<i>SLC2A9</i> Gene Polymorphism Is Associated with Elevated Serum Uric Acid Caused by Pyrazinamide

Dai, Yuyang; Wang, Yunyun; Wu, Wanfeng; Guo, Shaojie; Zhao, Xiuli

doi:https://doi.org/10.1155/2023/6677236

Journal of Clinical Pharmacy and Therapeutics

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Research Article | Open Access

Volume 2023 | Article ID 6677236 | https://doi.org/10.1155/2023/6677236

SLC2A9 Gene Polymorphism Is Associated with Elevated Serum Uric Acid Caused by Pyrazinamide

Yuyang Dai,^1,2Yunyun Wang,^1,3Wanfeng Wu,⁴Shaojie Guo,^1,2and Xiuli Zhao^1,2

Academic Editor: Samuel Silvestre

Received02 Feb 2023

Revised13 Apr 2023

Accepted24 Apr 2023

Published08 May 2023

Abstract

What Is Known and Objective. Elevated serum uric acid (SUA) is one of the most common adverse reactions during the administration of pyrazinamide, but patients exhibit significant individual differences. This study aimed to evaluate the relationship between gene polymorphisms and pyrazinamide-induced SUA elevation in Han Chinese tuberculosis patients. Methods. Tuberculosis patients treated with pyrazinamide were genotyped for the following three candidate genes: SLC22A12, SLC2A9, and ABCG2. Patients were divided into low-risk and high-risk groups according to the change of SUA after treatment. Intergroup comparisons were performed on clinical characteristics, allele and genotype frequencies, and haplotype distributions, and logistic regression analysis was used to explore the relevant risk factors. Results. In total, 143 patients were enrolled, including 83 in the high-risk groups and 60 in the low-risk groups. We observed a significant association between SLC2A9 polymorphism and pyrazinamide-induced SUA elevation. The G allele was significantly lower in the high-risk group than in the low-risk group (27.7% vs. 48.3%, OR = 0.410, 95% CI: 0.250–0.671, ). Patients with the GA and GG genotypes were less likely to have SUA elevation than those with the AA genotype (OR = 0.125, 95% CI: 0.053–0.293, and OR = 0.252, 95% CI: 0.074–0.851, , respectively). Regarding SLC2A9 rs13129697, the frequency of the G allele was significantly lower in the high-risk group than in the low-risk group (26.1% vs. 40.8%, OR = 0.531, 95% CI: 0.312–0.842, ). In the low-risk group, the proportion of patients with the TG genotype was significantly higher than that with the TT genotype (81.7% vs. 18.3%, OR = 0.279, 95% CI: 0.127–0.611, ). Haplotype analysis revealed that patients with the SLC2A9 (rs1014290–rs13129697) GG haplotype had lower risk of SUA elevation than those with the AT haplotype (27.11% vs. 63.25%, ). Furthermore, logistic regression analysis showed that drinking history was an independent risk factor for elevated SUA caused by PZA (OR = 3.943, 95% CI = 1.18–13.175, ) and that the rs1014290 GA genotype might be a protective factor (OR = 0.094, 95% CI = 0.023–0.386, ) after correction. What Is New and Conclusion. We found that SLC2A9 genetic polymorphisms were associated with elevated SUA caused by pyrazinamide. The G>A variant of rs1014290 and drinking history might be risk factors.

1. What Is Known and Objective

Tuberculosis (TB) is one of the top 10 major chronic infectious diseases worldwide, with approximately 10 million new cases worldwide each year. Pyrazinamide (PZA) is a first-line drug for TB treatment that has a strong bactericidal effect, especially for phagocytosis of TB bacteria. PZA plays an essential role in treatment of multidrug-resistant TB, which can shorten the treatment period and reduce the relapse rate [1, 2]. However, as a strong urate retention agent, PZA can cause a decrease of more than 80% in renal clearance of uric acid in patients treated with a dose of 300 mg per day [3] and induce an extremely high incidence of elevated serum uric acid (SUA). The mechanism is mainly related to uric acid excretion and transport, such as decreasing uric acid secretion and increasing uric acid reabsorption [4].

