RESUMO
OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
Assuntos
Doenças do Colo/genética , Tecido Conjuntivo/fisiologia , Doenças Diverticulares/genética , Epitélio/fisiologia , Estudo de Associação Genômica Ampla , Junção Neuromuscular/fisiologia , Adulto , Idoso , Estudos de Casos e Controles , Doenças do Colo/patologia , Bases de Dados Genéticas , Doenças Diverticulares/patologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reino UnidoRESUMO
Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m(2) per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, Assuntos
Anticorpos Monoclonais/administração & dosagem
, Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Talidomida/administração & dosagem
, Macroglobulinemia de Waldenstrom/tratamento farmacológico
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Anticorpos Monoclonais/efeitos adversos
, Anticorpos Monoclonais Murinos
, Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
, Intervalo Livre de Doença
, Relação Dose-Resposta a Droga
, Esquema de Medicação
, Feminino
, Seguimentos
, Humanos
, Imunoglobulina M/sangue
, Masculino
, Pessoa de Meia-Idade
, Terapia Neoadjuvante
, Receptores de IgG/genética
, Rituximab
, Talidomida/efeitos adversos
, Resultado do Tratamento
, Macroglobulinemia de Waldenstrom/sangue
, Macroglobulinemia de Waldenstrom/genética