Institute of Nutrition and Food Technology (INTA), University of Chile, Avenue El Líbano 5524, Santiago, Chile.
Eur J Hum Genet. 2012 Apr;20(4):480-2. doi: 10.1038/ejhg.2011.221. Epub 2011 Dec 14.
Calcium-sensing receptor polymorphism rs1042636 (Arg990Gly) affects the response to the calcimimetic cinacalcet, used to treat hypercalcemia in secondary hyperparathyroidism (sHPT) or parathyroid carcinoma. Carriers of the Arg allelle, show less parathyroid hormone secretion suppression in response to the drug. This effect was reproducible in transfected cultured human embryonic kidney cells, supporting a causal relationship on the protein level. We previously established that cinacalcet has an antilipolytic effect in isolated human adipocytes; however, there were a number of samples that did not respond to the treatment. The present work aimed to investigate whether the variable antilipolytic response to cinacalcet in adipocytes was consistent with the effect reported for the rs1042636 polymorphism. Lipolysis was assessed by measuring glycerol release after exposure to cinacalcet (10 μM) or vehicle in adipocytes isolated from 38 donors. Responsiveness was defined as lipolysis suppression (cinacalcet vs vehicle control) greater than 20%. Genotype analysis showed that 23 adipocyte donors were homozygous for Arg at position 990, 14 heterozygous and 1 homozygous Gly-Gly. Among the Arg homozygotes, one was responsive to cinacalcet, whereas five Gly carriers responded to the calcimimetic. In all, 83% of adipocytes showing response to cinacalcet carried the glycine allele, whereas in 96% of Arg-Arg individuals adipocytes did not respond to the calcimimetic (P=0.027, Fisher's exact test). Confirming sHPT observations, adipocytes from rs1042636 Gly-allele carriers show higher sensitivity to the antilipolytic action of cinacalcet. The potential benefit of cinacalcet as a suppressor of basal lipolysis and free fatty acid release in uremic patients needs to consider the rs1042636 single-nucleotide polymorphism.
钙敏感受体多态性 rs1042636（Arg990Gly）影响钙敏感受体激动剂西那卡塞治疗继发性甲状旁腺功能亢进（sHPT）或甲状旁腺癌所致高钙血症的疗效。Arg 等位基因携带者对药物的甲状旁腺激素分泌抑制作用较小。该作用在转染培养的人胚肾细胞中具有可重复性，支持其在蛋白水平上的因果关系。我们之前已经证实，西那卡塞在分离的人脂肪细胞中具有抗脂解作用；然而，有许多样本对治疗没有反应。本研究旨在探讨脂肪细胞中西那卡塞的可变抗脂解作用是否与 rs1042636 多态性的报道结果一致。通过测量暴露于西那卡塞（10 μM）或载体后脂肪细胞中甘油的释放来评估脂解作用。将脂解作用定义为西那卡塞与载体对照相比脂解抑制作用大于 20%。基因型分析显示，38 名供体中有 23 名脂肪细胞在 990 位Arg 纯合，14 名杂合，1 名 Gly-Gly 纯合。在 Arg 纯合子中，有 1 名对西那卡塞有反应，而 5 名 Gly 携带者对钙敏感受体激动剂有反应。在所有对西那卡塞有反应的脂肪细胞中，83%携带甘氨酸等位基因，而在 96%的 Arg-Arg 个体的脂肪细胞中，西那卡塞无反应（P=0.027，Fisher 确切检验）。证实了 sHPT 的观察结果，rs1042636 Gly 等位基因携带者的脂肪细胞对西那卡塞的抗脂解作用更敏感。西那卡塞作为尿毒症患者基础脂解和游离脂肪酸释放抑制剂的潜在益处需要考虑 rs1042636 单核苷酸多态性。
