Qi Han, Sun Mingshu, Terkeltaub Robert, Merriman Tony R, Chen Haibing, Li Zhiqiang, Ji Aichang, Xue Xiaomei, Sun Wenyan, Wang Can, Li Xinde, He Yuwei, Cui Lingling, Dalbeth Nicola, Li Changgui
The Affiliated Hospital of Qingdao University, Qingdao University, and Shandong Provincial Clinical Research Center for Immune Diseases and Gout, Qingdao, China.
The Affiliated Hospital of Qingdao University, Qingdao, China.
Arthritis Rheumatol. 2024 Jul;76(7):1130-1140. doi: 10.1002/art.42838. Epub 2024 Mar 27.
Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biologic characteristics (including genetic background) of clinically defined hyperuricemia subtypes in two large geographically independent gout cohorts.
Hyperuricemia subtype was defined as renal uric acid overload (ROL), renal uric acid underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNPs) previously identified as gout risk loci or associated with serum urate (SU) concentration in the East Asian population were genotyped. Weighted polygenic risk scores were calculated to assess the cumulative effect of genetic risks on the subtypes.
Of the 4,873 participants, 8.8% had an ROL subtype, 60.9% RUE subtype, 23.1% combined subtype, and 7.2% normal subtype. The ROL subtype was independently associated with older age at onset, lower SU, tophi, and diabetes mellitus; RUE was associated with lower body mass index (BMI) and non-diabetes mellitus; the combined subtype was associated with younger age at onset, higher BMI, SU, estimated glomerular filtration rate (eGFR), and smoking; and the normal subtype was independently associated with older age at onset, lower SU, and eGFR. Thirteen SNPs were associated with gout with 6 shared loci and subtype-dependent risk loci patterns. High polygenic risk scores were associated with ROL subtype (odds ratio [OR] = 9.63, 95% confidence interval [95% CI] 4.53-15.12), RUE subtype (OR = 2.18, 95% CI 1.57-3.03), and combined subtype (OR = 6.32, 95% CI 4.22-9.48) compared with low polygenic risk scores.
Hyperuricemia subtypes classified according to renal uric acid handling have subtype-specific clinical and genetic features, suggesting subtype-unique pathophysiologic mechanisms.
高尿酸血症可根据肾脏尿酸处理情况分为四种亚型。本研究的目的是全面描述两个地理位置独立的大型痛风队列中临床定义的高尿酸血症亚型的生物学特征（包括遗传背景）。
高尿酸血症亚型定义为肾脏尿酸过载（ROL）、肾脏尿酸排泄不足（RUE）、混合型或肾脏正常型。对先前确定为痛风风险位点或与东亚人群血清尿酸（SU）浓度相关的20个单核苷酸多态性（SNP）进行基因分型。计算加权多基因风险评分以评估遗传风险对各亚型的累积影响。
在4873名参与者中，8.8%为ROL亚型，60.9%为RUE亚型，23.1%为混合型，7.2%为正常型。ROL亚型与发病年龄较大、SU较低、痛风石和糖尿病独立相关；RUE与较低的体重指数（BMI）和非糖尿病相关；混合型与发病年龄较小、较高的BMI、SU、估计肾小球滤过率（eGFR）和吸烟相关；正常型与发病年龄较大、较低的SU和eGFR独立相关。13个SNP与痛风相关，有6个共享位点和亚型依赖性风险位点模式。与低多基因风险评分相比，高多基因风险评分与ROL亚型（优势比[OR]=9.63，95%置信区间[95%CI]4.53 - 15.12）、RUE亚型（OR = 2.18，95%CI 1.57 - 3.03）和混合型（OR = 6.32，95%CI 4.22 - 9.48）相关。
根据肾脏尿酸处理情况分类的高尿酸血症亚型具有亚型特异性的临床和遗传特征，提示存在亚型独特的病理生理机制。
