Browsing by Subject "Furin"

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    Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond
    (Springer Nature, 2022-10-07) Gaddis, Nathan; Mathur, Ravi; Marks, Jesse; Zhou, Linran; Quach, Bryan; Waldrop, Alex; Levran, Orna; Agrawal, Arpana; Randesi, Matthew; Adelson, Miriam; Jeffries, Paul W.; Martin, Nicholas G.; Degenhardt, Louisa; Montgomery, Grant W.; Wetherill, Leah; Lai, Dongbing; Bucholz, Kathleen; Foroud, Tatiana; Porjesz, Bernice; Runarsdottir, Valgerdur; Tyrfingsson, Thorarinn; Einarsson, Gudmundur; Gudbjartsson, Daniel F.; Webb, Bradley Todd; Crist, Richard C.; Kranzler, Henry R.; Sherva, Richard; Zhou, Hang; Hulse, Gary; Wildenauer, Dieter; Kelty, Erin; Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Schwab, Sibylle G.; Maher, Brion S.; Gruza, Richard; Kreek, Mary Jeanne; Nelson, Elliot C.; Thorgeirsson, Thorgeir; Stefansson, Kari; Berrettini, Wade H.; Gelernter, Joel; Edenberg, Howard J.; Bierut, Laura; Hancock, Dana B.; Johnson, Eric Otto; Medical and Molecular Genetics, School of Medicine
    Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.
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    STAT6 and Furin Are Successive Triggers for the Production of TGF-β by T Cells
    (The American Association of Immunologists, Inc., 2018-11) Li, Yue; Liu, Weiren; Guan, Xiaqun; Truscott, Jamie; Creemers, John W.; Chen, Hung-Lin; Pesu, Marko; El Abiad, Rami G.; Karacay, Bahri; Urban, Joseph F.; Elliott, David E.; Kaplan, Mark H.; Blazar, Bruce R.; Ince, M. Nedim; Pediatrics, School of Medicine
    Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.