Abstract
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.
Highlights
ATP-binding cassette transporter subfamily G member 2 (ABCG2) is located in a gout-susceptibility locus on chromosome 4q, which was identified by previous studies including genome-wide association studies of serum uric acid levels [1, 2]
A total of 1214 hemodialysis patients were evaluated and divided into quartiles according to serum uric acid levels (Table 1)
Using multiple linear regression analysis of uric acid levels with the dependent variables, estimated ABCG2 function was significantly associated with serum uric acid levels in the adjusted models (Table 4)
Summary
ATP-binding cassette transporter subfamily G member 2 (ABCG2) is located in a gout-susceptibility locus on chromosome 4q, which was identified by previous studies including genome-wide association studies of serum uric acid levels [1, 2]. ABCG2 is a high-capacity urate exporter in the kidney and intestine, the dysfunction of which increases the risk for gout and hyperuricemia [3,4,5,6]. Hyperuricemia is a risk factor for cardiovascular disease (CVD) in the general population [9, 10]. A previous study reported that serum uric acid levels were dependent on ABCG2 polymorphisms [3, 6, 11]. These results suggest that ABCG2 plays a prominent role in uric acid homeostasis
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