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1.
Front Immunol ; 10: 2160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695690

RESUMO

Background: Ninety percent of systemic lupus erythematosus (SLE) patients are women. X chromosome-dosage increases susceptibility to SLE and primary Sjögren's syndrome (pSS). Chromosome X open reading frame 21 (CXorf21) escapes X-inactivation and is an SLE risk gene of previously unknown function. We undertook the present study to delineate the function of CXorf21 in the immune system as well as investigate a potential role in the sex bias of SLE and pSS. Methods: Western blot protein analysis, qPCR, BioPlex cytokine immunoassay, pHrodo™ assays, as well as in vitro CRISPR-Cas9 knockdown experiments were employed to delineate the role of CXorf21 in relevant immunocytes. Results: Expressed in monocytes and B cells, CXorf21 basal Mrna, and protein expression levels are elevated in female primary monocytes, B cells, and EBV-transformed B cells compared to male cells. We also found CXorf21 mRNA and protein expression is higher in both male and female cells from SLE patients compared to control subjects. TLR7 ligation increased CXorf21 protein expression and CXorf21 knockdown abrogated TLR7-driven increased IFNA1 mRNA expression, and reduced secretion of both TNF-alpha and IL-6 in healthy female monocytes. Similarly, we found increased pH in the lysosomes of CXorf21-deficient female monocytes. Conclusion: CXorf21 is more highly expressed in female compared to male cells and is involved in a sexually dimorphic response to TLR7 activation. In addition, CXorf21 expression regulates lysosomal pH in a sexually dimorphic manner. Thus, sexually dimorphic expression of CXorf21 skews cellular immune responses in manner consistent with expected properties of a mediator of the X chromosome dose risk in SLE and pSS.

2.
BMC Med ; 17(1): 135, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31311600

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. METHODS: First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). RESULTS: Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10- 20). This effect was consistent in both pediatric (p = 9.92 × 10- 6) and adult (p = 9.73 × 10- 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10- 8, beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10- 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10- 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10- 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses. CONCLUSIONS: In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings.


Assuntos
Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Redes Comunitárias/organização & administração , Redes Comunitárias/estatística & dados numéricos , Progressão da Doença , Registros Eletrônicos de Saúde/organização & administração , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/organização & administração , Genômica/estatística & dados numéricos , Humanos , Lipase/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Morbidade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética
3.
Front Immunol ; 10: 578, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001245

RESUMO

Background: CXorf21 and SLC15a4 both contain risk alleles for systemic lupus erythematosus (SLE) and Sjögren's syndrome (pSS). The former escapes X inactivation. Our group predicts specific endolysosomal-dependent immune responses are driven by the protein products of these genes, which form a complex at the endolysosomal surface. Our previous studies have shown that knocking out CXorf21 increases lysosomal pH in female monocytes, and the present study assesses whether the lysosomal pH in 46,XX women, who overexpress CXorf21 in monocytes, B cells, and dendritic cells (DCs), differs from 46,XY men. Methods: To determine endolysosome compartment pH we used both LysoSensor™ Yellow/Blue DND-160 and pHrodo® Red AM Intracellular pH Indicator in primary monocyte, B cells, DCs, NK cells, and T cells from healthy men and women volunteers. Results: Compared to male samples, female monocytes, B cells, and DCs had lower endolysosomal pH (female/male pH value: monocytes 4.9/5.6 p < 0.0001; DCs 4.9/5.7 p = 0.044; B cells 5.0/5.6 p < 0.05). Interestingly, T cells and NK cells, which both express low levels of CXorf21, showed no differential pH levels between men and women. Conclusion: We have previously shown that subjects with two or more X-chromosomes have increased CXorf21 expression in specific primary immune cells. Moreover, knockdown of CXorf21 increases lysosomal pH in female monocytes. The present data show that female monocytes, DC, B cells, where CXorf21 is robustly expressed, have lower lysosomal pH compared to the same immune cell populations from males. The lower pH levels observed in specific female immune cells provide a function to these SLE/SS-associated genes and a mechanism for the reported inflated endolysosomal-dependent immune response observed in women compared to men (i.e., TLR7/type I Interferon activity).

