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1.
J Rheumatol ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262295

RESUMO

OBJECTIVE: Macrophage activation syndrome (MAS), a life-threatening inflammatory complication, is increasingly recognized in childhood-onset SLE (cSLE). It can be a challenge to differentiate active cSLE from MAS. We generated decision rules for discriminating MAS from active cSLE in newly diagnosed patients. METHODS: We conducted a retrospective cohort study of consecutive, newly diagnosed, active cSLE patients with fever, requiring hospital admission to SickKids from January 2003 - December 2007 (cohort 1), and January 2008 - December 2013 (Cohort 2). All patients met ≥4 ACR or SLICC criteria, were steroid naïve and infection free. MAS was diagnosed based on expert opinion. Recursive partitioning was applied to each cohort to derive a decision rule based on clinical and laboratory features, distinguishing MAS from non-MAS cSLE. Each decision rule was applied to the alternate, independent cohort. Sensitivity and specificity of these decision rules were compared to existing criteria. RESULTS: Cohort 1 (n=34) and cohort 2 (n=41) each had 10 MAS patients. Recursive partitioning in cohort 1 identified ferritin ≥699 µg/L, as the sole best discriminator between MAS and non- MAS patients (R2=0.48) and in cohort 2 ferritin ≥1107 µg/L, followed by lymphocytes < 0.72 x103/mm3 were the best discriminators for MAS (R2=0.52). Cross-validation of our decision rules maintained 90-100% sensitivity and 65-85% specificity. CONCLUSION: Our decision rule demonstrated improved performance compared to preliminary guidelines for MAS in cSLE from the Lupus Working Group of the Paediatric Rheumatology European Society, and familial Hemophagocytic Lymphohistiocytosis diagnostic criteria. Validation in independent cohorts is required.

2.
Am J Hum Genet ; 107(5): 882-894, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022220

RESUMO

Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32976694

RESUMO

OBJECTIVE: The aim of this study was to examine the impact of timing of childhood-onset systemic lupus erythematosus (cSLE) diagnosis relative to menarchal status, on final height, accounting for and disease associated factors. METHODS: A cohort study of female cSLE patients <18 years of age at diagnosis, followed at a tertiary care, pediatric center from July 1982 to March 2016, restricted to patients with documented age of menarche and final height. We compared final height between patients diagnosed pre- and post-menarche. We tested the association of timing of cSLE diagnosis with final height, adjusted for ethnicity, in linear regression models. We performed subgroup analyses of patients with growth during follow-up, additionally adjusting for average daily corticosteroid dose and disease activity. RESULTS: Of 401 female cSLE patients in the study, 115 patients (29%) were diagnosed pre-menarche and 286 (71%) post-menarche. Patients diagnosed pre-menarche were older at menarche compared with patients diagnosed post-menarche (13.5 ± 1.4 vs. 12.5 ± 1.3 years; p < 0.001). The mean final height for females diagnosed post-menarche (161.4 cm [SD 6.9 cm]) was greater than those diagnosed pre-menarche (158.8 cm [SD 7.3 cm], P=0.001). In regression analysis, those diagnosed post-menarche were significantly taller than those diagnosed pre-menarche, adjusted for ethnicity, and disease severity (Beta=2.6cm, [SD 0.7cm], P=0.0006). CONCLUSION: In this large cohort study of females with cSLE, patients diagnosed post-menarche achieved a taller final height than those diagnosed pre-menarche even after accounting for ethnicity and disease severity.

5.
Rheumatology (Oxford) ; 59(1): 90-98, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31236574

RESUMO

OBJECTIVE: LN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). METHODS: Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed <18 years) and aSLE patients (diagnosed ⩾18 years). Patients met ACR and/or SLICC SLE criteria and were genotyped on the Illumina Multi-Ethnic Global Array or Omni1-Quad arrays. We identified those with and without biopsy-confirmed LN. HLA and non-HLA additive SLE risk-weighted genetic risk scores (GRSs) were tested for association with LN risk in logistic models, stratified by cSLE/aSLE and ancestry. Stratified effect estimates were meta-analysed. RESULTS: Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002). CONCLUSION: We observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort.


