RESUMEN
Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Here we perform a genome-wide association analysis in the United Kingdom, comparing severe cases of acne (n=1,893) with controls (n=5,132). In a second stage, we genotype putative-associated loci in a further 2,063 acne cases and 1,970 controls. We identify three genome-wide significant associations: 11q13.1 (rs478304, Pcombined=3.23 × 10(-11), odds ratio (OR) = 1.20), 5q11.2 (rs38055, P(combined) = 4.58 × 10(-9), OR = 1.17) and 1q41 (rs1159268, P(combined) = 4.08 × 10(-8), OR = 1.17). All three loci contain genes linked to the TGFß cell signalling pathway, namely OVOL1, FST and TGFB2. Transcripts of OVOL1 and TFGB2 have decreased expression in affected compared with normal skin. Collectively, these data support a key role for dysregulation of TGFß-mediated signalling in susceptibility to acne.
Asunto(s)
Acné Vulgar/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Adulto , Estudios de Casos y Controles , Proteínas de Unión al ADN/genética , Femenino , Folistatina/genética , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética , Factor de Crecimiento Transformador beta2/genética , Adulto JovenRESUMEN
Glial Müller cells are known to undergo functional and morphological changes during retinal proliferative disorders, but very little is known of the contribution of these cells to extracellular matrix deposition during retinal wound healing and gliosis. This study constitutes the first demonstration that retinal Müller cells express two major matrix metalloproteinases (MMPs), gelatinase A (MMP-2) and gelatinase B (MMP-9), implicated in cell migration and matrix degradation. Although mRNA and gelatinolytic activity of MMP-2 remained unchanged in cultured Müller cells, basal levels of MMP-9 mRNA observed after subculture at 24 hours, markedly declined after 48 or 72 hours. This correlated with the expression of MMP-9 gelatinolytic activity that peaked at 24 hours, but gradually decreased at 48 and 72 hours. Tumor necrosis factor-alpha, in both a soluble form or bound to collagen and fibronectin, increased MMP-9 mRNA and gelatinolytic activity, but not MMP-2 expression, and its effect could be blocked by anti-tumor necrosis factor-alpha antibodies. The results suggest that Müller cells may aid in the local control of extracellular matrix deposition during retinal proliferative disorders, and that interaction of these cells with matrix-bound cytokine may influence their pathological behavior. Control of Müller cell production of MMP-9 may constitute an important target for the design of new therapeutic approaches to treat and prevent retinal proliferative disease.