4.
JCI Insight ; 2(5): e91288, 2017 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-28289719

RESUMO

Preterm birth (PTB) is a leading worldwide cause of morbidity and mortality in infants. Maternal inflammation induced by microbial infection is a critical predisposing factor for PTB. However, biological processes associated with competency of pathogens, including viruses, to induce PTB or sensitize for secondary bacterial infection-driven PTB are unknown. We show that pathogen/pathogen-associated molecular pattern-driven activation of type I IFN/IFN receptor (IFNAR) was sufficient to prime for systemic and uterine proinflammatory chemokine and cytokine production and induction of PTB. Similarly, treatment with recombinant type I IFNs recapitulated such effects by exacerbating proinflammatory cytokine production and reducing the dose of secondary inflammatory challenge required for induction of PTB. Inflammatory challenge-driven induction of PTB was eliminated by defects in type I IFN, TLR, or IL-6 responsiveness, whereas the sequence of type I IFN sensing by IFNAR on hematopoietic cells was essential for regulation of proinflammatory cytokine production. Importantly, we also show that type I IFN priming effects are conserved from mice to nonhuman primates and humans, and expression of both type I IFNs and proinflammatory cytokines is upregulated in human PTB. Thus, activation of the type I IFN/IFNAR axis in pregnancy primes for inflammation-driven PTB and provides an actionable biomarker and therapeutic target for mitigating PTB risk.

5.
PLoS One ; 9(12): e115614, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25545785

RESUMO

UNLABELLED: To explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population. METHODS: Principal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed. RESULTS: Three subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non-inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18×10(-7), OR = 1.18, 95%CI = 1.10-1.26). CONCLUSION: Our results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus.


Assuntos
Cromossomos Humanos Par 8/genética , Lúpus Eritematoso Sistêmico/genética , Inversão de Sequência , Quinases da Família src/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Feminino , Loci Gênicos , Haplótipos , Homozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estados Unidos
6.
Am J Hum Genet ; 94(4): 586-98, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24702955

RESUMO

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Regiões Promotoras Genéticas , Transcrição Genética , Quinases da Família src/genética , Alelos , Cromossomos Humanos Par 8 , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
7.
Front Genet ; 5: 450, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25620976

RESUMO

Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3' UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10(-10), OR 0.81 (0.75-0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.

8.
Hepatology ; 59(5): 1830-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24115079

RESUMO

UNLABELLED: Inflammation plays a central pathogenic role in the pernicious metabolic and end-organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)-17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL-17RA signaling in the progression of NAFLD. We further examined whether microbe-driven IL-17A regulated NAFLD development and progression. We show here that IL-17RA(-/-) mice respond to high-fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild-type controls. However, obesity-driven lipid accumulation was uncoupled from its end-organ consequences in IL-17RA(-/-) mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme expression, and hepatocellular damage. Neutralization of IL-17A significantly reduced obesity-driven hepatocellular damage in wild-type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL-17A production, exacerbated obesity-induced hepatocellular damage. In contrast, SFB depletion protected from obesity-induced hepatocellular damage. CONCLUSION: These data indicate that obesity-driven activation of the IL-17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL-17 pathway as a novel therapeutic target in this condition.


Assuntos
Fígado Gorduroso/etiologia , Interleucina-17/fisiologia , Transdução de Sinais/fisiologia , Animais , Infecções Bacterianas/complicações , Dieta Hiperlipídica , Progressão da Doença , Fígado Gorduroso/microbiologia , Inflamação/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , Espécies Reativas de Oxigênio/metabolismo , Receptores de Interleucina-17/fisiologia
9.
Int J Rheum Dis ; 16(6): 674-80, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24330273

RESUMO

AIM: Prolidase deficiency is a rare autosomal recessive disease in which one of the last steps of collagen metabolism, cleavage of proline-containing dipeptides, is impaired. Only about 93 patients have been reported with about 10% also having systemic lupus erythematosus (SLE). METHODS: We studied a large extended Amish pedigree with four prolidase deficiency patients and three heterozygous individuals for lupus-associated autoimmunity. Eight unaffected Amish children served as normal controls. Prolidase genetics and enzyme activity were confirmed. Antinuclear antibodies (ANA) were determined using indirect immunofluorescence and antibodies against extractable nuclear antigens were determined by various methods, including double immunodiffusion, immunoprecipitation and multiplex bead assay. Serum C1q levels were determined by enzyme-linked immunosorbent assay. RESULTS: Two of the four homozygous prolidase deficiency subjects had a positive ANA. One had anti-double-stranded DNA, while another had precipitating anti-Ro. By the simultaneous microbead assay, three of the four had anti-Sm and anti-chromatin. One of the three heterozygous subjects had a positive ANA and immunoprecipitation of a 75 000 molecular weight protein. The unaffected controls had normal prolidase activity and were negative for autoantibodies. CONCLUSIONS: Prolidase deficiency may be associated with the loss of immune tolerance to lupus-associated autoantigens even without clinical SLE.


