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.
Atherosclerosis-Driven Treg Plasticity Results in Formation of a Dysfunctional Subset of Plastic IFN gamma(+) Th1/Tregs
CIRCULATION RESEARCH
Authors: Butcher, Matthew J.; Filipowicz, Adam R.; Waseem, Tayab C.; McGary, Christopher M.; Crow, Kevin J.; Magilnick, Nathaniel; Boldin, Mark; Lundberg, Patric S.; Galkina, Elena V.
Abstract
Rationale: Forkhead box P3(+) T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Evidence suggests that Tregs respond to environmental cues to permit or suppress inflammation. In atherosclerosis, Th1-driven inflammation affects Treg homeostasis, but the mechanisms governing this phenomenon are unclear. Objective: Here, we address whether atherosclerosis impacts Treg plasticity and functionality in Apoe(-/-) mice, and what effect Treg plasticity might have on the pathology of atherosclerosis. Methods and Results: We demonstrate that atherosclerosis promotes Treg plasticity, resulting in the reduction of CXCR3(+) Tregs and the accumulation of an intermediate Th1-like interferon (IFN)-gamma(+) CCR5(+) Treg subset (Th1/Tregs) within the aorta. Importantly, Th1/Tregs arise in atherosclerosis from bona fide Tregs, rather than from T-effector cells. We show that Th1/Tregs recovered from atherosclerotic mice are dysfunctional in suppression assays. Using an adoptive transfer system and plasticity-prone Mir146a-/-Tregs, we demonstrate that elevated IFN gamma(+)Mir146a(-/-)Th1/Tregs are unable to adequately reduce atherosclerosis, arterial Th1, or macrophage content within Apoe(-/-) mice, in comparison to Mir146a(+/+) Tregs. Finally, via single-cell RNA-sequencing and real-time-polymerase chain reaction, we show that Th1/Tregs possess a unique transcriptional phenotype characterized by coexpression of Treg and Th1 lineage genes and a downregulation of Treg-related genes, including Ikzf2, Ikzf4, Tigit, Lilrb4, and Il10. In addition, an ingenuity pathway analysis further implicates IFN gamma, IFN alpha, interleukin-2, interleukin-7, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), T-cell receptor, and Csnk2b-related pathways in regulating Treg plasticity. Conclusions: Atherosclerosis drives Treg plasticity, resulting in the accumulation of dysfunctional IFN gamma(+) Th1/Tregs that may permit further arterial inflammation and atherogenesis.
COA
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