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1.
Crit Care Med ; 48(2): 142-150, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31939781

RESUMO

OBJECTIVES: Epigenetic alterations are an important regulator of gene expression in health and disease; however, epigenetic data in sepsis are lacking. To demonstrate proof of concept and estimate effect size, we performed the first epigenome-wide methylation analysis of whole blood DNA samples from a cohort of septic and nonseptic critically ill patients. DESIGN: A nested case-control study using genomic DNA isolated from whole blood from septic (n = 66) and nonseptic (n = 68) critically ill patients on "Day 1" of ICU admission. Methylation patterns were identified using Illumina 450K arrays with percent methylation expressed as ß values. After quality control, 134 participants and 414,818 autosomal cytosine-phosphate-guanine sites were used for epigenome-wide methylation analyses. SETTING: Tertiary care hospitals. SUBJECTS: Critically ill septic and nonseptic patients. INTERVENTIONS: Observational study. MEASUREMENTS AND MAIN RESULTS: A total of 668 differentially methylated regions corresponding to 443 genes were identified. Known sepsis-associated genes included complement component 3; angiopoietin 2; myeloperoxidase; lactoperoxidase; major histocompatibility complex, class I, A; major histocompatibility complex, class II, isotype DR ß I; major histocompatibility complex, class I, C; and major histocompatibility complex, class II, isotype DQ ß I. When compared with whole blood gene expression data from seven external datasets containing septic and nonseptic patients, 81% of the differentially methylated region-associated genes were differentially expressed in one or more datasets and 31% in three or more datasets. Functional analysis showed enrichment for antigen processing and presentation, methyltransferase activity, cell adhesion, and cell junctions. Analysis by weighted gene coexpression network analysis revealed DNA comethylation modules that were associated with clinical traits including severity of illness, need for vasopressors, and length of stay. CONCLUSIONS: DNA methylation marks may provide important causal and potentially biomarker information in critically ill patients with sepsis.


Assuntos
Estado Terminal , Metilação de DNA/genética , Epigênese Genética/genética , Sepse/genética , Biomarcadores , Estudos de Casos e Controles , Cromossomos Humanos Par 6/genética , Feminino , Humanos , Unidades de Terapia Intensiva , Interferons/metabolismo , Masculino , Escores de Disfunção Orgânica , Projetos Piloto , Centros de Atenção Terciária
3.
Diabetes Care ; 43(2): 418-425, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31843946

RESUMO

OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, ß [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (ß [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, ß [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Genes MHC da Classe II/genética , Genes MHC Classe I/genética , Testes Genéticos , Diabetes Autoimune Latente em Adultos/genética , Adolescente , Adulto , Idade de Início , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Cromossomos Humanos Par 6/genética , Estudos de Coortes , Diabetes Mellitus Tipo 1/classificação , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Diagnóstico Diferencial , Feminino , Estudos de Associação Genética , Testes Genéticos/métodos , Humanos , Diabetes Autoimune Latente em Adultos/classificação , Diabetes Autoimune Latente em Adultos/diagnóstico , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
4.
Nat Commun ; 10(1): 5732, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844061

RESUMO

The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as ~23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus.  Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on thegenetic determinants of malaria resistance in diverse populations.


Assuntos
Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Malária Falciparum/genética , Adulto , África/epidemiologia , Ásia/epidemiologia , Estudos de Casos e Controles , Criança , Conjuntos de Dados como Assunto , Feminino , Loci Gênicos/genética , Antígenos HLA/genética , Humanos , Malária Falciparum/epidemiologia , Masculino , Oceania/epidemiologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo de Nucleotídeo Único , Prevalência
5.
Skelet Muscle ; 9(1): 28, 2019 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-31757224

