RESUMO
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Quinases da Família src/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Criança , Modelos Animais de Doenças , Feminino , Frequência do Gene , Células HEK293 , Voluntários Saudáveis , Humanos , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto , Sequenciamento do Exoma , Quinases da Família src/metabolismoRESUMO
STUDY DESIGN: Single-group, pre-, and postintervention repeated measures design. OBJECTIVE: To determine the impact of custom semirigid foot orthotics on pain and disability for individuals with plantar fasciitis. BACKGROUND: Few studies have examined the efficacy of foot orthotics for plantar fasciitis, and no single study has yet examined the effects of semirigid foot orthotics on an established quality-of-life instrument. METHODS AND MEASURES: Eight men and 7 women (mean ages 44.7 +/- 9.0 years) who reported having plantar fasciitis symptoms for an average of 21.3 +/- 23.7 months participated in the study. Subjects were timed for a 100-m walk at a self-selected speed, then they rated the pain they experienced during the walk using a 10-cm visual analog scale. Subjects also completed the pain and disability subsections of the Foot Function Index questionnaire. All measures were acquired before the fabrication of custom semirigid foot orthotics and 12 to 17 days following onset of foot orthotic use. RESULTS: Postorthotic 100-m walk times were not significantly different (t = 0.39, P = 0.70) than preorthotic values. Postorthotic pain ratings (mean = 0.7 +/- 0.7) for the 100-m walk were significantly less than (Wilcoxon t = 1, P < 0.005) preorthotic pain ratings (mean = 3.0 +/- 1.7). Postorthotic Foot Function Index pain subsection ratings (Wilcoxon t = 0, P < 0.005) were significantly less than preorthotic ratings, demonstrating a 66% reduction in pain ratings. Postorthotic Foot Function Index disability subsection ratings (Wilcoxon t = 0, P < 0.005) were significantly less than preorthotic ratings, demonstrating a 75% reduction in disability ratings. CONCLUSION: Custom semirigid foot orthotics may significantly reduce pain experienced during walking and may reduce more global measures of pain and disability for patients with chronic plantar fasciitis.