Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
and cell morphology. Fluorescent images of fura 2-10aded neutrophils attached to albumin-coated glass were recorded with a high sensitivity CCD camera while [Ca2+]~ was assessed with a dual excitation microfluorimetry. The majority of the initially round cells studied showed changes in shape which started either before or at the same time as the onset of the [Ca2+]~ transients.These data suggested that a rise in [Ca2+]i is not a prerequisite for shape change. This conclusion was confirmed by observation of movement and spreading in cells whose [Ca2÷]i transients were abolished by chelation of extraceUular Ca 2÷. Instead, our data suggest that spreading or adhesion itself initiates the [Ca2+]t activity. In keeping with this hypothesis, cytochalasin B, which prevents both cell movement and adhesion, completely inhibited generation of Using a rapid monitoring system We have described spontaneous and chemoattractant-triggered, multiple [Ca2+]~ elevations in neutrophils adherent both to albumin or fibronectin-coated surfaces (11). More recently Marks and Maxfield (19) have shown that such [Ca2÷]i transients appear to be linked to neutrophil movement during chemotaxis on poly-D-lysine-coated glass in the presence of serum. Neutrophils that extended pseudopods and assumed a polarized morphology were always observed to exhibit [Ca2÷]i transients even in the absence of chemoattractants. While [Ca2+]i transients are associated with cell spreading and locomotion, it is not clear whether transients in some way cause the movement, or if they are the result of cell movement.Spreading and locomotion are mediated by receptors that bridge the cell to the substrate. The numerically and functionally dominant adhesion receptor of neutrophils is the integrin CR3 (also known as Mac-l, Mol, CDllb/CD18, and am~2) (36). Blockade of this receptor with mAbs prevents spreading and/or chemotaxis on a variety of substrates including albumin (6), fibrinogen (38), complement protein C3bi (39), as well as on endothelial cells in vitro (9, 17) and in vivo (4,26,33). CR3 is likely to make a major contribution to cell locomotion since the chemoattractant stimuli C5a (17), tumor necrosis factor (TNF)a (17), interleukin (IL)-8 (7), and PMA (35) cause dramatic enhancement of the ca-
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