Assuntos
Idade de Início , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Adolescente , Adulto , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/etnologia , Nefrite Lúpica/etnologia , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Adulto Jovem
6.
J Am Soc Nephrol ; 30(10): 2000-2016, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31537649

RESUMO

BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1). CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.


Assuntos
Autoantígenos/genética , Colágeno Tipo IV/genética , Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Estudo de Associação Genômica Ampla , Membrana Basal Glomerular , Mutação , Estudos de Coortes , Feminino , Humanos , Masculino
7.
Front Med (Lausanne) ; 6: 94, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31131280

RESUMO

This perspective article aims to highlight the importance of values-driven personal reflection and collaboration for effective translational medicine training. We frame the dilemma in translational medicine and provide an approach for solution emphasizing collaboration and co-creation for innovative change in translational medicine. We cite the science in transition literature suggesting why personal reflection and a collaborative approach is important. We identify the problem with publication pressures and the bibliometric mindset. We focus on motivation to seek and find results that really matter for patients and individuals to maintain health in the real world. We review how the international EUREKA Institute for Translational Medicine (established in 2007) works with students, to harness their core values and develop personal growth skills to improve their leadership effectiveness, to work toward collaborative gain and potentially more meaningful results for patients and medical needs. We describe how the EUREKA Institute's unique setting, curriculum and hidden curriculum aspects effectively train program participants. The article highlights creating an immersive safe space, personal reflection, connection, structured brainstorming, group problem solving, collaboration and co-creation to facilitate innovation in translational medicine. The article relates program features to their theoretical underpinnings such as Theory U, Mediation Theory and Strategic Innovation Theory. The six authors from different global regions, ages, career stages, translational medicine contexts and years of attendance at the EUREKA Institute provide their reflections on training impact. Lessons learned and recommendations for research and application are discussed.

8.
J Rheumatol ; 46(7): 731-738, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30770510

RESUMO

OBJECTIVE: Currently there are 2 different classification criteria for systemic lupus erythematosus (SLE): American College of Rheumatology (ACR) and Systemic Lupus International Collaborating Clinics (SLICC). The aim of this study was to compare the sensitivities of ACR and SLICC criteria in childhood-onset SLE (cSLE) using a large, multiethnic cohort. METHODS: We conducted a retrospective study of 722 patients diagnosed with cSLE at The Hospital for Sick Children (SickKids). Prospectively collected data from SickKids' Lupus Database were reviewed/validated against medical records prior to ACR and SLICC scoring based on cumulative symptoms up to the last visit. Sensitivities were compared using McNemar's test. Descriptive statistics were used to identify SLE features unique to each set of criteria and autoantibodies not included in either. RESULTS: ACR and SLICC sensitivities were as follows: 92.4% and 96.3% overall (p = 0.001); 82.5% and 91.3% (p = 0.01) in those scored ≤ 1 year from diagnosis; 92.7% and 97.9% (p = 0.02) in those scored 2-3 years from diagnosis. Forty-eight of 55 (87.3%) patients who did not meet ACR criteria met SLICC criteria through SLICC-specific criterion or renal biopsy. Twenty of 27 (74.1%) patients who did not meet SLICC criteria met ACR criteria as a result of photosensitivity (73.9%) and ACR lymphopenia criteria (26.1%). Six of 7 patients (85.7%) who were clinically diagnosed with cSLE but did not meet either SLICC or ACR criteria had anti-Ro antibodies. CONCLUSION: SLICC criteria were significantly more sensitive than ACR criteria in cSLE classification, especially early in the disease course. Because of the extreme rarity of primary Sjögren syndrome in children, one may consider adding anti-Ro antibodies to the classification criteria for cSLE because they are present in ∼40% of patents with cSLE.