Assuntos
Anticorpos Antinucleares/sangue , Autoantígenos/imunologia , Autoimunidade , Lúpus Eritematoso Sistêmico/imunologia , Deficiência de Prolidase/imunologia , Tolerância a Antígenos Próprios , Amish/genética , Antígenos Nucleares/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Complemento C1q/análise , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Linhagem , Fenótipo , Deficiência de Prolidase/sangue , Deficiência de Prolidase/etnologia , Deficiência de Prolidase/genética , Estados Unidos/epidemiologia
10.
Mol Metab ; 2(3): 171-83, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24049732

RESUMO

Alterations in the gut microbiota have been proposed to modify the development and maintenance of obesity and its sequelae. Definition of underlying mechanisms has lagged, although the ability of commensal gut microbes to drive pathways involved in inflammation and metabolism has generated compelling, testable hypotheses. We studied C57BL/6 mice from two vendors that differ in their obesogenic response and in their colonization by specific members of the gut microbiota having well-described roles in regulating gut immune responses. We confirmed the presence of robust differences in weight gain in mice from these different vendors during high fat diet stress. However, neither specific, highly divergent members of the gut microbiota (Lactobacillus murinus, segmented filamentous bacteria) nor the horizontally transmissible gut microbiota were found to be responsible. Constitutive differences in locomotor activity were observed, however. These data underscore the importance of selecting appropriate controls in this widely used model of human obesity.

11.
Arthritis Rheum ; 64(6): 1960-9, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22231568

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. METHODS: Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10(-5) and P = 4.73 × 10(-5) , respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r(2) = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10(-4) , OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10(-6) , OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. CONCLUSION: Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Fator 6 Associado a Receptor de TNF/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino
12.
Mol Metab ; 1(1-2): 21-31, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-24024115

RESUMO

The gut microbiome has been proposed to play a causal role in obesity. Here, we review the historical context for this hypothesis, highlight recent key findings, and critically discuss issues central to further progress in the field, including the central epistemological problem for the field: how to define causality in the relationship between microbiota and obesity phenotypes. Definition of such will be critical for the field to move forward.

13.
J Allergy Clin Immunol ; 128(4): 753-760.e11, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21696813

RESUMO

BACKGROUND: Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification. OBJECTIVE: We sought to identify asthma susceptibility genes in children. METHODS: A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n = 116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n = 112) and normal controls (n = 165). A genomic region containing the ATPAF1 gene was found to be significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in 8 independent study populations of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in 2 consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatic patients and controls. RESULTS: Asthma was found to be associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene, with 2 SNPs achieving significance at a genome-wide level (P = 2.26 × 10(-5) to 2.2 × 10(-8)). Asthma severity was also found to be associated with SNPs and SNP haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the 4 non-Hispanic populations. Haplotype associations were also confirmed in the non-Hispanic populations (P = .045-.0009). ATPAF1 total RNA expression was significantly (P < .01) higher in bronchial biopsies from asthmatic patients than from controls. CONCLUSION: Genetic variation in the ATPAF1 gene predisposes children of different ancestries to asthma.


Assuntos
Asma/genética , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Haplótipos , Polimorfismo de Nucleotídeo Único , Asma/enzimologia , Asma/patologia , Brônquios/enzimologia , Brônquios/patologia , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , ATPases Mitocondriais Próton-Translocadoras , Chaperonas Moleculares , Índice de Gravidade de Doença
14.
Artigo em Inglês | MEDLINE | ID: mdl-20706608

RESUMO

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.


