Genetic variants of calcium and vitamin D metabolism in kidney stone disease
Genetic variants of calcium and vitamin D metabolism in kidney stone disease
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肾结石疾病中钙和维生素 D 代谢的遗传变异
DOI：
10.1101/515882
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Howles S
中科院分区：
文献类型：
--
作者：
Howles S
< jats: p>肾结石病（肾结石）是一种主要的临床和经济健康负担< jats: sup>1，2，遗传率约为45-60% < jats: sup>3。为了确定与肾结石相关的遗传变异，我们在英国和日本人群中进行了全基因组关联研究（GWAS）和荟萃分析，包括12，123例肾结石病例和416，928例对照。20个位点与肾结石的鉴定，其中10个是新的。预计一个新< jats: italic>的CYP 24 A1基因座会影响维生素D代谢，< jats: italic>而DGKD、DGKH、WDR 72、GPIC 1和< jats: italic>BCR这五个基因座预计会影响钙敏感受体（CaSR）信号传导。在肾结石患者的验证队列中，< jats: italic>CYP 24 A1相关位点与血清钙浓度和肾结石发作次数相关，< jats: italic>DGKD相关位点与尿钙排泄相关。此外，DGKD敲低损害体外CaSR信号转导< jats: italic>，这种作用可以用拟钙剂西那卡塞纠正。我们的研究结果表明，基因分型可以在补充维生素D之前告知肾结石疾病的风险，并通过针对复发性肾结石患者的CaSR信号传导或维生素D激活途径来促进精准医学方法。
< jats: p> Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden< jats: sup> 1, 2 with a heritability of~ 45-60%< jats: sup> 3. To identify genetic variants associated with nephrolithiasis we performed genome-wide association studies (GWAS) and meta-analysis in British and Japanese populations, including 12,123 nephrolithiasis cases and 416,928 controls. Twenty loci associated with nephrolithiasis were identified, ten of which are novel. A novel< jats: italic> CYP24A1 locus is predicted to affect vitamin D metabolism and five loci,< jats: italic> DGKD, DGKH, WDR72, GPIC1, and< jats: italic> BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of nephrolithiasis patients the< jats: italic> CYP24A1-associated locus correlated with serum calcium concentration and number of kidney stone episodes, and the< jats: italic> DGKD-associated locus correlated with urinary calcium excretion. Moreover, DGKD knockdown impaired CaSR-signal transduction< jats: italic> in vitro, an effect that was rectifiable with the calcimimetic cinacalcet. Our findings indicate that genotyping may inform risk of incident kidney stone disease prior to vitamin D supplementation and facilitate precision-medicine approaches, by targeting CaSR-signaling or vitamin D activation pathways in patients with recurrent kidney stones.
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影响因子：
7.1
作者：
Wallace, Robert B.;Wactawski-Wende, Jean;Masaki, Kamal
通讯作者：
Masaki, Kamal
JPHC研究的基线调查——设计和参与率。
影响因子：
4.7
作者：
S. Tsugane;T. Sobue
通讯作者：
T. Sobue
西那卡塞可纠正由种系功能丧失 Gα11 突变引起的 2 型家族性低钙尿性高钙血症 (FHH2) 患者的高钙血症
影响因子：
6.2
作者：
C. Gorvin;F. Hannan;T. Cranston;H. Valta;O. Makitie;Camilla Schalin;R. Thakker
通讯作者：
R. Thakker
影响因子：
6
作者：
Goldfarb, David S.;Avery, Ally R.;Goldberg, Jack
通讯作者：
Goldberg, Jack
影响因子：
4.7
作者：
Kuriyama S;Yaegashi N;Nagami F;Arai T;Kawaguchi Y;Osumi N;Sakaida M;Suzuki Y;Nakayama K;Hashizume H;Tamiya G;Kawame H;Suzuki K;Hozawa A;Nakaya N;Kikuya M;Metoki H;Tsuji I;Fuse N;Kiyomoto H;Sugawara J;Tsuboi A;Egawa S;Ito K;Chida K;Ishii T;Tomita H;Taki Y;Minegishi N;Ishii N;Yasuda J;Igarashi K;Shimizu R;Nagasaki M;Koshiba S;Kinoshita K;Ogishima S;Takai-Igarashi T;Tominaga T;Tanabe O;Ohuchi N;Shimosegawa T;Kure S;Tanaka H;Ito S;Hitomi J;Tanno K;Nakamura M;Ogasawara K;Kobayashi S;Sakata K;Satoh M;Shimizu A;Sasaki M;Endo R;Sobue K;Tohoku Medical Megabank Project Study Group T;Yamamoto M
通讯作者：
Yamamoto M