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1.
Chem Sci ; 8(4): 2923-2930, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28451358

RESUMO

Tools for editing the genome and epigenome have revolutionised the field of molecular biology and represent a new frontier in targeted therapeutic intervention. Although efficiencies and specificities of genome editing technologies have improved with the development of TALEs and CRISPR platforms, intracellular delivery of these larger constructs still remains a challenge using existing delivery agents. Viral vectors, including lentiviruses and adeno-associated viruses, as well as some non-viral strategies, such as cationic polymers and liposomes, are limited by packaging capacity, poor delivery, toxicity, and immunogenicity. We report a highly controlled synthetic strategy to engineer a flexible dendritic polymer using click chemistry to overcome the aforementioned delivery challenges associated with genome engineering technologies. Using a systematic approach, we demonstrate that high transfection efficiencies and packaging capacity can be achieved using this non-viral delivery methodology to deliver zinc fingers, TALEs and CRISPR/dCas9 platforms.

2.
Nat Genet ; 45(7): 804-7, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23749188

RESUMO

To identify genetic risk factors underlying non-Hodgkin lymphomas (NHLs) from the B cell lineage, we conducted a genome-wide association study (GWAS) of 253 Chinese individuals with B cell NHL (cases) and 1,438 controls and further validation in 1,175 cases and 5,492 controls. We identified a new susceptibility locus, rs6773854, located between BCL6 (encoding B cell lymphoma protein 6) and LPP (encoding lipoma preferred partner) on oncogene-rich chromosome 3q27 that was significantly associated with increased risk of B cell NHL (meta-analysis P = 3.36 × 10⁻¹³, per-allele odds ratio (OR) = 1.44) and with diffuse large B cell lymphoma (DLBCL) in particular (meta-analysis P = 1.14 × 10⁻¹¹, OR = 1.47). We found no evidence of association of rs6773854 with non-B cell NHLs (T cell and natural killer (NK) lineages) (P = 0.17, OR = 1.12) and observed significant heterogeneity between B cell and non-B cell subtypes (Phet = 0.01, I² = 84%). Our results provide insight that germline variation in the intergenic region between BCL6 and LPP has a role in risk of B cell lymphomagenesis.


Assuntos
Cromossomos Humanos Par 3/genética , Loci Gênicos , Predisposição Genética para Doença , Linfoma de Células B/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Linfoma de Células B/etnologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , Estudos de Validação como Assunto , Adulto Jovem
3.
Nat Genet ; 43(12): 1241-6, 2011 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-22081228

RESUMO

Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 individuals with Kawasaki disease and 9,383 controls from five independent sample collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274; P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B; P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.


Assuntos
Predisposição Genética para Doença , Síndrome de Linfonodos Mucocutâneos/genética , Receptores de IgG/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Loci Gênicos , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Desequilíbrio de Ligação , Família Multigênica , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal
4.
Nat Genet ; 43(11): 1139-41, 2011 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-22001756

RESUMO

Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, P(meta) = 4.41 × 10(-11), per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23-1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, P(meta) = 3.08 × 10(-10), per-allele OR = 0.80 (95% confidence interval: 0.75-0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.


Assuntos
Estudo de Associação Genômica Ampla , Antígenos de Histocompatibilidade Classe I/genética , Fosfoinositídeo Fosfolipase C/genética , Estudos de Casos e Controles , Humanos , Polimorfismo de Nucleotídeo Único
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