Assuntos
Interferon Tipo I/genética , Lúpus Eritematoso Sistêmico/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/sangue , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Fenômenos Fisiológicos da Pele , Estatísticas não Paramétricas
15.
Pediatr Blood Cancer ; 55(2): 248-53, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20582981

RESUMO

BACKGROUND: The variant polymorphism in the gene MDM2, SNP309, leads to increased level of mdm2 protein and subsequent downregulation of p53 tumor suppressor pathway. Presence of this single nucleotide polymorphism (SNP) has been associated with earlier tumorigenesis in patients with Li-Fraumeni syndrome, as well as decreased survival in patients with CLL. In addition, cells homozygous (G/G) for SNP 309 were found to have 10-fold increase resistance to topoisomerase II inhibitors in vitro. PROCEDURE: We genotyped children (n = 575) with de novo acute myeloid leukemia (AML) treated on three Children's Oncology Group protocols (CCG 2941/2961/AAML 03P1) for the presence of SNP309. Healthy blood donors were genotyped as control population. RESULTS: The variant G/G genotype was associated with an increased susceptibility to AML (OR 1.5; P = 0.049). However, the presence of the variant allele at SNP309 did not modify disease response or toxicity in children treated on CCG protocols 2941/2961. CONCLUSIONS: The variant SNP 309 influences susceptibility to pediatric AML, but does not impact overall response to therapy.


Assuntos
Predisposição Genética para Doença , Leucemia Mieloide Aguda/genética , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-mdm2/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Masculino , Resultado do Tratamento , Adulto Jovem
16.
Nat Rev Genet ; 10(5): 285-90, 2009 05.
Artigo em Inglês | MEDLINE | ID: mdl-19337289

RESUMO

Genome-wide association studies and fine mapping of candidate regions have rapidly advanced our understanding of the genetic basis of systemic lupus erythematosus (SLE). More than 20 robust associations have now been identified and confirmed, providing insights at the molecular level that refine our understanding of the involvement of host immune response processes. In addition, genes with unknown roles in SLE pathophysiology have been identified. These findings may provide new routes towards improved clinical management of this complex disease.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/tendências , Lúpus Eritematoso Sistêmico/genética , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Modelos Biológicos
17.
Nature ; 458(7241): 1039-42, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19242412

RESUMO

Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-kappaB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease-a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.


Assuntos
Fibrose Cística/genética , Fibrose Cística/patologia , Proteínas Imediatamente Precoces/genética , Animais , Células Cultivadas , Estudos de Coortes , Modelos Animais de Doenças , Genótipo , Humanos , Proteínas Imediatamente Precoces/deficiência , Inflamação/genética , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/patogenicidade , Fator de Transcrição RelA/metabolismo
18.
PLoS One ; 3(3): e0001757, 2008 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-18335026

RESUMO

Osteopontin (SPP1) is an important bone matrix mediator found to have key roles in inflammation and immunity. SPP1 genetic polymorphisms and increased osteopontin protein levels have been reported to be associated with SLE in small patient collections. The present study evaluates association between SPP1 polymorphisms and SLE in a large cohort of 1141 unrelated SLE patients [707 European-American (EA) and 434 African-American (AA)], and 2009 unrelated controls (1309 EA and 700 AA). Population-based case-control association analyses were performed. To control for potential population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT), and principal components analysis (PCA) were applied. Combined analysis of 2 ethnic groups, showed the minor allele of 2 SNPs (rs1126616T and rs9138C) significantly associated with higher risk of SLE in males (P = 0.0005, OR = 1.73, 95% CI = 1.28-2.33), but not in females. Indeed, significant gene-gender interactions in the 2 SNPs, rs1126772 and rs9138, were detected (P = 0.001 and P = 0.0006, respectively). Further, haplotype analysis identified rs1126616T-rs1126772A-rs9138C which demonstrated significant association with SLE in general (P = 0.02, OR = 1.30, 95%CI 1.08-1.57), especially in males (P = 0.0003, OR = 2.42, 95%CI 1.51-3.89). Subgroup analysis with single SNPs and haplotypes also identified a similar pattern of gender-specific association in AA and EA. GC, STRAT, and PCA results within each group showed consistent associations. Our data suggest SPP1 is associated with SLE, and this association is especially stronger in males. To our knowledge, this report serves as the first association of a specific autosomal gene with human male lupus.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Osteopontina/fisiologia , Fatores Sexuais , Alelos , Feminino , Frequência do Gene , Humanos , Masculino , Osteopontina/genética , Polimorfismo de Nucleotídeo Único
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