International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways
NATURE COMMUNICATIONS
Authors: Cordell, Heather J.; Han, Younghun; Mells, George F.; Li, Yafang; Hirschfield, Gideon M.; Greene, Casey S.; Xie, Gang; Juran, Brian D.; Zhu, Dakai; Qian, David C.; Floyd, James A. B.; Morley, Katherine I.; Prati, Daniele; Lleo, Ana; Cusi, Daniele; Gershwin, M. Eric; Anderson, Carl A.; Lazaridis, Konstantinos N.; Invernizzi, Pietro; Seldin, Michael F.; Sandford, Richard N.; Amos, Christopher I.; Siminovitch, Katherine A.
Abstract
Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n = 2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n = 3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (P-combined <5 x 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.
Low Dose, Low Dose Rate Photon Radiation Modifies Leukocyte Distribution and Gene Expression in CD4(+) T Cells
JOURNAL OF RADIATION RESEARCH
Authors: Gridley, Daila S.; Rizvi, Asma; Xian Luo-Owen; Makinde, Adeola Y.; Pecaut, Michael J.
Abstract
A better understanding of low dose radiation effects is needed to accurately estimate health risks. In this study, C57BL/6 mice were gamma-irradiated to total doses of 0, 0.01, 0.05, and 0.1 Gy (Co-57; similar to 0.02 cGy/h). Subsets per group were euthanized at the end of irradiation (day 0) and on days 4 and 21 thereafter. Relative spleen mass and splenic white blood cell (WBC) counts, major leukocyte populations, and spontaneous DNA synthesis were consistently higher in the irradiated groups on day 0 compared to 0 Gy controls, although significance was not always obtained. In the spleen, all three major leukocyte types were significantly elevated on day 0 (P < 0.05). By day 21 post-irradiation the T, B, and natural killer (NK) cell counts, as well as CD4(+) T cells and CD4:CD8 T cell ratio, were low especially in the 0.01 Gy group. Although blood analyses showed no significant differences in leukocyte counts or red blood cell and platelet characteristics, the total T cells, CD4(+) T cells, and NK cells were increased by day 21 after 0.01 Gy (P < 0.05). Gene analysis of CD4(+) T cells negatively isolated from spleens on day 0 after 0.1 Gy showed significantly enhanced expression of Il27 and Tcfcp2, whereas Inha and Socs5 were down-regulated regulated by 0.01 Gy and 0.1 Gy, respectively (P < 0.05). A trend for enhancement was noted in two additional genes (Illr1 and Tbx2l) in the 0.1 Gy group (P < 0.1). The data show that protracted low dose photons had dose- and time-dependent effects on CD4(+) T cells after whole-body exposure.
COA
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