Akwo Elvis A, Chen Hua-Chang, Liu Ge, Triozzi Jefferson L, Tao Ran, Yu Zhihong, Chung Cecilia P, Giri Ayush, Ikizler T Alp, Stein C Michael, Siew Edward D, Feng QiPing, Robinson-Cohen Cassianne, Hung Adriana M
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Vanderbilt Center for Kidney Disease, Nashville, Tennessee, USA.
Kidney Int Rep. 2022 May 18;7(8):1802-1818. doi: 10.1016/j.ekir.2022.05.011. eCollection 2022 Aug.
Common variants in the gene are considered an evolutionary adaptation against urinary tract infections (UTIs) and have been implicated in kidney stone formation, chronic kidney disease (CKD), and hypertension. However, differences in variant-phenotype associations across population groups are unclear.
We tested associations between variants and up to 1528 clinical diagnosis codes mapped to phenotype groups in the Million Veteran Program (MVP), using published phenome-wide association study (PheWAS) methodology. Associations were tested using logistic regression adjusted for age, sex, and 10 principal components of ancestry. Bonferroni correction for multiple comparisons was applied.
Among 648,593 veterans, mean (SD) age was 62 (14) years; 9% were female, 19% Black, and 8% Hispanic. In White patients, the rs4293393 risk variant associated with increased uromodulin was associated with increased odds of CKD (odds ratio [OR]: 1.22, 95% CI: 1.20-1.24, = 5.90 × 10), end-stage kidney disease (OR: 1.17, 95% CI: 1.11-1.24, = 2.40 × 10), and hypertension (OR: 1.03, 95% CI: 1.05-1.05, = 2.11 × 10) and significantly lower odds of UTIs (OR: 0.94, 95% CI: 0.92-0.96, = 1.21 × 10) and kidney calculus (OR: 0.85, 95% CI: 0.83-0.86, = 4.27 × 10). Similar findings were observed across variants. The rs77924615 variant had stronger associations with acute cystitis in White female (OR: 0.73, 95% CI: 0.59-0.91, = 4.98 × 10) versus male (OR: 0.99, 95% CI: 0.89-1.11, = 8.80 × 10) ( interaction = 0.01) patients. In Black patients, the rs77924615 variant was significantly associated with pyelonephritis (OR: 0.65, 95% CI: 0.54-0.79, = 1.05 × 10), whereas associations with promoter variants were attenuated.
Robust associations were observed between variants linked with increased uromodulin expression and lower odds of UTIs and calculus and increased odds of CKD and hypertension. However, these associations varied significantly across ancestry groups and sex.
该基因中的常见变异被认为是针对尿路感染（UTIs）的一种进化适应，并且与肾结石形成、慢性肾脏病（CKD）和高血压有关。然而，不同人群组中变异-表型关联的差异尚不清楚。
我们使用已发表的全表型关联研究（PheWAS）方法，在百万退伍军人计划（MVP）中测试了该变异与多达1528个映射到表型组的临床诊断代码之间的关联。使用对年龄、性别和10个祖先主成分进行校正的逻辑回归来测试关联。应用Bonferroni多重比较校正。
在648,593名退伍军人中，平均（标准差）年龄为62（14）岁；9%为女性，19%为黑人，8%为西班牙裔。在白人患者中，与尿调节蛋白增加相关的rs4293393风险变异与CKD（比值比[OR]：1.22，95%置信区间：1.20 - 1.24，P = 5.90×10）、终末期肾病（OR：1.17，95%置信区间：1.11 - 1.24，P = 2.40×10）和高血压（OR：1.03，95%置信区间：1.05 - 1.05，P = 2.11×10）的几率增加相关，并且UTIs（OR：0.94，95%置信区间：0.92 - 0.96，P = 1.21×10）和肾结石（OR：0.85，95%置信区间：0.83 - 0.86，P = 4.27×10）的几率显著降低。在其他变异中也观察到了类似的发现。rs77924615变异在白人女性（OR：0.73，95%置信区间：0.59 - 0.91，P = 4.98×10）与男性（OR：0.99，95%置信区间：0.89 - 1.11，P = 8.80×10）（交互作用P = 0.01）患者中与急性膀胱炎的关联更强。在黑人患者中，rs77924615变异与肾盂肾炎显著相关（OR：0.65，95%置信区间：0.54 - 0.79，P = 1.05×10），而与该基因启动子变异的关联减弱。
观察到与尿调节蛋白表达增加相关的该变异与UTIs和结石几率降低以及CKD和高血压几率增加之间存在显著关联。然而，这些关联在不同祖先群体和性别之间有显著差异。
