Department of Pediatrics, University of California, Los Angeles, Los Angeles, California 90095-1752, USA.
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3866-e3876. doi: 10.1210/clinem/dgac318.
Chronic kidney disease (CKD) causes multiple interrelated disturbances in mineral metabolism. Genetic studies in the general population have identified common genetic variants associated with circulating phosphate, calcium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).
In this study we aimed to discover genetic variants associated with circulating mineral markers in CKD.
We conducted candidate single-nucleotide variation (SNV) analysis in 3027 participants in the multiethnic Chronic Renal Insufficiency Cohort (CRIC) to determine the associations between SNVs and circulating levels of mineral markers.
SNVs adjacent to or within genes encoding the regulator of G protein-coupled signaling 14 (RGS14) and the calcium-sensing receptor (CASR) were associated with levels of mineral metabolites. The strongest associations (P < .001) were at rs4074995 (RGS14) for phosphate (0.09 mg/dL lower per minor allele) and FGF23 (8.6% lower), and at rs1801725 (CASR) for calcium (0.12 mg/dL higher). In addition, the prevalence of hyperparathyroidism differed by rs4074995 (RGS14) genotype (chi-square P < .0001). Differential inheritance by race was noted for the minor allele of RGS14. Expression quantitative loci (eQTL) analysis showed that rs4074995 was associated with lower RGS14 gene expression in glomeruli (P = 1.03 × 10-11) and tubules (P = 4.0 × 10-4).
We evaluated genetic variants associated with mineral metabolism markers in a CKD population. Participants with CKD and the minor allele of rs4074995 (RGS14) had lower phosphorus, lower plasma FGF23, and lower prevalence of hyperparathyroidism. The minor allele of RGS14 was also associated with lower gene expression in the kidney. Further studies are needed to elucidate the effect of rs4074995 on the pathogenesis of disordered mineral metabolism in CKD.
慢性肾脏病（CKD）导致矿物质代谢的多种相互关联的紊乱。在普通人群中的遗传研究已经确定了与循环磷酸盐、钙、甲状旁腺激素（PTH）和成纤维细胞生长因子 23（FGF23）相关的常见遗传变异。
本研究旨在发现与 CKD 中循环矿物质标志物相关的遗传变异。
我们在多民族慢性肾功能不全队列（CRIC）中的 3027 名参与者中进行了候选单核苷酸变异（SNV）分析，以确定 SNV 与矿物质代谢产物循环水平之间的关系。
与调节 G 蛋白偶联信号转导 14（RGS14）和钙敏感受体（CASR）基因相邻或内部的 SNVs 与矿物质代谢产物的水平相关。最强的关联（P<0.001）位于 rs4074995（RGS14）的磷酸盐（每一个等位基因少 0.09mg/dL）和 FGF23（低 8.6%），rs1801725（CASR）的钙（高 0.12mg/dL）。此外，rs4074995（RGS14）的基因型不同，甲状旁腺功能亢进的患病率也不同（卡方 P<0.0001）。种族之间的差异遗传也注意到了 RGS14 的次要等位基因。表达数量性状基因座（eQTL）分析表明，rs4074995 与肾小球（P=1.03×10-11）和肾小管（P=4.0×10-4）中 RGS14 基因表达降低有关。
我们评估了 CKD 人群中与矿物质代谢标志物相关的遗传变异。CKD 患者和 rs4074995（RGS14）的次要等位基因携带者的磷、血浆 FGF23 水平较低，甲状旁腺功能亢进的患病率较低。RGS14 的次要等位基因也与肾脏中基因表达降低有关。需要进一步的研究来阐明 rs4074995 对 CKD 中矿物质代谢紊乱发病机制的影响。
