Interactions between FGF23 and Genotype in Autosomal Dominant Polycystic Kidney Disease.
Interactions between FGF23 and Genotype in Autosomal Dominant Polycystic Kidney Disease.
复制标题
DOI：
10.34067/kid.0001692020
复制
发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Nowak KL
中科院分区：
文献类型：
--
作者：
Grau L;Gitomer B;McNair B;Wolf M;Harris P;Brosnahan G;Torres V;Steinman T;Yu A;Chapman A;Chonchol M;Nowak KL
在HALT-PKD研究中，较高的血清完整成纤维细胞生长因子23(IFGF23)与常染色体显性遗传性多囊肾病(ADPKD)参与者的疾病进展相关。PKD突变也是疾病进展的重要决定因素。我们假设血清iFGF23和维生素D代谢产物(1，25-二羟基维生素D[1，25(OH)2D]和25-羟基维生素D[25[OH]D])水平根据ADPKD突变而不同，并根据基因差异预测临床终点(基因和矿物代谢物之间的显著交互作用)。共有864名ADPKD患者参加了HALT-PKD研究A或B，并测量了矿物代谢物(1，25[OH]2D，25[OH]D，iFGF23)，按PKD突变(PKD1截断，PKD1非截断，PKD2，或未检测到突变[NMD])进行分类。通过线性回归和COX比例风险回归，评估了基因型×iFGF23、基因型×1，25(OH)2D和基因型×25(OH)D的交互作用与(1)EGFR的年化变化；(2)校正身高的总肾体积的平均年化百分比变化；以及(3)EGFR、ESKD或死亡减少50%的综合时间的关系。中位数(四分位数范围)iFGF23按PKD基因型不同有差异(PKD1截断，55.8[40.7~76.8]；PKD1非截断，49.9[37.7~71.0]；PKD2，49.0[33.8~70.5]；NMD，50.3[39.7~67.4]pg/ml；P=0.03)和平均值±SD1，25(OH)2D差异(PKD1截断，32.8±12.8；PKD1非截断，33.4±12.5；PKD2，34.1±13.1；NMD，38.0±14.6pg/ml；P=0.02)。在完全调整的模型中，iFGF23与复合终点的基因型有显著交互作用(P=0.02)，而1，25(OH)2D或25(OH)D与临床终点的基因型无显著交互作用。ADPKD基因与FGF23显著相互作用，影响临床终点。虽然最糟糕的结果发生在具有PKD1截断或非截断突变和最高iFGF23三分位数的个体中，但复合终点的风险根据iFGF23的不同而不同，在PKD1非截断和PKD2组中最大。
Higher serum intact fibroblast growth factor 23 (iFGF23) was associated with disease progression in participants with autosomal dominant polycystic kidney disease (ADPKD) in the HALT-PKD Studies. PKD mutation is also an important determinant of progression. We hypothesized that serum levels of iFGF23 and vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)2D] and 25-hydroxyvitamin D [25[OH]D]) differ according to ADPKD mutation and differentially predict clinical end points according to genotype (significant interaction between genotype and mineral metabolites). A total of 864 individuals with ADPKD who participated in the HALT-PKD Study A or B and had measurements of mineral metabolites (1,25[OH]2D, 25[OH]D, iFGF23) were categorized by PKD mutation (PKD1 truncating, PKD1 nontruncating, PKD2, or no mutation detected [NMD]). The association of the interactions of genotype × iFGF23, genotype × 1,25(OH)2D, and genotype × 25(OH)D with (1) annualized change in eGFR; (2) mean annualized percentage change in height-corrected total kidney volume (Study A only); and (3) time to a composite of 50% reduction in eGFR, ESKD, or death were evaluated using linear regression and Cox proportional hazards regression. Median (interquartile range) iFGF23 differed (PKD1 truncating, 55.8 [40.7–76.8]; PKD1 nontruncating, 49.9 [37.7–71.0]; PKD2, 49.0 [33.8–70.5]; NMD, 50.3 [39.7–67.4] pg/ml; P=0.03) and mean±SD 1,25(OH)2D differed (PKD1 truncating, 32.8±12.8; PKD1 nontruncating, 33.4±12.5; PKD2, 34.1±13.1; NMD, 38.0±14.6 pg/ml; P=0.02) according to PKD genotype. There was a significant interaction between iFGF23 and genotype (P=0.02) for the composite end point in fully adjusted models, but no significant interaction between 1,25(OH)2D or 25(OH)D and genotype for clinical end points. ADPKD genotype interacts significantly with FGF23 to influence clinical end points. Whereas the worst outcomes were in individuals with a PKD1-truncating or -nontruncating mutation and the highest iFGF23 tertile, risk of the composite end point differed according to iFGF23 the most in the PKD1-nontruncating and PKD2 groups.