Susceptibility to elevated SUA has been extensively studied by several studies, and most of the findings emphasize the critical roles of urate reabsorption transporter 1 (GLUT9), urate reabsorption transporter 1 (URAT1), and ATP-binding cassette subfamily G member 2 (ABCG2) in urate reabsorption and secretion in the proximal tubule [5, 6]. GLUT9, encoded by the SLC2A9 gene, is a glucose transporter gene expressed primarily in the liver and kidney. Genome-wide studies in several countries have demonstrated that SLC2A9 gene polymorphisms are associated with SUA levels [7]. A meta-analysis of genome-wide association scans in 28,141 people of European descent showed that the SLC2A9 rs734553 T allele might be the strongest marker of elevated SUA described to date [8]. URAT1 is a member of the OAT (organic anion transporter) family; it is encoded by the SLC22A12 gene located on the short arm of chromosome 11 [9]. Mutations in the SLC22A12 gene might lead to abnormal function of kidney uric acid transport and reduce excretion of uric acid, thus causing elevated SUA. Tatrai et al. found that in determining the effect of drugs on serum urate levels, interaction with the major reabsorptive urate transporter salt transporter URAT1 appeared to be more significant than that with the secretory transporter [10]. The reabsorption of urate is largely mediated by URAT1 and GLUT9 [11]; hence, loss of function of SLC22A12 or SLC2A9 may be one of the causes of elevated SUA. The ABCG2 gene is located at 4q22-23 and encodes 655 amino acids. ABCG2 physiologically mediates renal urate excretion and extrarenal (intestinal) urate excretion, and its dysfunctional mutation is involved in elevated SUA [12]. However, the above studies did not reveal the association of genetic polymorphisms with pyrazinamide-induced SUA elevation. In this study, we sought to verify whether SLC2A9, SLC22A12, and ABCG2 gene polymorphisms affect the occurrence of pyrazinamide-induced SUA elevation in Han Chinese patients, and the following most widely studied SNPs were evaluated: SLC2A9 (rs1014290, rs11722228, and rs13129697), SLC22A12 (rs3825016, rs475688, and rs7929627, rs893006), and ABCG2 (rs2054576, rs2231142, rs2728109, and rs3114018).

2. Methods

2.1. Subjects and Sample Collection

From June 2021 to June 2022, Han Chinese patients with TB who regularly took quadruple antituberculosis drugs from Jincheng People’s Hospital and Jincheng Third People’s Hospital were included in this nonintervention case-control study. Patients taking additional drugs that may affect SUA levels (e.g., chloramphenicol, thiazide diuretics, and immunosuppressants) before admission and during antituberculosis treatment were excluded. Patients with combined renal insufficiency (eGFR ≤60 mL/min/1.73 m²) or chronic kidney disease, those who discontinued or changed their treatment regimen due to serious adverse reactions during treatment, those who had hyperuricaemia or gout prior to PZA use, and those who ate high-purine food during PZA use were excluded. In addition, to minimize the intergroup differences at baseline, the initial SUA levels of the included patients were 150–300 mol/L.

Approximately 2 mL of residual peripheral blood was collected for genotyping. This study was performed in compliance with the Helsinki Declaration and was approved by the Ethics Committee of Jincheng People’s Hospital (No. JCPH20210521001). An informed consent form was signed by each patient.

2.2. Data Collection

The characteristics of the participants were collected, including sex, age, residence, ethnicity, history of alcohol consumption, smoking, family history, disease history, medication history, history of hypertension, and history of diabetes. The patients in this study were given lifestyle guidance on a low-purine diet prior to medication administration. SUA levels were detected at baseline and at week 2 and week 6 after PZA administration. Mean SUA levels at week 2 and week 6 () were compared with those at baseline (C₀). If < 2C₀, the patients were classified into a low-risk group with elevated SUA caused by pyrazinamide; the others ( ≥ 2C₀) were classified into a high-risk group. In addition, causality assessments of pyrazinamide-induced SUA elevation were conducted to confirm that the increase of SUA was caused by pyrazinamide.

2.3. Genotyping

Genomic DNA was extracted from peripheral blood samples using a Wizard Genomic DNA Purification Kit (Promega, Madison, Wisconsin, USA) following the instructions. SLC2A9 (rs1014290, rs11722228, and rs13129697), SLC22A12 (rs3825016, rs475688, rs7929627, and rs893006), and ABCG2 (rs2054576, rs2231142, rs2728109, and rs3114018) polymorphisms were genotyped by improved Multiple Ligase Detection Reaction (iMLDR) as previously reported [13]. The above tests were completed by Genesky Biotechnologies Inc. (Shanghai, China), and 5% of the total DNA samples were directly sequenced to confirm the results.

2.4. Statistical Analysis

Statistical analysis was performed using SPSS 26.0 for Windows (IBM Inc.). Quantitative data were expressed using mean ± SD and compared between groups by ANOVA analysis. Group comparisons of frequency data were performed using the chi-square test. Hardy–Weinberg equilibrium (HWE) was tested using the online SNPstats software (https://snpstats.net/start.htm). The analysis of gene distribution included allele, codominant model, dominant model, and recessive model. In addition, linkage disequilibrium analysis and haplotype frequencies were estimated using Haploview 4.2. Logistic regression analysis was conducted to analyse risk factors associated with elevated SUA caused by PZA. Odds ratios (ORs), 95% confidence intervals (CIs), and values were calculated. In all tests, was considered statistically significant.