RESUMO

BACKGROUND: Low lean body mass is the most important predictor of sarcopenia with strong genetic background. The aim of this study was to uncover genetic factors underlying lean mass development. MATERIALS AND METHODS: We performed a genome-wide association study (GWAS) of fat-adjusted leg lean mass in the Framingham Heart Study (FHS, N = 6587), and replicated in the Women's Health Initiative-African American sub-sample (WHI-AA, N = 847) and the Kansas City Osteoporosis Study (KCOS, N = 2219). We also cross-validated significant variants in the publicly available body mass index (BMI) summary results (N ~ 700,000). We then performed a series of functional investigations on the identified variants. RESULTS: Four correlated SNPs at 6p21.1 were identified at the genome-wide significance (GWS, α = 5.0 × 10-8) level in the discovery FHS sample (rs551145, rs524533, rs571770, and rs545970, p = 3.40-9.77 × 10-9), and were successfully replicated in both the WHI-AA and the KCOS samples (one-sided p = 1.61 × 10-3-0.04). They were further cross-validated by the large-scale BMI summary results (p = 7.0-9.8 × 10-3). Cis-eQTL analyses associated these SNPs with the NFKBIE gene expression. Electrophoresis mobility shift assay (EMSA) in mouse C2C12 myoblast cells implied that rs524533 and rs571770 were bound to an unknown transcription factor in an allelic specific manner, while rs551145 and rs545970 did not. Dual-luciferase reporter assay revealed that both rs524533 and rs571770 downregulated luciferase expression by repressing promoter activity. Moreover, the regulation pattern was allelic specific, strengthening the evidence towards their differential regulatory effects. CONCLUSIONS: Through a large-scale GWAS followed by a series of functional investigations, we identified 2 correlated functional variants at 6p21.1 associated with leg lean mass. Our findings not only enhanced our understanding of molecular basis of lean mass development but also provided useful candidate genes for further functional studies.


Assuntos
Cromossomos Humanos Par 6/genética , Polimorfismo de Nucleotídeo Único , Sarcopenia/genética , Magreza/genética , Idoso , Animais , Índice de Massa Corporal , Linhagem Celular , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteínas I-kappa B/genética , Desequilíbrio de Ligação , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Locos de Características Quantitativas , Sarcopenia/patologia , Magreza/patologia
6.
BMC Cancer ; 19(1): 769, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382924

RESUMO

BACKGROUND: ROS1 rearrangements are validated drivers in lung cancer, which have been identified in a small subset (1-2%) of patients with non-small cell lung cancer (NSCLC). To date, 18 fusion genes of ROS1 have been identified in NSCLC. The ALK inhibitor (crizotinib) exhibits therapeutic effect against ROS1-rearranged NSCLC. Next-generation sequencing (NGS) technology represents a novel tool for ROS1 detection that covers many fusion genes. CASE PRESENTATION: A 55-year-old female with EGFR mutation (L858R) was diagnosed with lung adenocarcinoma, who was responsive to first-generation EGFR-tyrosine kinase inhibitor (TKI). Afterwards, she developed acquired resistance accompanied with a ROS1 rearrangement. A NGS assay showed that the tumor had a novel ROS1-ADGRG6 rearrangement generated by the fusion of exons of 1-33 of ROS1 on chr6: q22.1 to exons of 2-26 of ADGRG6 on chr6: q24.2. The patient was obviously responsive to crizotinib. CONCLUSION: We firstly identified ROS1-ADGRG6 fusion variant in NSCLC by NGS, which should be considered in further ROS1 detecting assays.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Cromossomos Humanos Par 6/genética , Crizotinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Éxons/genética , Feminino , Seguimentos , Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Medicina de Precisão , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Resultado do Tratamento
7.
Gene ; 715: 143957, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276734

RESUMO

MPIG6B has orthologous physiological effects in human and mice, which regulates platelet production and function. For this reason, germline loss-of-function mutations in this gene cause congenital thrombocytopenia that is associated with bone marrow fibrosis, organomegaly and subsequent anemia. This was described in a consanguineous Arabian family with a novel truncation mutation (p.C108*) in chromosome 6, open reading frame 25 gene, also known as MPIG6B. In our case, we identified a homozygous frameshift variation (c.392delC,p.P134Lfs*10) in a ten-month-old boy presenting with signs of pallor, splenomegaly and resistant hemocytopenia. Interestingly, this is a new form of a MPIG6B variation, which could disrupt the effector protein for the key hematopoiesis regulators. This report adds to the growing number of mutations causing complex clinical manifestations associated with pancytopenia and splenomegaly in children.


