National Heart, Lung, and Blood Institute's Framingham Heart Study and Center for Population Studies, Framingham, Massachusetts, United States of America ; Renal Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
PLoS Genet. 2013;9(9):e1003796. doi: 10.1371/journal.pgen.1003796. Epub 2013 Sep 19.
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.
钙对多个器官系统的正常功能至关重要，其血清浓度受到严格调节。除了 CASR，与血清钙相关的基因在很大程度上尚不清楚。我们对来自 17 个基于人群的队列的 39400 个人进行了全基因组关联荟萃分析，并在≤21679 名额外个体中研究了 14 个与血清钙最密切相关的位点。确定并复制了与血清钙相关的七个位点（六个新区域）。CYP24A1 附近的 Rs1570669（P=9.1E-12）、GATA3 上游的 rs10491003（P=4.8E-09）和 CARS 中的 rs7481584（P=1.2E-10）提示涉及孟德尔钙代谢紊乱的区域：DGKD 中的 rs1550532（P=8.2E-11）也与骨密度相关，DGKH/KIAA0564 附近的 rs7336933（P=9.1E-10）位于编码二酰基甘油激酶不同同工型的基因附近。rs780094 在 GCKR 中。我们在肠道、肾脏和骨骼中对这些基因的表达进行了特征描述，并证明了在小鼠中，基因表达在骨骼中对膳食钙的反应发生了调节。我们的研究结果为钙稳态的遗传学提供了新的线索。
