Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo
NATURE GENETICS
Authors: Jin, Ying; Birlea, Stanca A.; Fain, Pamela R.; Ferrara, Tracey M.; Ben, Songtao; Riccardi, Sheri L.; Cole, Joanne B.; Gowan, Katherine; Holland, Paulene J.; Bennett, Dorothy C.; Luiten, Rosalie M.; Wolkerstorfer, Albert; van der Veen, J. P. Wietze; Hartmann, Anke; Eichner, Saskia; Schuler, Gerold; van Geel, Nanja; Lambert, Jo; Kemp, E. Helen; Gawkrodger, David J.; Weetman, Anthony P.; Taieb, Alain; Jouary, Thomas; Ezzedine, Khaled; Wallace, Margaret R.; McCormack, Wayne T.; Picardo, Mauro; Leone, Giovanni; Overbeck, Andreas; Silverberg, Nanette B.; Spritz, Richard A.
Abstract
We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 x 10(-8)), MC1R (P = 1.82 x 10(-13)), a region near TYR (P = 1.57 x 10(-13)), IFIH1 (P = 4.91 x 10(-15)), CD80 (P = 3.78 x 10(-10)), CLNK (P = 1.56 x 10(-8)), BACH2 (P = 2.53 x 10(-8)), SLA (P = 1.58 x 10(-8)), CASP7 (P = 3.56 x 10(-8)), CD44 (P = 1.78 x 10(-9)), IKZF4 (P = 2.75 x 10(-14)), SH2B3 (P = 3.54 x 10(-18)) and TOB2 (P = 6.81 x 10(-10)). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration.
miR-17-92 Cluster Targets Phosphatase and Tensin Homology and Ikaros Family Zinc Finger 4 to Promote TH17-mediated Inflammation
JOURNAL OF BIOLOGICAL CHEMISTRY
Authors: Liu, Si-Qi; Jiang, Shan; Li, Chaoran; Zhang, Baojun; Li, Qi-Jing
Abstract
Background: miRNA is a key component of post-transcriptional network governing the fate of T cells. Results: By targeting PTEN and IKZF4, miR-17-92 cluster promotes T(H)17 differentiation and T(H)17-related inflammation. Conclusion: miR-19b and miR-17 within the cluster additively promote T(H)17 responses through distinct regulatory networks. Significance: Our study provides novel regulatory mechanisms and potential therapeutic candidates against autoimmunity. The miR-17-92 cluster regulates a broad spectrum of biological processes of T cell immunity. This cluster was found to facilitate T cell proliferation, enhance antitumor activities and promote T cell-dependent antibody responses. However, little is known about the role of this miRNA cluster in the development of autoimmune diseases. Multiple sclerosis is a neuro-destructive autoimmune disease caused by the pathogenicity of T(H)17 cells, whose differentiation is tightly controlled by a variety of transcriptional and post-transcriptional regulators. Our study unveils the critical role of miR-17-92 in T(H)17 differentiation: T cell-specific miR-17-92 deficiency reduced T(H)17 differentiation and ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. We demonstrated that miR-17 and miR-19b are the two miRNAs in this cluster responsible for promoting T(H)17 responses. MiR-19b represses the expression of Phosphatase and Tensin Homology (PTEN), thereby augmenting the PI3K-AKT-mTOR axis essential for proper T(H)17 differentiation. Meanwhile, miR-17 enhances T(H)17 polarization by inhibiting a novel target, Ikaros Family Zinc Finger 4 (IKZF4). By establishing the miR-17-92 cluster as a key driver of T(H)17 responses, our data identify this miRNA cluster as a potential therapeutic target for the clinical intervention of multiple sclerosis.
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