Assuntos
Cromossomos Humanos Par 6/genética , Mutação da Fase de Leitura , Fases de Leitura Aberta , Pancitopenia/genética , Esplenomegalia/genética , Grupo com Ancestrais do Continente Asiático , Humanos , Lactente , Masculino , Pancitopenia/patologia , Esplenomegalia/patologia
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 682-685, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302910

RESUMO

OBJECTIVE: To make molecular diagnosis of an infant affected with severe developmental delay and multiple birth defects, assisting prenatal diagnosis for the second pregnancy. METHODS: Standard G-banded karyotyping was performed for the fetus and his parents. Single nucleotide polymorphism array (SNP array) was used to detect submicroscopic chromosomal aberration. Fluorescence in situ hybridization (FISH) was employed to determine the parental origin of the aberration. RESULTS: Both the proband and the fetus harbored a 5.4 Mb distal 4p deletion and a 6.9 Mb distal 6q duplication. FISH confirmed that the mother has carried a balanced translocation involving 4p and 6q. CONCLUSION: The unbalanced chromosomal aberration in the proband and the fetus were both derived from the mother. Both patients showed a Wolf-Hirschhorn syndrom phenotype and partial phenotype of 6q trisomy. SNP array combined with FISH are essential for the detection of cryptic chromosomal aberrations which may be missed by coventional karyotyping analysis.


Assuntos
Diagnóstico Pré-Natal , Translocação Genética , Síndrome de Wolf-Hirschhorn/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 6/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Linhagem , Gravidez
9.
Anticancer Res ; 39(6): 2861-2869, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177124

RESUMO

BACKGROUND/AIM: PON1 gene has an executive role in antioxidant defense, protecting cells from genotoxic factors. Q192R and L55M PON1 polymorphisms reduce catalytic activity of the encoded protein. These polymorphisms were studied in 300 chronic lymphocytic leukemia (CLL) patients and 106 healthy donors. They were also associated with patients' cytogenetic findings, to investigate their possible implication in CLL pathogenesis. MATERIALS AND METHODS: SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Karyotypic analysis was also performed by chromosome G-banding analysis and fluorescence in situ hybridization. RESULTS: Genotypic and allelic distribution of Q192R polymorphism showed a statistically significant higher frequency of mutant genotypes and mutant alleles in patients compared to controls. The same observation was noted in patients with abnormal karyotypes and those carrying abn14q32 and del(6q). A statistically increased frequency for the mutant allele was also revealed in patients with del(11q). On the contrary, L55M polymorphism showed a similar distribution between patients and controls. CONCLUSION: Q192R polymorphism plays a role in CLL predisposition and the formation of specific chromosomal aberrations.


Assuntos
Arildialquilfosfatase/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 6/genética , Leucemia Linfocítica Crônica de Células B/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Aberrações Cromossômicas , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade
10.
Nat Commun ; 10(1): 1653, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971697

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Células Dendríticas/patologia , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Proliferação de Células/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Humanos , Células Jurkat , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Translocação Genética/genética , Irradiação Corporal Total
11.
Neuropathology ; 39(2): 97-105, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30856298

RESUMO

Subependymomas of the spinal cord are rare, do not often involve multiple levels, and very rarely recur. Here, we present a series of spinal cord subependymomas with a detailed description of the clinical, radiological and pathological features, and characterization by chromosomal microarray analysis. Briefly, the four patients included two men and two women, between the ages of 22 and 48 years. The most common presenting symptoms were neck and arm pain with upper extremity weakness. By imaging, the tumors were found to involve multiple spinal levels, including cervical/ cervico-thoracic (three patients) and thoracic (one patient), were all eccentric, and had minimal to no post-contrast enhancement. Two patients underwent gross total resection, one had a sub-total resection, and one underwent biopsy alone with a decompressive laminectomy. Follow up ranged from 6 months to 22 years. One patient (case 4) had recurrence 15 years following gross total resection and chromosomal microarray analysis revealed deletions on the long arm of chromosome 6. Our limited series suggests that spinal cord subependymomas can rarely recur, even following gross total resection, suggesting a possible role for long-term surveillance for these rare tumors.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 6/genética , Glioma Subependimal/genética , Glioma Subependimal/patologia , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/patologia , Adulto , Feminino , Deleção de Genes , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Adulto Jovem
12.
Morphologie ; 103(341 Pt 2): 116-121, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30885456

