Dysfunctional ABCG2 gene polymorphisms are associated with serum uric acid levels and all-cause mortality in hemodialysis patients

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.

The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update

“…One of the best-studied variations of the ABCG2 amino acid sequence is the previously discussed Q141K polymorphism, which also gives rise to other important clinical phenotypes, such as in the pharmacokinetics and tissue distribution of drugs transported by ABCG2 [97]. The polymorphism is highly associated with early-onset hyperuricemia, gout, and hyperuricemia-associated comorbidities, which cause a high mortality rate in hemodialysis patients [98]. Although the F489L polymorphism has not been as well studied in the context of disease, it shows a similar inhibitory effect on the ABCG2 transport function as the Q141K mutation.…”

Examining an Association of Single Nucleotide Polymorphisms with Hyperuricemia in Chinese Flight Attendants

“…Because male flight attendants showed a higher prevalence of elevated SUA than males of the Chinese population ( Table 3 ), we examined whether there is a link of genetic variants with hyperuricemia in recruited male hyperuricemia and control groups. Previous studies have reported that polymorphisms of ABCG2 , rs2231142 (Q141K), rs72552713 (Q126X) and rs2231137 (V12M); GCKR , rs780094; SLC2A9 , rs1014290 and SLC17A1 , rs1183201 might be associated with hyperuricemia, 21 , 26 , 44 , 45 we thus decided to analyze these six SNPs among studied subjects by performing AS-PCR ( Table 2 ). Except the SNP rs2231137 of ABCG2 ( P < 0.05 in controls), genotype distributions of other SNPs in the two groups were in accordance with the Hardy-Weinberg equilibrium (HWE) test ( P > 0.05).…”

Polymorphisms of the genes ABCG2, SLC22A12 and XDH and their relation with hyperuricemia and hypercholesterolemia in Mexican young adults

“…The first corresponds to the exchange of a glutamine for a lysine at position 141 of an adenosine triphosphate (ATP)-binding cassette transporter subfamily G member 2 ( ABCG2 ). This exchange predisposes individuals to hyperuricemia ( Nakashima et al , 2020 ; Wrigley et al ., 2020 ). A frequency of 0.25 for the risk for T allele was found, a slightly lower prevalence than that reported in Asian and New Zealand populations ( Kim et al , 2015 ; Liu et al , 2020b ; Toyoda et al , 2019 ).…”