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1.
Laryngoscope ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31441955

RESUMO

OBJECTIVE: Characterize long-term cranial nerve (CN) outcomes following sentinel lymph node biopsy (SLNB) based management for head and neck cutaneous melanoma (HNCM). METHODS: Longitudinal review of HNCM patients undergoing SLNB from 1997-2007. RESULTS: Three hundred fifty-six patients were identified, with mean age 53.5 ± 19.0 years, mean Breslow depth 2.52 ± 1.87 mm, and 4.9 years median follow-up. One hundred five (29.4%) patients had SLNB mapping to the parotid basin. Eighteen patients had positive parotid SLNs and underwent immediate parotidectomy / immediate completion lymph node dissection (iCLND), with six possessing positive parotid non-sentinel lymph nodes (NSLNs). Fifty-two of 356 (14.6%) patients developed delayed regional recurrences, including 20 total intraparotid recurrences: five following false negative (FN) parotid SLNB, three following prior immediate superficial parotidectomy, two following iCLND without parotidectomy, and the remaining 12 parotid recurrences had negative extraparotid SLNBs. Parotid recurrences were multiple (4.9 mean recurrent nodes) and advanced (n = 4 extracapsular extension), and all required salvage dissection including parotidectomy. Immediate parotidectomy/iCLND led to no permanent CN injuries. Delayed regional HNCM macrometastasis precipitated 16 total permanent CN injuries in 13 patients: 10 CN VII, five CN XI, and one CN XII deficits. Fifty percent (n = 10) of parotid recurrences caused ≥1 permanent CN deficits. CONCLUSIONS: Regional HNCM macrometastases and salvage dissection confer marked CN injury risk, whereas early surgical intervention via SLNB ± iCLND ± immediate parotidectomy yielded no CN injuries. Further, superficial parotidectomy performed in parotid-mapping HNCM does not obviate delayed intraparotid recurrences, which increase risk of CN VII injury. Despite lack of a published disease-specific survival advantage in melanoma, early disease control in cervical and parotid basins is paramount to minimize CN complications. LEVEL OF EVIDENCE: 4 (retrospective case series) Laryngoscope, 2019.

2.
Birth Defects Res ; 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31328417

RESUMO

BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a multisite, population-based, case-control study of genetic and nongenetic risk factors for major structural birth defects. Eligible women had a pregnancy affected by a birth defect or a liveborn child without a birth defect between 1997 and 2011. They were invited to complete a telephone interview to collect pregnancy exposure data and were mailed buccal cell collection kits to collect specimens from themselves, their child (if living), and their child's father. Over 23,000 families representing more than 30 major structural birth defects provided DNA specimens. METHODS: To evaluate their utility for exome sequencing (ES), specimens from 20 children with colonic atresia were studied. Evaluations were conducted on specimens collected using cytobrushes stored and transported in open versus closed packaging, on native genomic DNA (gDNA) versus whole genome amplified (WGA) products and on a library preparation protocol adapted to low amounts of DNA. RESULTS: The DNA extracted from brushes in open packaging yielded higher quality sequence data than DNA from brushes in closed packaging. Quality metrics of sequenced gDNA were consistently higher than metrics from corresponding WGA products and were consistently high when using a low input protocol. CONCLUSIONS: This proof-of-principle study established conditions under which ES can be applied to NBDPS specimens. Successful sequencing of exomes from well-characterized NBDPS families indicated that this unique collection can be used to investigate the roles of genetic variation and gene-environment interaction effects in birth defect etiologies, providing a valuable resource for birth defect researchers.

3.
Hum Mutat ; 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215115

RESUMO

Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.

4.
Otolaryngol Clin North Am ; 52(4): 703-712, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078307

RESUMO

Laryngeal mucosal precursor lesions represent a challenging clinical entity. Updated classification systems allow for grade-based categorization. Multiple management options exist, with treatment decisions made jointly by physician and patient and focused on both appropriate lesion treatment and preservation of laryngeal structure and function. Traditional methods include cold steel and CO2 laser excision, with newer modalities using angiolytic lasers for lesion ablation. Both operating room-based and office-based treatment options exist, and there are advantages and disadvantages to each approach. Research is ongoing to advance the understanding of lesion biology, and to optimize prevention and treatment.

