You Ruilian, Chen Lanlan, Xu Lubin, Zhang Dingding, Li Haitao, Shi Xiaoxiao, Zheng Yali, Chen Limeng
Department of Nephrology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
First Clinical Medical College of Norman Bethune Health Science Center, Jilin University, Changchun, China.
Front Cardiovasc Med. 2021 Sep 1;8:736001. doi: 10.3389/fcvm.2021.736001. eCollection 2021.
The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure. We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension ( = 46,188), systolic blood pressure (SBP, = 1,194,020), and diastolic blood pressure (DBP, = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis. MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension ("ukb-b-14057" and "ukb-b-14177") is 1.04 (95% Confidence Interval (CI), 1.03-1.04, < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, = 8.92E-06) and 0.03 (SE = 0.01, = 2.70E-04) in "ieu-b-38" and "ukb-b-20175", respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, = 4.38E-06) in "ieu-b-39" and 0.05 (SE = 0.01, = 2.13E-10) in "ukb-b-7992". As for the sUMOD, the OR of hypertension ("ukb-b-14057" and "ukb-b-14177") is 1.01 (95% CI 1.01-1.02, all < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, = 1.26E-07) in "ieu-b-38" and 0.01 (SE = 0.003, = 1.04E-04) in "ukb-b-20175". The sUMOD is causally associated with elevated DBP ("ieu-b-39": β = 0.313, SE = 0.050, = 3.43E-10; "ukb-b-7992": β = 0.018, SE = 0.003, = 8.41E-09). Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.
临床研究中已观察到尿调节蛋白与高血压之间的关联，但尚未通过因果关系得到证实。我们进行了一项两样本孟德尔随机化（MR）分析，以研究尿调节蛋白与血压之间的因果关系。我们从一项大型全基因组关联研究（GWAS）荟萃分析研究以及PubMed中的研究中选择了与尿中尿调节蛋白（uUMOD）和血清尿调节蛋白（sUMOD）相关的单核苷酸多态性（SNP）。基于英国生物银行和国际血压联盟（ICBP）的六个数据集用作高血压（n = 46,188）、收缩压（SBP，n = 1,194,020）和舒张压（DBP，n = 1,194,020）大样本量的结果。在uUMOD MR分析中采用逆方差加权（IVW）方法，而在sUMOD MR分析中使用IVW、MR-Egger、加权中位数和孟德尔随机化多效性残差和异常值（MR-PRESSO）方法。IVM的MR分析显示，uUMOD与高血压（“ukb-b-14057”和“ukb-b-14177”）的比值比（OR）为1.04（95%置信区间（CI），1.03 - 1.04，P < 0.001）；在“ieu-b-38”和“ukb-b-20175”中，uUMOD对SBP的效应大小分别为1.10（标准误（SE） = 0.25，P = 8.92E - 06）和0.03（SE = 0.01，P = 2.70E - 04）。在“ieu-b-39”中，uUMOD对DBP的β系数为0.88（SE = 0.19，P = 4.38E - 06），在“ukb-b-7992”中为0.05（SE = 0.01，P = 2.13E - 10）。至于sUMOD，高血压（“ukb-b-14057”和“ukb-b-14177”）的OR为1.01（95% CI 1.01 - 1.02，均P < 0.001）。在“ieu-b-38”中，SBP的β系数为0.37（SE = 0.07，P = 1.26E - 07），在“ukb-b-20175”中为0.01（SE = 0.003，P = 1.04E - 04）。sUMOD与DBP升高存在因果关联（“ieu-b-39”：β = 0.313，SE = 0.050，P = 3.43E - 10；“ukb-b-7992”：β = 0.018，SE = 0.003，P = 8.41E - 09）。我们的结果表明，高尿和血清尿调节蛋白水平在升高血压方面可能具有有害作用，并作为高血压的一个因果风险因素。