Assuntos
Lúpus Eritematoso Sistêmico/classificação , Lúpus Eritematoso Sistêmico/imunologia , Projetos de Pesquisa , Adolescente , Anticorpos Antinucleares/sangue , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Cooperação Internacional , Rim/patologia , Leucopenia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/patologia , Linfopenia , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Sensibilidade e Especificidade , Estados Unidos
10.
J Rheumatol ; 45(10): 1426-1439, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30173152

RESUMO

OBJECTIVE: To develop recommendations for the assessment of people with systemic lupus erythematosus (SLE) in Canada. METHODS: Recommendations were developed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. The Canadian SLE Working Group (panel of Canadian rheumatologists and a patient representative from Canadian Arthritis Patient Alliance) was created. Questions for recommendation development were identified based on the results of a previous survey of SLE practice patterns of members of the Canadian Rheumatology Association. Systematic literature reviews of randomized trials and observational studies were conducted. Evidence to Decision tables were prepared and presented to the panel at 2 face-to-face meetings and online. RESULTS: There are 15 recommendations for assessing and monitoring SLE, with varying applicability to adult and pediatric patients. Three recommendations focus on diagnosis, disease activity, and damage assessment, suggesting the use of a validated disease activity score per visit and annual damage score. Strong recommendations were made for cardiovascular risk assessment and measuring anti-Ro and anti-La antibodies in the peripartum period and conditional recommendations for osteoporosis and osteonecrosis. Two conditional recommendations were made for peripartum assessments, 1 for cervical cancer screening and 2 for hepatitis B and C screening. A strong recommendation was made for annual influenza vaccination. CONCLUSION: These are considered the first guidelines using the GRADE method for the monitoring of SLE. Existing evidence is largely of low to moderate quality, resulting in more conditional than strong recommendations. Additional rigorous studies and special attention to pediatric SLE populations and patient preferences are needed.


Assuntos
Diretrizes para o Planejamento em Saúde , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/terapia , Programas de Rastreamento , Adulto , Canadá , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Criança , Feminino , Pessoal de Saúde , Hepatite C/diagnóstico , Hepatite C/etiologia , Humanos , Infecções/diagnóstico , Infecções/etiologia , Lúpus Eritematoso Sistêmico/complicações , Masculino , Osteonecrose/diagnóstico , Osteonecrose/etiologia , Osteoporose/diagnóstico , Osteoporose/etiologia , Período Periparto/sangue , Gravidez , Reumatologistas , Medição de Risco , Índice de Gravidade de Doença , Revisões Sistemáticas como Assunto , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/etiologia , Vacinação
11.
Diabetes ; 67(7): 1414-1427, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29703844

RESUMO

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética
12.
Arthritis Rheumatol ; 70(4): 616-624, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29342508

RESUMO

OBJECTIVE: To describe the features and treatment of macrophage activation syndrome (MAS) in a single-center cohort of patients with childhood-onset systemic lupus erythematosus (SLE), and to compare childhood-onset SLE manifestations and outcomes between those with and those without MAS. METHODS: We included all patients with childhood-onset SLE followed up at The Hospital for Sick Children from 2002 to 2012, and identified those also diagnosed as having MAS. Demographic, clinical, and laboratory features of MAS and SLE, medication use, hospital and pediatric intensive care unit (PICU) admissions, as well as damage indices and mortality data were extracted from the Lupus database. Student's t-tests and Fisher's exact tests were used to compare continuous and categorical variables, respectively. We calculated incidence rate ratios of hospital and PICU admissions comparing patients with and those without MAS, using Poisson models. Kaplan-Meier survival analysis was used to examine the time to disease damage accrual. RESULTS: Of the 403 patients with childhood-onset SLE, 38 (9%) had MAS. The majority (68%) had concomitant MAS and SLE diagnoses. Fever was the most common MAS clinical feature. The frequency of renal and central nervous system disease, hospital admissions, the average daily dose of steroids, and time to disease damage were similar between those with and those without MAS. We observed a higher mortality rate among those with MAS (5%) than those without MAS (0.2%) (P = 0.02). CONCLUSION: MAS was most likely to develop concomitantly with childhood-onset SLE diagnosis. The majority of the MAS patients were successfully treated with corticosteroids with no MAS relapses. Although the numbers were small, there was a higher risk of death associated with MAS compared to SLE without MAS.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Síndrome de Ativação Macrofágica/mortalidade , Adolescente , Corticosteroides/uso terapêutico , Idade de Início , Criança , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Estimativa de Kaplan-Meier , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/imunologia , Masculino , Estudos Prospectivos
13.
Rheum Dis Clin North Am ; 43(3): 415-434, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28711143