5.
ACS Nano ; 13(6): 6522-6530, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31091074

RESUMO

Multifunctional metal nanoparticles (NPs) such as anisotropic multimetallic NPs are crucial for boosting nanomaterial-based applications. Advanced synthetic protocols exist to make a large variety of such nanostructures. However, a major limiting factor for the usability of them in real life applications is their stability. Here, we show that Au/Pd octopods, eight-branched nanocrystals with O h symmetry, with only a low amount of Pd exhibited a high thermal stability and maintained strong plasmon resonances up to 600 °C. Furthermore, we study the influence of the composition, morphology, and environment on the thermal stability and define key parameters for the design of thermally stable multifunctional NPs.

7.
Ann Surg Oncol ; 26(8): 2542-2548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30830535

RESUMO

BACKGROUND: Indications for and efficacy of paratracheal nodal dissection (PTND) in patients undergoing laryngectomy (salvage) for persistent or recurrent laryngeal squamous cell carcinoma are not well-defined. METHODS: A retrospective cohort study was performed for patients undergoing salvage laryngectomy with clinically and radiographically negative neck disease between 1998 and 2015 (n = 210). Univariate and multivariate Cox regression analyses were performed. RESULTS: PTND was performed on 77/210 patients (36%). The PTND cohort had a greater proportion of advanced T classification (rT3/rT4) tumors (78%) than subjects without PTND (55%; p = 0.001). There was a 14% rate of occult nodal metastases in the paratracheal basin; of these, 55% did not have pathologic lateral neck disease. Multivariate analysis controlling for tumor site, tumor stage, and pathologic lateral neck disease demonstrated that PTND was associated with improved overall survival [OS] (p = 0.03; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.38-0.96), disease-free survival [DFS] (p = 0.03; HR 0.55, 95% CI 0.31-0.96), and distant DFS survival (p = 0.01; HR 0.29, 95% CI 0.11-0.77). The rate of hypocalcemia did not differ between subjects who underwent bilateral PTND, unilateral PTND, or no PTND (p = 0.19 at discharge, p = 0.17 at last follow-up). CONCLUSIONS: PTND at the time of salvage laryngectomy was more common in patients with rT3/rT4 tumors and was associated with improved OS and DFS, with no effect on hypocalcemia. In patients undergoing PTND, the finding of occult paratracheal metastases was often independent of lateral neck metastases.

8.
Hum Genet ; 138(3): 257-269, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30806792

RESUMO

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%). No causative mutation is identified in up to 30% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring-Opitz, Kabuki and Wiedemann-Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.


Assuntos
Estudos de Associação Genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Sequenciamento Completo do Exoma , Proteína de Ligação a CREB/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Proteína p300 Associada a E1A/genética , Epigênese Genética , Facies , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fenótipo
9.
Am J Hum Genet ; 104(2): 246-259, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30661772

RESUMO

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.

10.
Laryngoscope ; 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30693523

RESUMO

OBJECTIVES: Surgical repair of persistent tracheocutaneous fistula in children may be complicated by tracheal air leak with resultant subcutaneous emphysema, pneumomediastinum, and/or pneumothorax. We first sought to identify clinical risk factors for postoperative complications after primary repair of persistent tracheocutaneous fistula in children. Second, the type and frequency of complications in patients administered positive airway pressure ventilation (e.g., bag-valve mask ventilation, continuous positive airway pressure [CPAP], or bilevel positive airway pressure [BiPAP]) postoperatively was determined and compared to a control population. METHODS: This was a retrospective investigation of all pediatric patients (n = 108) undergoing surgical repair of persistent tracheocutaneous fistula from January 2000 and April 2016 at a tertiary, academic referral center. Type and frequency of postoperative complications were compared among patients who were administered positive airway pressure ventilation postoperatively versus those who were not. RESULTS: Of 108 pediatric patients, complications after tracheocutaneous fistula repair occurred in 22 (20.4%) patients. These included symptoms of respiratory distress requiring intervention (e.g., supplemental O2 , racemic epinephrine, intubation), subcutaneous emphysema, pneumomediastinum and/or pneumothorax, bleeding, wound infection, and readmission. Frequency of all postoperative complications was significantly higher in patients administered positive airway pressure ventilation versus those who were not (50.0% vs. 16.7%, P = 0.015), as were rates of subcutaneous emphysema, pneumomediastinum, and/or pneumothorax (33.3% vs. 4.2%, P = 0.005). CONCLUSION: Positive airway pressure ventilation after primary repair of persistent tracheocutaneous fistula in children may increase risk of serious respiratory complications. In practice, we advocate for avoidance of bag-valve mask ventilation and caution when utilizing CPAP or BiPAP postoperatively in these patients. LEVEL OF EVIDENCE: 4. Laryngoscope, 2019.

