Grzegorzewska Alicja E, Bednarski Dariusz, Świderska Monika, Mostowska Adrianna, Jagodziński Paweł P
Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznań, Poland,
Student Nephrology Research Group, Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznań, Poland.
Kidney Blood Press Res. 2018;43(3):719-734. doi: 10.1159/000489747. Epub 2018 May 10.
BACKGROUND/AIMS: The calcium-sensing receptor gene (CASR) rs1801725 variant is responsible for a non-conservative amino-acid change (A986S) in the calcium-sensing receptor cytoplasmic tail. We hypothesized that rs1801725 polymorphism might be helpful in understanding Ca-related abnormalities in HD patients.
In 1215 subjects (245 on cinacalcet), we determined the associations of rs1801725 with secondary hyperparathyroidism (sHPT)-related laboratory parameters, PTH-decreasing effect of cinacalcet hydrochloride, coronary artery disease (CAD), myocardial infarction (MI), nephrolithiasis-related ESRD, and mortality. CASR rs7652589(A<G)_rs1801725(G>T) haplotypes and rs1801725 epistatic interactions with vitamin D signaling pathway genes were examined for associations with selected phenotypes.
The rs1801725 variant allele showed an increasing independent effect on plasma PTH (Pcorrected = 0.009). CASR rs7652589_rs1801725 AT haplotype was associated with 1.7-fold higher frequency of PTH levels over 437 pg/mL than the reference haplotype GG (P = 0.001). CASR rs7652589_rs1801725 AG haplotype was 1.5-fold more frequent in nephrolithiasis-related ESRD than the GG haplotype (P = 0.004). There were no significant associations between rs1801725, CAD, MI, and response to cinacalcet. Variant homozygosity of rs1801725 correlated independently with higher infection-related mortality compared with heterozygosity (HR 7.95, 95%CI 2.15 - 29.37, P = 0.003) and major homozygosity (HR 5.89, 95%CI 1.69 - 20.55, P = 0.040). CASR rs1801725 did not show epistatic interactions with vitamin D signaling pathway genes concerning tested associations.
The variant allele of CASR rs1801725 solely and together with the variant allele of rs7652589 increases risk of more advanced sHPT. Homozygosity of the rs1801725 variant allele contributes to infection-related mortality in HD patients.
背景/目的：钙敏感受体基因（CASR）rs1801725变异导致钙敏感受体胞质尾出现非保守氨基酸变化（A986S）。我们推测rs1801725多态性可能有助于理解HD患者的钙相关异常情况。
在1215名受试者（245名使用西那卡塞）中，我们确定了rs1801725与继发性甲状旁腺功能亢进（sHPT）相关实验室参数、盐酸西那卡塞的降甲状旁腺素作用、冠状动脉疾病（CAD）、心肌梗死（MI）、肾结石相关的终末期肾病（ESRD）以及死亡率之间的关联。研究了CASR rs7652589（A<G）_rs1801725（G>T）单倍型以及rs1801725与维生素D信号通路基因的上位相互作用与选定表型的关联。
rs1801725变异等位基因对血浆甲状旁腺素显示出越来越强的独立影响（P校正 = 0.009）。与参考单倍型GG相比，CASR rs7652589_rs1801725 AT单倍型与甲状旁腺素水平超过437 pg/mL的频率高1.7倍相关（P = 0.001）。在肾结石相关的ESRD中，CASR rs7652589_rs1801725 AG单倍型比GG单倍型的频率高1.5倍（P = 0.004）。rs1801725、CAD、MI与西那卡塞反应之间无显著关联。与杂合子相比，rs1801725的变异纯合子与较高的感染相关死亡率独立相关（风险比7.95，95%置信区间2.15 - 29.37，P = 0.003），与主要纯合子相比也是如此（风险比5.89，95%置信区间1.69 - 20.55，P = 0.040）。就所测试的关联而言，CASR rs1801725与维生素D信号通路基因未显示上位相互作用。
CASR rs1801725的变异等位基因单独以及与rs7652589的变异等位基因共同增加了更严重sHPT的风险。rs1801725变异等位基因的纯合子导致HD患者的感染相关死亡率增加。