RESUMO

Systemic lupus erythematosus (SLE) is a systemic, autoimmune, multisystem disease with a heterogeneous clinical phenotype. Genome-wide association studies have identified multiple susceptibility loci, but these explain a fraction of the estimated heritability. This is partly because within the broad spectrum of SLE are monogenic diseases that tend to cluster in patients with young age of onset, and in families. This article highlights insights into the pathogenesis of SLE provided by these monogenic diseases. It examines genetic causes of complement deficiency, abnormal interferon production, and abnormalities of tolerance, resulting in monogenic SLE with overlapping clinical features, autoantibodies, and shared inflammatory pathways.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Autoanticorpos/genética , Doenças Autoimunes/imunologia , Predisposição Genética para Doença , Genômica , Humanos , Lúpus Eritematoso Sistêmico/imunologia
14.
Arthritis Care Res (Hoboken) ; 69(11): 1620-1626, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28217919

RESUMO

OBJECTIVE: To investigate the nationwide prevalence and incidence of serious infections among children with systemic lupus erythematosus (SLE) enrolled in Medicaid, the US health insurance program for low-income patients. METHODS: From Medicaid claims (2000-2006) we identified children ages 5 to <18 years with SLE (≥3 International Classification of Diseases, Ninth Revision [ICD-9] codes of 710.0, each >30 days apart) and lupus nephritis (LN; ≥2 ICD-9 codes for kidney disease on/after SLE codes). From hospital discharge diagnoses, we identified infection subtypes (bacterial, fungal, and viral). We calculated incidence rates (IRs) per 100 person-years, mortality rates, and hazard ratios adjusted for sociodemographic factors, medications, and preventive care. RESULTS: Among 3,500 children with identified SLE, 1,053 serious infections occurred over 10,108 person-years; the IR was 10.42 per 100 person-years (95% confidence interval [95% CI] 9.80-11.07) among all those with SLE and 17.65 per 100 person-years (95% CI 16.29-19.09) among those with LN. Bacterial infections were most common (87%, of which 39% were bacterial pneumonias). In adjusted models, African Americans and American Indians had higher rates of infections compared with white children, and those with comorbidities or receiving corticosteroids had higher infection rates than those without. Males had lower rates of serious infections compared to females. The 30-day postdischarge mortality rate was 4.4%. CONCLUSION: Overall, hospitalized infections were very common in children with SLE, with bacterial pneumonia being the most common infection. Highest infection risks were among African American and American Indian children, those with LN, comorbidities, and those taking corticosteroids.


Assuntos
Doenças Transmissíveis/epidemiologia , Hospitalização/tendências , Lúpus Eritematoso Sistêmico/epidemiologia , Medicaid/tendências , Adolescente , Criança , Pré-Escolar , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/terapia , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/terapia , Masculino , Estados Unidos/epidemiologia
15.
J Am Soc Nephrol ; 28(2): 557-574, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27647854

RESUMO

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Adolescente , Adulto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Diabetes ; 65(7): 2060-71, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27207532