11.
Head Neck ; 41(2): 423-428, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30548484

RESUMO

BACKGROUND: We sought to describe targeted DNA sequencing data of persistent/recurrent laryngeal squamous cell carcinoma (LSCC) and to compare gene-specific alteration frequencies with that of primary, untreated LSCC specimens from The Cancer Genome Atlas (TCGA). METHODS: The tumors of 21 patients with persistent/recurrent LSCC were subjected to targeted DNA sequencing using the Ion AmpliSeq Comprehensive Cancer Panel. Gene-specific alteration frequencies were compared (Chi-Square test) to primary, untreated LSCC sequencing data from TCGA using the cBioPortal platform. RESULTS: Persistent/recurrent LSCC was characterized by a high rate of inactivating alterations in TP53 (38.1%) and CDKN2A (33%), amplification events of CCND1 (19.1%), and ERBB2 (14.3%), and NOTCH1 (19.1%) mutations. Comparison of primary vs persistent/recurrent LSCC revealed significant differences in alteration frequencies of eight critical genes: BAP1, CDKN2A, DCUN1D1, MSH2, MTOR, PIK3CA, TET2, and TP53. CONCLUSIONS: Our results provide preliminary support for a distinct mutational profile of persistent/recurrent LSCC that requires validation in larger cohorts.

12.
Nanoscale ; 11(2): 512-519, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30543237

RESUMO

Nanostructures with well-defined crystallite sizes, shapes, and compositions are finding use in areas such as energy, security, and even medicine. Seeded growth is a promising strategy to achieve shape-controlled nanostructures, where specific structural features are often directed by the underlying symmetry of the seeds. Here, thiophenol derivatives capable of different metal-thiolate interactions were introduced into the synthesis of Au/Pd nanostructures by seed-mediated co-reduction. Our systematic analysis reveals that the symmetry and composition of the bimetallic nanoparticles (NPs) can be tuned as a function of additive binding strength and concentration, with symmetry reduction observed in some cases. Furthermore, additives with both thiol and amine functionalities facilitate random branching on the octahedral seed. Significantly, this synthetic versatility arises because the thiophenol derivatives modify both the surface capping of the growing nanostructures and the local ligand environment of the metal precursors, highlighting how the dual roles of synthesis components can be exploited to achieve high quality bimetallic nanostructures.

13.
Nat Genet ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510241

RESUMO

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30361882

RESUMO

BACKGROUND: Recurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4+, CD8+ and/or CD103+ TIL status in patients with advanced LSCC. METHODS: Tissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4+, CD8+, and CD103+ TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4+, CD8+, and CD103+ TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC. RESULTS: High tumor CD103+ TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8+ or CD4+ TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103+ and CD4+ TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC. CONCLUSIONS: An immune profile driven by CD103+ TIL content, alone and in combination with CD4+ TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.

15.
Am J Hum Genet ; 102(6): 1143-1157, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29805042

RESUMO

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.

16.
PLoS Genet ; 14(3): e1007293, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29590102

RESUMO

Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (-α3.7 deletion) and ß-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the -α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the -α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the -α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the -α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and ß-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.


Assuntos
Anemia Falciforme/genética , Hemoglobina Falciforme/genética , Traço Falciforme , alfa-Globinas/genética , Adulto , Afro-Americanos , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Estudos de Coortes , Variações do Número de Cópias de DNA , Eritrócitos Anormais , Taxa de Filtração Glomerular , Hemoglobina A Glicada/metabolismo , Humanos , Fenótipo , Adulto Jovem , Talassemia alfa/genética
17.
Head Neck ; 40(5): 943-954, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29427520

RESUMO

BACKGROUND: The past 2 decades have seen an increased incidence of head and neck squamous cell carcinoma (HNSCC) in a nontraditional, low-risk patient population (ie, ≤45 years of age, no substance use history), owing to a combination of human papillomavirus (HPV) infection and individual genetic variation. METHODS: Articles positing genetic variants as contributing factors in HNSCC incidence in low-risk, nontraditional patients were identified using a PubMed search, reviewed in detail, and concisely summarized herein. RESULTS: Recent data suggest that common polymorphisms in DNA repair enzymes, cell-cycle control proteins, apoptotic pathway members, and Fanconi anemia-associated genes likely modulate susceptibility to HNSCC development in low-risk, nontraditional patients. CONCLUSION: At present, there is a lack of robust, comprehensive data on genetic drivers of oncogenesis in low-risk patients and a clear need for further research on genetic alterations underlying the rising incidence of HNSCC in low-risk, nontraditional patients.