3. Results

3.1. Clinical Characteristics

A total of 143 TB patients treated with PZA were included and completed the study, including 60 in the low-risk group and 84 in the high-risk group. The sample size included in the study basically met the requirement of a minimum sample size. The causality assessments of pyrazinamide-induced SUA elevation were “probable” or “certain.” After statistical analysis, we found no significant differences between patients in the low-risk and high-risk groups in terms of sex, age, BMI, history of hypertension, history of diabetes, smoking history, and place of residence (all ), as shown in Table 1. However, the proportion of patients with a drinking history was significantly higher in the high-risk group than in the low-risk group (27.70% vs. 11.70%, ). There was no significant difference in initial SUA between the groups (), though SUA levels in the high-risk group were much higher than those in the low-risk group after 2 weeks and 6 weeks of PZA treatment (both ).

3.2. Hardy–Weinberg Equilibrium Test

SLC2A9 (rs1014290, rs11722228, and rs13129697), SLC22A12 (rs475688 and rs7929627), and ABCG2 (rs2054576, rs2231142, rs2728109, and rs3114018) were all consistent with HWE, indicating that the sampled population was representative of the general population (all ), as shown in Table 2. The genetic equilibrium of SLC22A12 rs3825016 and rs893006 was unbalanced in the overall sample, but they were normally distributed between the low-risk and high-risk groups (both and ). Moreover, the MAFs of most SNPs in this study were consistent with the data in the 1000 g-CHBS database, except that SLC22A12 rs475688 showed the opposite result.

3.3. Associations between Gene Polymorphisms and Elevated SUA Caused by Pyrazinamide

The results showed statistically significant differences for the gene distributions of SLC2A9 rs1014290 and rs13129697 between the low-risk and high-risk groups, which were not observed for the other SNPs (Table 3). Regarding SLC2A9 rs1014290, the frequency of the G allele was significantly lower in the high-risk group than in the low-risk group (27.7% vs. 48.3%, OR = 0.410, 95% CI: 0.250–0.671, ). Patients with the GA and GG genotypes were less likely to have elevated SUA than those with the AA genotype (OR = 0.125, 95% CI: 0.053–0.293, and OR = 0.252, 95% CI: 0.074–0.851, , respectively). The dominant model analysis showed consistent results as well (OR = 0.142, 95% CI: 0.062–0.326, ). Regarding SLC2A9 rs13129697, the frequency of the G allele was significantly lower in the high-risk group than in the low-risk group (26.1% vs. 40.8%, OR = 0.531, 95% CI: 0.312–0.842, ). In the low-risk group, the proportion of patients with the TG genotype was significantly higher than that with the TT genotype (81.7% vs. 18.3%, OR = 0.279, 95% CI: 0.127–0.611, ).

3.4. Linkage Disequilibrium and Haplotype Analysis

SLC2A9 rs1014290 and rs13129697, SLC22A12 rs7929627 and rs893006, ABCG2 rs2054576 and rs2231142 and rs3114018, and ABCG2 rs2054576 and rs2728109 were found to be in strong linkage disequilibrium. Moreover, SLC22A12 rs3825016, rs475688 and rs893006 were in complete linkage disequilibrium. The specific D’ values are shown in Figure 1. We performed haplotype analysis for genes in linkage disequilibrium and found that the haplotype portion of SLC2A9 (rs1014290–rs13129697) differed significantly between the low-risk and high-risk groups (Table 4). Patients carrying the GG haplotype had lower rates of elevated SUA than patients carrying the AT haplotype (27.11% vs. 63.25%, ). Conversely, the haplotype distribution of the other genes did not show significant intergroup differences (all ).

3.5. Risk Factors for Elevated SUA Caused by Pyrazinamide

Binary logistic regression analysis was next performed. Grouping was considered the dependent variable, whereas sex, age, BMI, hypertension, diabetes, smoking history, drinking history, place of residence, initial SUA, and SLC2A9 rs1014290 and rs13129697 genotyping were considered independent variables (Table 5). The results showed that drinking history was an independent risk factor for elevated SUA caused by PZA (OR = 3.943, 95% CI = 1.18–13.175, ) and that the rs1014290 GA genotype might be a protective factor (OR = 0.094, 95% CI = 0.023–0.386, ) after correction.

4. Discussion

PZA is an indispensable first-line drug in the treatment of TB, and its most common adverse reaction is elevated SUA. The initial symptoms of SUA elevation are often not obvious and easily ignored, which brings potential safety risks for clinical treatment [14], but the incidence was reported to be as high as 43% to 100% [3, 15]. The induction mechanism might involve the PZA metabolite pyrazinic acid, which increases uric acid reabsorption at the brush-like boundary of proximal curved tubules [4]. In addition, some mutations in these transport sites may disrupt the balance of serum uric acid and determine individual differences in its expression, which is the main reason for individual differences in PZA-induced SUA elevation.