RESUMO

The 6p terminal deletions are rare and usually early diagnosed because of their association with eye and cranio-facial anomalies, particularly as part of Axenfeld-Rieger syndrome in relation with the haploinsufficiency of FOXC1 gene. Deletions in the 22q11 region are frequent, highly correlated with DiGeorge syndrome also named CATCH22, and may be associated with many clinical features of various severities. We report a 31-year-old man with an unbalanced 45,XY,der(6)t(6;22)(p25;q11.2),-22 karyotype leading to monosomies in both 6p25 and 22q11 regions, confirmed by FISH and array-CGH. The length of the deletions was respectively 770 Kb for 6pter and 2.9 Mb for 22q11. This karyotype was discovered at adult age following problems of fertility. The chromosomal formula was unexpected, regarding the patient's medical history and clinical features. This case makes a great example of the difficulties to correlate genotype and phenotype, and furthermore demonstrates the complexity of genetic counselling even in a case with two different chromosomal unbalances.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 6/genética , Fenótipo , Translocação Genética , Adulto , Humanos , Infertilidade Masculina/genética , Cariotipagem , Masculino
13.
Pediatr Neurosurg ; 54(3): 196-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30889612

RESUMO

Developmental dolichoectasia of the intracranial vessels is a rare occurrence. The authors report 2 sibling pediatric patients who were born with 6p25.3 deletion, associated with carotid and vertebrobasilar dolichoectasia. MRI imaging of both children showed asymptomatic elongation and dilation of the vertebrobasilar system and "kissing" carotid arteries. A microarray analysis was also performed for both patients, which identified a 1.5-Mb deletion of 6p25.3 covering 15 genes including FOXC1, which has been implicated in defects in vascular morphogenesis.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Deficiências do Desenvolvimento/genética , Insuficiência Vertebrobasilar/genética , Adolescente , Artéria Basilar/patologia , Artérias Carótidas/patologia , Criança , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Análise em Microsséries , Fenótipo , Insuficiência Vertebrobasilar/diagnóstico por imagem
14.
Mol Genet Genomic Med ; 7(3): e553, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30693664

RESUMO

BACKGROUND: Several genome-wide association studies already explored the associations between 6q25.1 rs2046210 polymorphism and breast cancer (BC), but the results of these studies were not consistent. Thus, we conducted a meta-analysis of relevant studies to better analyze the effects of rs2046210 polymorphism on individual susceptibility to BC. METHODS: PubMed, Web of Science, and Embase were searched for eligible studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Totally 21 studies with 261,703 subjects were analyzed. A significant association with BC was observed for the rs2046210 polymorphism in GG versus GA +AA (dominant comparison, p < 0.0001, OR = 0.78, 95% CI 0.73-0.83), AA versus GG + GA (recessive comparison, p < 0.0001, OR = 1.21, 95% CI 1.18-1.24), GA versus GG + AA (overdominant comparison, p < 0.0001, OR = 1.12, 95% CI 1.08-1.16), and G versus A (allele comparison, p < 0.0001, OR = 0.86, 95% CI 0.82-0.89). Further subgroup analyses yielded similar positive results in both Asians and Caucasians. CONCLUSION: In summary, our findings suggested that the rs2046210 polymorphism may serve as a potential genetic biomarker of BC in both Asians and Caucasians.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Polimorfismo Genético , Feminino , Humanos
16.
Breast Cancer Res ; 21(1): 3, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642363

RESUMO

BACKGROUND: Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas. METHODS: We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach. RESULTS: We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10- 8 - 6.0 × 10- 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017). CONCLUSION: Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Idoso , Mama , Estudos de Casos e Controles , Mapeamento Cromossômico , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
17.
Br J Haematol ; 184(3): 405-417, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30450575

