Dysfunctional ABCG2 gene polymorphisms are associated with serum uric acid levels and all-cause mortality in hemodialysis patients
Dysfunctional ABCG2 gene polymorphisms are associated with serum uric acid levels and all-cause mortality in hemodialysis patients
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DOI：
10.1007/s13577-020-00342-w
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发表时间：
2020-03
期刊：
影响因子：
4.3
通讯作者：
Akio Nakashima;K. Ichida;I. Ohkido;K. Yokoyama;H. Matsuo;Y. Ohashi;T. Takada;A. Nakayama;H. Suzuki;N. Shinomiya;M. Urashima;T. Yokoo
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作者：
Akio Nakashima;K. Ichida;I. Ohkido;K. Yokoyama;H. Matsuo;Y. Ohashi;T. Takada;A. Nakayama;H. Suzuki;N. Shinomiya;M. Urashima;T. Yokoo
ATP 结合盒转运蛋白亚家族 G 成员 2 (ABCG2)（肾脏和肠道中的尿酸盐转运蛋白）的功能失调变异是高尿酸血症和痛风的主要原因。最近的一项研究发现 ABCG2 是尿毒症毒素的主要转运蛋白；然而，很少有研究探讨ABCG2基因多态性与死亡率之间的关系。这项针对 1214 名血液透析患者的前瞻性队列研究调查了血清尿酸水平与 ABCG2 基因型和死亡率之间的关联。使用患者的 DNA 对功能失调的 ABCG2 变异 Q126X (rs72552713) 和 Q141K (rs2231142) 进行基因分型。研究期间，220 名患者死亡。较低的血清尿酸水平与较高的死亡率相关（风险比[HR] 1.89，95%置信区间[CI] 1.14–3.10，P≤0.001）。通过遗传变异估计的 ABCG2 功能障碍与血清尿酸水平呈显着正相关（全功能：7.4±±1.2 mg/dl，3/4 功能：7.9±±1.3 mg/dl，1/2 功能：8.2±1.4 mg/dl，≤ 1/4 功能： 8.7 ± 1.3 mg/dl，P≤ 0.001）。这种关联在多元回归分析中仍然显着。 Cox比例风险分析表明，ABCG2 ≤ 1/4功能类型与其他功能类型相比死亡率较高（HR 6.66，95% CI 2.49～17.8，P≤ 0.001）。这些结果表明ABCG2在尿酸排泄中发挥着重要的生理作用，ABCG2功能障碍是血液透析患者死亡的危险因素。
Dysfunctional variants of ATP-binding cassette transporter subfamily G member 2 (ABCG2), a urate transporter in the kidney and intestine, are the major causes of hyperuricemia and gout. A recent study found that ABCG2 is a major transporter of uremic toxins; however, few studies have investigated the relationship between ABCG2 gene polymorphisms and mortality. This prospective cohort study of 1214 hemodialysis patients investigated the association between serum uric acid levels and ABCG2 genotype and mortality. Genotyping of dysfunctional ABCG2 variants, Q126X (rs72552713) and Q141K (rs2231142), was performed using the patients’ DNA. During the study period, 220 patients died. Lower serum uric acid levels were associated with higher mortality (hazard ratio [HR] 1.89, 95% confidence interval [CI] 1.14–3.10,P≤ 0.001). ABCG2 dysfunction, estimated by genetic variants, had a significant positive association with serum uric acid levels (full function: 7.4 ± 1.2 mg/dl, 3/4 function: 7.9 ± 1.3 mg/dl, 1/2 function: 8.2 ± 1.4 mg/dl, ≤ 1/4 function: 8.7 ± 1.3 mg/dl,P≤ 0.001). This association remained significant on multiple regression analysis. The Cox proportional hazard analysis indicated that the ABCG2 ≤ 1/4 function type was significantly associated with higher mortality (HR 6.66, 95% CI 2.49 to 17.8,P≤ 0.001) than the other function types. These results showed that ABCG2 plays a physiologically important role in uric acid excretion, and that ABCG2 dysfunction is a risk factor for mortality in hemodialysis patients.