RESUMO

Skin fluorescence (SF) noninvasively measures advanced glycation end products (AGEs) in the skin and is a risk indicator for diabetes complications. N-acetyltransferase 2 (NAT2) is the only known locus influencing SF. We aimed to identify additional genetic loci influencing SF in type 1 diabetes (T1D) through a meta-analysis of genome-wide association studies (N = 1,359) including Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). A locus on chromosome 1, rs7533564 (P = 1.9 × 10(-9)), was associated with skin intrinsic fluorescence measured by SCOUT DS (excitation 375 nm, emission 435-655 nm), which remained significant after adjustment for time-weighted HbA1c (P = 1.7 × 10(-8)). rs7533564 was associated with mean HbA1c in meta-analysis (P = 0.0225), mean glycated albumin (P = 0.0029), and glyoxal hydroimidazolones (P = 0.049), an AGE measured in skin biopsy collagen, in DCCT. rs7533564 was not associated with diabetes complications in DCCT/EDIC or with SF in subjects without diabetes (nondiabetic [ND]) (N = 8,721). In conclusion, we identified a new locus associated with SF in T1D subjects that did not show similar effect in ND subjects, suggesting a diabetes-specific effect. This association needs to be investigated in type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Loci Gênicos , Pele/metabolismo , Alelos , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/metabolismo , Fluorescência , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Pele/diagnóstico por imagem
17.
Diabetes ; 65(3): 803-17, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26631737

RESUMO

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.


Assuntos
Albuminúria/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Túbulos Renais/metabolismo , Adulto , Idoso , Albuminúria/etiologia , Animais , Catepsina C/genética , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Feminino , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ratos , Receptores de Superfície Celular/genética , Sulfotransferases/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
18.
Arthritis Rheumatol ; 67(6): 1577-85, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25772621

RESUMO

OBJECTIVE: To examine the epidemiology of serious infections, a significant cause of morbidity and mortality in systemic lupus erythematosus (SLE), in a nationwide cohort of SLE and lupus nephritis (LN) patients. METHODS: Using the Medicaid Analytic eXtract database for the years 2000-2006, we identified patients ages 18-64 years who had SLE and the subset who had LN. We ascertained cases of serious hospitalized infections using validated algorithms, and we determined 30-day mortality rates. Poisson regression was used to calculate infection incidence rates and multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) for the first infection, adjusted for sociodemographic variables, medication use, and an SLE-specific risk adjustment index. RESULTS: We identified 33,565 patients with SLE, 7,113 of whom had LN. There were 9,078 serious infections in 5,078 SLE patients and 3,494 infections in 1,825 LN patients. The infection incidence rate per 100 person-years was 10.8 in the SLE cohort and 23.9 in the LN subcohort. In adjusted models for the SLE cohort, we observed increased risks of infection in men as compared to women (HR 1.33 [95% confidence interval (95% CI) 1.20-1.47]), in blacks as compared to whites (HR 1.14 [95% CI 1.06-1.21]), and in users of glucocorticoids (HR 1.51 [95% CI 1.43-1.61]) and immunosuppressive drugs (HR 1.11 [95% CI 1.03-1.20]) as compared to never users. Hydroxychloroquine users had a reduced risk of infection as compared to never users (HR 0.73 [95% CI 0.68-0.77]). The 30-day mortality rate per 1,000 person-years among those hospitalized with infections was 21.4 in the SLE cohort and 38.6 in the LN subcohort. CONCLUSION: In this diverse, nationwide cohort of SLE patients, we observed a substantial burden of serious infections with many subsequent deaths, particularly among those with LN.