Elevated SUA is a pathological phenomenon caused by a combination of genetic and environmental factors. Kottgen et al. [16] found 16 uric acid excretion-related genes in the kidney and intestine, especially SLC2A9 and ABCG2, with an increase in SUA concentration of 0.22 mg/dL for each additional risk allele of the ABCG2 gene and 0.37 mg/dL for SLC2A9. In addition, significant sex differences between ABCG2 and SLC2A9 have been observed, with the association being more pronounced in men than in women. Our study similarly revealed the association of SLC2A9 gene polymorphism with elevated SUA, but no sex differences were detected.

SLC2A9 is located at 4p16.1 and encodes the following two different isoforms: GLUT9-l (540 amino acid residues) and GLUT9-s (512 amino acid residues). Some studies [17] have found that the distribution of these two isoforms differs. GLUT9-l appears to be expressed mainly in the basement membrane of the proximal tubules of the kidney and in tissues such as the pancreas, with GLUT9-s being abundantly expressed in the parietal membrane of the renal collecting duct and in the placenta. Kimura et al. [18] reported that the rate of uric acid excretion was significantly higher in GLUT9 transgenic rats than in wild-type rats, suggesting that GLUT9 might play a pivotal role in SUA metabolism. This was confirmed by the study of Auberson et al. [19]. SLC2A9 gene mutation significantly alters the affinity and transport capacity of GLUT9 for uric acid. In addition, SLC2A9 polymorphism is significantly race specific. For example, SLC2A9 rs3775948 is reported to be associated with SUA levels in Caucasians [20] but not in Asians [16].

Rs1014290 and rs13129697 are located in the third and seventh introns of SLC2A9, respectively. Some studies have suggested that the two SNPs are associated with SUA levels in the Han Chinese population. A meta-analysis [21] found that the minor allele of the SLC2A9 rs1014290 polymorphism protects against the development of gout in Asian patients (OR = 0.597, 95% CI = 0.478–0.746, ). Zeng et al. [22] showed that the GA/AA genotype (rs1014290) is associated with elevated SUA in patients with metabolic-associated fatty liver disease and Zhang et al. [23] that the TT genotype of rs13129697 is significantly associated with high triglyceride and SUA levels. High triglyceride levels cause some free fatty acids to be largely re-esterified or stored in other tissues, resulting in accelerated degradation of ATP and higher SUA levels. The results of this study are consistent with those of previous studies, with rs1014290 and rs13129697 gene polymorphisms being significantly associated with elevated SUA caused by PZA. Indeed, patients with the rs1014290 A allele/AA genotype or rs13129697 TT genotype were more likely to have elevated SUA after taking PZA. Haplotype analysis revealed that patients carrying the SLC2A9 (rs1014290–rs13129697) GG haplotype had a lower risk of elevated SUA than those carrying the AT haplotype, consistent with the gene distribution results. Furthermore, logistic regression analysis showed that patients with the rs1014290 AA genotype were approximately 10 times more likely to cause SUA elevation after PZA treatment than those with the GA genotype.

The relationship between increased SUA and drinking history has been a subject of intense debate. Several studies have shown that ethanol metabolites in alcohol can inhibit uric acid excretion and accelerate purine catabolism and that alcohol (especially strong alcohol from beer) may increase the risk of gout [24–26]. In this study, we found that patients with a drinking history had a higher risk of elevated SUA levels, nearly 4 times higher than those of nondrinkers.

However, this study has some limitations. For example, the Hardy–Weinberg equilibrium of two SNPs was unbalanced in the total sample due to an insufficient sample size; however, these SNPs were still included in the analysis considering their balanced distribution within each group. More standardized and large-scale clinical studies are needed, which is our future direction.

5. What Is New and Conclusion

In conclusion, we found that SLC2A9 genetic polymorphisms are associated with elevated SUA caused by PZA. The G>A variant of rs1014290 and drinking history are risk factors.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethical Approval

This study was in compliance with the Helsinki Declaration and was approved by the Ethics Committee of Jincheng People’s Hospital (No. JCPH20210521001). Authorization comes from the Ethical Committee of Jincheng People’s Hospital and patients enrolled in our study.

The authors have obtained written consent from each subject.

Disclosure

Yuyang Dai and Yunyun Wang are the co-first authors.

Conflicts of Interest

The authors declare that there are no conflicts of interest related to the work described in this manuscript.

Authors’ Contributions

Yuyang Dai and Yunyun Wang contributed equally to this work.

Acknowledgments

The authors would like to thank the Department of Infectious Diseases of Jincheng People’s Hospital and Jincheng Third People’s Hospital. This work was supported by grants from Foundation of Beijing Science and Technology Project (No. Z191100007619038).

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Copyright © 2023 Yuyang Dai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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