Associations of adiposity, kidney stone disease, and serum calcium concentrations; observational and genetic epidemiological studies-猫眼课题宝

DOI：

10.1101/2022.06.10.22276271

发表时间：

2022-06

期刊：

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

C. Lovegrove;J. Bešević;A. Wiberg;B. Lacey;T. Littlejohns;N. Allen;M. Goldsworthy;J. Kim;F. Hannan;G. Curhan;M. McCarthy;A. Mahajan;B. Turney;R. Thakker;M. Holmes;D. Furniss;S. Howles

背景资料：肾结石病（KSD）与肥胖、代谢综合征和生化改变（包括血清钙浓度升高）有关。这些表型与KSD相关的机制尚不确定。我们的目的是建立肥胖对KSD的影响，使用传统和遗传流行病学技术。方法：我们评估了来自英国生物银行的479，405人的肥胖测量和事件KSD之间的观察关联。为了便于孟德尔随机化（MR）分析，我们在英国生物库中进行了KSD的全基因组关联研究（GWAS），包括组合和性别特异性子集。使用单变量、多变量和中介MR分析来计算每种基因检测的较高肥胖标志物、代谢综合征参数、生化表型和炎症的KSD风险的比值比（OR）或β系数（{β}），并识别MR假设的违背。调查结果：观察分析表明，中心性肥胖的措施（腰臀比，WHR，腰围，WC）与事件KSD比一般肥胖的措施（体重指数，BMI）更强的相关性。三个新的KSD-GWAS基因座（SLC 2A 12，TRPV 5和SLC 28 A1），未检测到性别特异性基因座。MR分析证实，较高的中心性肥胖与KSD和较高的校正血清钙浓度存在因果关系，与BMI无关（WHR高一个标准差：KSD的OR =1.43，p=4.1x10-6;血清钙浓度的{beta}=0.12mol/L，p=2.7x10-7）。中介分析表明，WHR对KSD的影响中有12%是由于其升高血清钙浓度的作用。我们的MR研究表明，代谢综合征的其他成分、血清尿酸水平和炎症生物标志物不太可能与KSD的病因有关。解释：我们的研究表明，内脏脂肪库升高血清钙浓度，导致KSD的风险增加。针对中心脂肪沉积的治疗可能影响钙稳态，并可用于预防KSD。

Background: Kidney stone disease (KSD) is linked to obesity, metabolic syndrome and biochemical alterations including higher serum calcium concentration. The mechanisms by which these phenotypes associate with KSD are uncertain. We aimed to establish the effects of adiposity on KSD using conventional and genetic epidemiological techniques. Methods: We assessed observational associations between measures of adiposity and incident KSD in 479,405 people from the UK Biobank. To facilitate Mendelian randomization (MR) analyses, we undertook genome-wide association studies (GWAS) of KSD in the UK Biobank in combined and sex-specific subsets. Univariable, multivariable and mediation MR analyses were used to calculate odds ratio (OR) or beta coefficient ({beta}) for risk of KSD per genetically instrumented higher marker of adiposity, metabolic syndrome parameter, biochemical phenotype, and inflammation and identify violations of MR assumptions. Findings: Observational analyses demonstrated that measures of central adiposity (waist-hip ratio, WHR, and waist circumference, WC) are more strongly associated with incident KSD than measures of general adiposity (body mass index, BMI). Three novel KSD-GWAS loci were identified (SLC2A12, TRPV5, and SLC28A1); no sex-specific loci were detected. MR analyses established that higher central adiposity is causally linked to both KSD and higher adjusted serum calcium concentrations independent of BMI (one standard deviation higher WHR: OR for KSD=1.43, p=4.1x10-6; {beta} for serum calcium concentration=0.12mol/L, p=2.7x10-7). Mediation analyses indicated that 12% of the effect of WHR on KSD is due its role in elevating serum calcium concentration. Our MR studies indicated that other components of the metabolic syndrome, serum uric acid levels, and biomarkers of inflammation are unlikely to be implicated in the causation of KSD. Interpretation: Our study indicates that visceral adipose depots elevate serum calcium concentration and cause an increased risk of KSD. Therapies targeting central adipose deposition may affect calcium homeostasis and have utility for the prevention of KSD.

Associations of adiposity, kidney stone disease, and serum calcium concentrations; observational and genetic epidemiological studies

文献摘要

相似文献