Assuntos
Infecções/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Nefrite Lúpica/epidemiologia , Adolescente , Adulto , Afro-Americanos/estatística & dados numéricos , Antirreumáticos/uso terapêutico , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imunossupressores/uso terapêutico , Infecções/mortalidade , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Masculino , Medicaid , Pessoa de Meia-Idade , Análise Multivariada , Distribuição de Poisson , Modelos de Riscos Proporcionais , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Estados Unidos/epidemiologia , Adulto Jovem
19.
PLoS One ; 10(2): e0117620, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25692470

RESUMO

OBJECTIVES: The human papillomavirus (HPV) vaccine is safe and efficacious in patients with systemic inflammatory diseases (SID) who have higher rates of persistent HPV infection. We compared HPV vaccine uptake among SID and non-SID patients. METHODS: Using a U.S. insurance claims database (2006-2012), we identified individuals 9-26 years with ≥2 SID diagnosis codes ≥7 days apart with ≥12 months of continuous enrollment prior to the second code (index date). We matched SID patients by age, sex and index date to randomly selected non-SID subjects and selected those with ≥24 months of post-index date continuous follow-up. We also identified a non-SID subcohort with ≥1 diagnosis code for asthma. We defined initiation as ≥1 HPV vaccination claim after 2007, and completion as 3 claims. We used multivariable logistic regression to assess uptake in females 11-26 years comparing SID, non-SID and asthma cohorts, adjusting for demographics, region, comorbidities, and healthcare utilization. RESULTS: We identified 5,642 patients 9-26 years with SID and 20,643 without. The mean age was 18.1 years (SD 4.9). We identified 1,083 patients with asthma; the mean age was 17.2 (SD 5.1). Among females, 20.6% with SID, 23.1% without SID and 22.9% with asthma, received ≥1 HPV vaccine. In our adjusted models, the odds of receipt of ≥1 vaccine was 0.87 times lower in SID (95% CI 0.77-0.98) compared to non-SID and did not differ for 3 vaccines (OR 1.03, 95% CI 0.83-1.26). The odds of initiation and completion were not statistically different between SID and non-SID asthma cohorts. CONCLUSIONS: In this nationwide cohort, HPV vaccine uptake was extremely low. Despite the heightened risk of persistent HPV infection among those with SID, no increase in HPV vaccine uptake was observed. Public health efforts to promote HPV vaccination overall are needed, and may be particularly beneficial for those at higher risk.


Assuntos
Vacinas contra Papillomavirus , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Criança , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Inflamação/virologia , Masculino , Risco , Fatores Sexuais , Adulto Jovem
20.
Ann Rheum Dis ; 74(8): 1522-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24685909

RESUMO

OBJECTIVE: To develop and validate rheumatoid arthritis (RA) risk models based on family history, epidemiologic factors and known genetic risk factors. METHODS: We developed and validated models for RA based on known RA risk factors, among women in two cohorts: the Nurses' Health Study (NHS, 381 RA cases and 410 controls) and the Epidemiological Investigation of RA (EIRA, 1244 RA cases and 971 controls). Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in logistic regression models for the study population and for those with positive family history. The joint effect of family history with genetics, smoking and body mass index (BMI) was evaluated using logistic regression models to estimate ORs for RA. RESULTS: The complete model including family history, epidemiologic risk factors and genetics demonstrated AUCs of 0.74 for seropositive RA in NHS and 0.77 for anti-citrullinated protein antibody (ACPA)-positive RA in EIRA. Among women with positive family history, discrimination was excellent for complete models for seropositive RA in NHS (AUC 0.82) and ACPA-positive RA in EIRA (AUC 0.83). Positive family history, high genetic susceptibility, smoking and increased BMI had an OR of 21.73 for ACPA-positive RA. CONCLUSIONS: We developed models for seropositive and seronegative RA phenotypes based on family history, epidemiological and genetic factors. Among those with positive family history, models using epidemiologic and genetic factors were highly discriminatory for seropositive and seronegative RA. Assessing epidemiological and genetic factors among those with positive family history may identify individuals suitable for RA prevention strategies.


Assuntos
Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Idoso , Consumo de Bebidas Alcoólicas , Ácido Aminolevulínico/análogos & derivados , Área Sob a Curva , Artrite Reumatoide/sangue , Autoanticorpos/sangue , Índice de Massa Corporal , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença/epidemiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos/imunologia , Fenótipo
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