RESUMO

Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9·37 × 10-6 ) and TAP2 (P = 1·59 × 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hipersensibilidade a Drogas/genética , Predisposição Genética para Doença , Variação Genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Asparaginase/administração & dosagem , Criança , Pré-Escolar , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 6/genética , Feminino , Estudo de Associação Genômica Ampla , Antígenos HLA-DQ/genética , Humanos , Lactente , Masculino , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fatores de Transcrição/genética
18.
Congenit Anom (Kyoto) ; 59(5): 174-178, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30225942

RESUMO

Here, we report a patient with ring chromosome 6 [r(6)], associated with anterior segment dysgenesis (ASD) and other anomalies. The phenotype was due to a 1880 kb microdeletion at 6p25.3 identified by whole-genome array analysis, and was mainly attributable to a FOXC1 haploinsufficiency. Currently 37 patients with r(6) have been reported. We found that facial dysmorphism, ASD, heart anomalies, brain anomalies, and hearing loss are constant features only in severe cases of r(6), mainly related to hemizygosity of FOXC1. Thus, overlaps with other FOXC1 related phenotypes, such as the 6p25 deletion syndrome, Axenfeld-Rieger syndrome type 3, and ASD type 3. Contrarily, those patients whose r(6) does not disrupt FOXC1, have mild or moderate phenotypes and do not exhibit ASD.


Assuntos
Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Fatores de Transcrição Forkhead/genética , Deleção de Genes , Fenótipo , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Feminino , Humanos , Recém-Nascido , Cariótipo , Masculino , Cromossomos em Anel , Adulto Jovem
19.
Am J Hum Genet ; 104(1): 157-163, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30583798

RESUMO

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10-14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Disfunção Erétil/etiologia , Disfunção Erétil/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hipotálamo/patologia , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cromossomos Humanos Par 6/genética , Simulação por Computador , Europa (Continente) , Humanos , Masculino , Proteínas Repressoras/genética
20.
Schizophr Bull ; 45(1): 222-232, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29474680

RESUMO

Genetic factors are known to influence both risk for schizophrenia (SZ) and variation in brain structure. A pressing question is whether the genetic underpinnings of brain phenotype and the disorder overlap. Using multivariate analytic methods and focusing on 1,402 common single-nucleotide polymorphisms (SNPs) mapped from the Psychiatric Genomics Consortium (PGC) 108 regions, in 777 discovery samples, we identified 39 SNPs to be significantly associated with SZ-discriminating gray matter volume (GMV) reduction in inferior parietal and superior temporal regions. The findings were replicated in 609 independent samples. These 39 SNPs in chr6:28308034-28684183 (6p22.1), the most significant SZ-risk region reported by PGC, showed regulatory effects on both DNA methylation and gene expression of postmortem brain tissue and saliva. Furthermore, the regulated methylation site and gene showed significantly different levels of methylation and expression in the prefrontal cortex between cases and controls. In addition, for one regulated methylation site we observed a significant in vivo methylation-GMV association in saliva, suggesting a potential SNP-methylation-GMV pathway. Notably, the risk alleles inferred for GMV reduction from in vivo imaging are all consistent with the risk alleles for SZ inferred from postmortem data. Collectively, we provide evidence for shared genetic risk of SZ and regional GMV reduction in 6p22.1 and demonstrate potential molecular mechanisms that may drive the observed in vivo associations. This study motivates dissecting SZ-risk variants to better understand their associations with focal brain phenotypes and the complex pathophysiology of the illness.


Assuntos
Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença/genética , Substância Cinzenta/patologia , Lobo Parietal/patologia , Córtex Pré-Frontal/patologia , Transtornos Psicóticos/genética , Transtornos Psicóticos/patologia , Esquizofrenia/genética , Esquizofrenia/patologia , Adolescente , Adulto , Feminino , Estudos de Associação Genética , Substância Cinzenta/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Parietal/diagnóstico por imagem , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/diagnóstico por imagem , Transtornos Psicóticos/diagnóstico por imagem , Risco , Esquizofrenia/diagnóstico por imagem , Adulto Jovem
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