RESUMEN
OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). METHODS: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. RESULTS: PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Poliangitis Microscópica , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Anticuerpos Anticitoplasma de Neutrófilos , Células Endoteliales , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/genética , Humanos , Poliangitis Microscópica/complicaciones , Poliangitis Microscópica/genética , Mieloblastina/genética , PeroxidasaRESUMEN
BACKGROUND: Molybdenum is an essential trace element and a component of xanthine oxidase, which catalyses the formation of urate. The toxicity of molybdenum in humans is considered to be low, but hyperuricaemia and gout-like symptoms have been observed sporadically. METHODS: A case of hyperuricaemia and gouty arthritis in a young man with occupational exposure to molybdenum is described. Improvement during an exposure-free period was followed by a relapse after a reconstruction designed to quantify his molybdenum exposure. CONCLUSION: This case seems to represent the first observation of gout associated with occupational molybdenum exposure, but the association might also be entirely circumstantial.