OBJECTIVE: Recent evidence from genetic, cell biology, and animal model studies has suggested a pivotal role of autophagy in mediating systemic lupus erythematosus (SLE). However, the genetic basis has not yet been thoroughly examined. Therefore, the aim of the present study was to identify additional susceptibility variants in autophagy-related genes along with their functional significance. METHODS: First, we performed a gene family-based genetic association analysis in SLE patients with the use of ImmunoChip arrays, and then we selected the most strongly associated polymorphisms for replication in additional cohorts. To identify regulatory clues, we analyzed publicly available blood expression quantitative trait locus data and Encyclopedia of DNA Elements data on transcription factor binding sites and cell type-specific differential expression. Functional effects were tested by luciferase reporter assays, electrophoretic mobility shift assays, and differential gene expression assays. RESULTS: In 14,474 samples, we observed that the rare Chinese variant rs933717T was associated with susceptibility to SLE (0.11% in cases versus 0.87% in controls; P = 2.36 × 10-10 , odds ratio 0.13). The rs933717 risk allele C correlated with increased MAP1LC3B expression; increased MAP1LC3B messenger RNA was observed in SLE patients and in lupus-prone mice. In reporter gene constructs, the risk allele increased luciferase activity up to 2.7-3.8-fold in both HEK 293T and Jurkat cell lines, and the binding of HEK 293T and Jurkat cell nuclear extracts to the risk allele was also increased. CONCLUSION: We observed a likely genetic association between light chain 3B, a widely used marker for autophagy, and susceptibility to SLE.
OBJECTIVE: Recent evidence from genetic, cell biology, and animal model studies has suggested a pivotal role of autophagy in mediating systemic lupus erythematosus (SLE). However, the genetic basis has not yet been thoroughly examined. Therefore, the aim of the present study was to identify additional susceptibility variants in autophagy-related genes along with their functional significance. METHODS: First, we performed a gene family-based genetic association analysis in SLEpatients with the use of ImmunoChip arrays, and then we selected the most strongly associated polymorphisms for replication in additional cohorts. To identify regulatory clues, we analyzed publicly available blood expression quantitative trait locus data and Encyclopedia of DNA Elements data on transcription factor binding sites and cell type-specific differential expression. Functional effects were tested by luciferase reporter assays, electrophoretic mobility shift assays, and differential gene expression assays. RESULTS: In 14,474 samples, we observed that the rare Chinese variant rs933717T was associated with susceptibility to SLE (0.11% in cases versus 0.87% in controls; P = 2.36 × 10-10 , odds ratio 0.13). The rs933717 risk allele C correlated with increased MAP1LC3B expression; increased MAP1LC3B messenger RNA was observed in SLEpatients and in lupus-prone mice. In reporter gene constructs, the risk allele increased luciferase activity up to 2.7-3.8-fold in both HEK 293T and Jurkat cell lines, and the binding of HEK 293T and Jurkat cell nuclear extracts to the risk allele was also increased. CONCLUSION: We observed a likely genetic association between light chain 3B, a widely used marker for autophagy, and susceptibility to SLE.
Authors: Cristen J Willer; Laura J Scott; Lori L Bonnycastle; Anne U Jackson; Peter Chines; Randall Pruim; Craig W Bark; Ya-Yu Tsai; Elizabeth W Pugh; Kimberly F Doheny; Leena Kinnunen; Karen L Mohlke; Timo T Valle; Richard N Bergman; Jaakko Tuomilehto; Francis S Collins; Michael Boehnke Journal: Genet Epidemiol Date: 2006-02 Impact factor: 2.135
Authors: I Arsov; X Li; G Matthews; J Coradin; B Hartmann; A K Simon; S C Sealfon; Z Yue Journal: Cell Death Differ Date: 2008-05-02 Impact factor: 15.828
Authors: Jill Henault; Jennifer Martinez; Douglas R Green; Miguel A Sanjuan; Jeffrey M Riggs; Jane Tian; Payal Mehta; Lorraine Clarke; Miwa Sasai; Eicke Latz; Melanie M Brinkmann; Akiko Iwasaki; Anthony J Coyle; Roland Kolbeck Journal: Immunity Date: 2012-12-06 Impact factor: 31.745