search of gene-environment (G × E) interactions in post-menopausal African-American and Hispanic women from the Women's Health Initiative SNP Health Association Resource GWAS study. Single SNP linear regression on body mass index (BMI) and waist-to-hip circumference ratio (WHR) adjusted for multidimensional-scaling-derived axes of ancestry and age was run in race-stratified data with 871,512 SNPs available from African-Americans (N = 8,203) and 786,776 SNPs from Hispanics (N = 3,484). Tests of G × E interaction at all SNPs for recreational physical activity (m h/week), dietary energy intake (kcal/day), alcohol intake (categorical), cigarette smoking years, and cigarette smoking (ever vs. never) were run in African-Americans and Hispanics adjusted for ancestry and age at interview, followed by meta-analysis of G × E interaction terms. The strongest evidence for concordant G × E interactions in African-Americans and Hispanics was for smoking and marker rs10133840 (Q statistic P = 0.70, beta = -0.01, P = 3.81 × 10(-7)) with BMI as the outcome. The strongest evidence for G × E interaction within a cohort was in African-Americans with WHR as outcome for dietary energy intake and rs9557704 (SNP × kcal = -0.04, P = 2.17 × 10(-7)). No results exceeded the Bonferroni-corrected statistical significance threshold.


Assuntos
Afro-Americanos/genética , Índice de Massa Corporal , Interação Gene-Ambiente , Hispano-Americanos/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Relação Cintura-Quadril , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Ingestão de Energia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Atividade Motora , Estudos Prospectivos , Fatores de Risco , Fumar/epidemiologia , Estados Unidos/epidemiologia , Saúde da Mulher
19.
Neurobiol Aging ; 34(1): 357.e7-19, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22959728

RESUMO

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [OR] = 1.21; p = 4.41 × 10(-7)), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10(-7)), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10(-7)). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R(2)(partial) = 0.0061; p = 6.59 × 10(-8)) and rs803675 (R(2)(partial) = 0.0060; p = 6.96 × 10(-8)). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease.


Assuntos
Idade de Início , Esclerose Amiotrófica Lateral/genética , Cromossomos Humanos Par 1/genética , Predisposição Genética para Doença , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia
20.
Circ Cardiovasc Genet ; 5(2): 167-74, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22337857

RESUMO

BACKGROUND: Human exome sequencing is a recently developed tool to aid in the discovery of novel coding variants. Now broadly applied, exome sequencing data sets provide a novel opportunity to evaluate the allele frequencies of previously published pathogenic rare variants. METHODS AND RESULTS: We examined the exome data set from the National Heart, Lung and Blood Institute Exome Sequencing Project and compared this data set with a catalog of 197 previously published rare variants reported as causative of dilated cardiomyopathy (DCM) from familial and sporadic cases. Of these 197, 33 (16.8%) were also present in the Exome Sequencing Project database, raising the question of whether they were uncommon polymorphisms. Supporting functional data has been published for 14 of the 33 (42%), suggesting they are unlikely to be false-positives. The frequencies of these functional variants in the Exome Sequencing Project data set ranged from 0.02 to 1.33% (median 0.04%), which when applied as a cutoff to filter variants in a DCM pedigree identified an additional DCM candidate gene. A greater proportion of sporadic DCM cases had variants that were present in the Exome Sequencing Project data set versus novel variants (ie, not in the Exome Sequencing Project; 44% versus 21%; P=0.002), suggesting some of the variants identified as disease causing in sporadic DCM are either false-positives or low penetrance alleles in human populations. CONCLUSIONS: Rare nonsynonymous variants identified in DCM subjects also present at very low frequencies in public databases are likely relevant for DCM. Allele frequencies >0.04% are of less certain pathogenicity, especially if identified in sporadic cases, although this cutoff should be viewed as preliminary.


Assuntos
Cardiomiopatia Dilatada/genética , Exoma , Variação Genética , Éxons , Feminino , Humanos , Masculino , Linhagem
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