18.
Am J Med Genet A ; 176(2): 290-300, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29168297

RESUMO

We report RNA-Sequencing results on a cohort of patients with single suture craniosynostosis and demonstrate significant enrichment of heterozygous, rare, and damaging variants among key craniosynostosis-related genes. Genetic burden analysis identified a significant increase in damaging variants in ATR, EFNA4, ERF, MEGF8, SCARF2, and TGFBR2. Of 391 participants, 15% were found to have damaging and potentially causal variants in 29 genes. We observed transmission in 96% of the affected individuals, and thus penetrance, epigenetics, and oligogenic factors need to be considered when recommending genetic testing in patients with nonsyndromic craniosynostosis.

19.
PLoS One ; 12(11): e0186518, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29161273

RESUMO

BACKGROUND: The evaluation of less frequent genetic variants and their effect on complex disease pose new challenges for genomic research. To investigate whether epigenetic data can be used to inform aggregate rare-variant association methods (RVAM), we assessed whether variants more significantly associated with colorectal cancer (CRC) were preferentially located in non-coding regulatory regions, and whether enrichment was specific to colorectal tissues. METHODS: Active regulatory elements (ARE) were mapped using data from 127 tissues and cell-types from NIH Roadmap Epigenomics and Encyclopedia of DNA Elements (ENCODE) projects. We investigated whether CRC association p-values were more significant for common variants inside versus outside AREs, or 2) inside colorectal (CR) AREs versus AREs of other tissues and cell-types. We employed an integrative epigenomic RVAM for variants with allele frequency <1%. Gene sets were defined as ARE variants within 200 kilobases of a transcription start site (TSS) using either CR ARE or ARE from non-digestive tissues. CRC-set association p-values were used to evaluate enrichment of less frequent variant associations in CR ARE versus non-digestive ARE. RESULTS: ARE from 126/127 tissues and cell-types were significantly enriched for stronger CRC-variant associations. Strongest enrichment was observed for digestive tissues and immune cell types. CR-specific ARE were also enriched for stronger CRC-variant associations compared to ARE combined across non-digestive tissues (p-value = 9.6 × 10-4). Additionally, we found enrichment of stronger CRC association p-values for rare variant sets of CR ARE compared to non-digestive ARE (p-value = 0.029). CONCLUSIONS: Integrative epigenomic RVAM may enable discovery of less frequent variants associated with CRC, and ARE of digestive and immune tissues are most informative. Although distance-based aggregation of less frequent variants in CR ARE surrounding TSS showed modest enrichment, future association studies would likely benefit from joint analysis of transcriptomes and epigenomes to better link regulatory variation with target genes.


Assuntos
Neoplasias Colorretais/genética , Epigenômica , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Neoplasias Colorretais/patologia , Frequência do Gene , Estudo de Associação Genômica Ampla , Genômica , Humanos , Polimorfismo de Nucleotídeo Único
20.
Arterioscler Thromb Vasc Biol ; 37(11): 2220-2227, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28912365

RESUMO

OBJECTIVE: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease. APPROACH AND RESULTS: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, ß=0.284, P=3.24×10-11). The rs2022030 effect size was nearly 3× larger among women (ß=0.373, P=9.06×10-13) than among men (ß=0.135, P=0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women (P interaction =0.001). Finally, the African ancestral sickle cell variant (HBB rs334) was significantly associated with higher D-dimer in JHS (ß=0.507, P=1.41×10-14), and this association was successfully replicated in 1933 AAs (P=2.3×10-5). CONCLUSIONS: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs.


Assuntos
Afro-Americanos/genética , Doenças Cardiovasculares/genética , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hemoglobinas Anormais/genética , Traço Falciforme/genética , Tromboplastina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/mortalidade , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Fenótipo , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Traço Falciforme/sangue , Traço Falciforme/etnologia , Traço Falciforme/mortalidade , Fatores de Tempo , Estados Unidos/epidemiologia , Adulto Jovem
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