The role of ABCG2 rs2231142 and SLC2A9 rs1014290 urate transporter gene polymorphisms in the development of chronic non-communicable diseases

Introduction. Hyperuricemia (HU) is a risk factor for a wide spectrum of chronic non-communicable diseases (NCDs). Genetic variants of urate transporters ABCG2 (rs2231142, Q141K) and SLC2A9 (rs1014290) are associated with impaired uric acid (UA) excretion and may modulate the risk of NCDs.
Objective. To investigate the association between NCDs and uric acid metabolism disorders, and to evaluate the role of ABCG2 rs2231142 (c.421C>A, p.Gln141Lys, Q141K) and SLC2A9 rs1014290 urate transporter gene polymorphisms in the development of NCDs.
Materials and methods. A cross-sectional study enrolled 171 metallurgical plant workers with NCDs and HU (serum UA ≥360 µmol/L) and/or urate-lowering therapy: 101 men (59.1%) and 70 women (40.9%), median age 49 [43; 54] years, median BMI 28.0 [25.5; 30.9] kg/m². Biochemical blood analyses, eGFR calculation using the CKD-EPI equation, and genotyping of SLC2A9 rs1014290 and ABCG2 rs2231142 were performed. Multivariable analysis included logistic regression adjusted for age, sex, and eGFR; false discovery rate (FDR) correction was applied using the Benjamini–Hochberg method.
Results. HU was detected in 30.4% of workers, significantly more frequently in men (43.6% vs. 11.4% in women). The leading NCDs were hypertension (48.5%), obesity (36.3%), gout (21.1%), and urolithia­sis (10.5%). In multivariable models, HU was independently associated with hypertension (OR 5.19; 95% CI: 1.87–14.44), urolithiasis (OR 5.38; 95% CI: 1.63–17.79), and gout (OR 3.27; 95% CI: 1.39–7.69). Carriage of the ABCG2 minor allele A was associated with urolithiasis (OR 6.28; 95% CI: 2.19–18.03; p_adj = 0.032), higher serum UA levels, and reduced eGFR compared to C/C homozygotes (p < 0.001). The protective effect of the SLC2A9 allele G against HU (OR 0.41; 95% CI: 0.23–0.75) did not reach statistical significance after FDR correction (p_adj = 0.095).
Conclusion. HU is independently associated with hypertension, urolithiasis, and gout. Carriage of the ABCG2 rs2231142 minor allele A increases the risk of urate nephrolithiasis. The SLC2A9 polymorphism demonstrates a trend toward a protective effect. Urate transporter genotyping is warranted for personalized prevention of NCDs in metallurgical workers.

For citation: Georginova OA, Anokhin DM, Masterova MM, Gabbasova LA, Krasnova TN, Jain M, Samokhodskaya LM, Domashenko MA. The role of ABCG2 rs2231142 and SLC2A9 rs1014290 urate transporter gene polymorphisms in the development of chronic non-communicable diseases. Therapy (Moscow). 2026;12(5S):51–57. 
https://doi.org/10.18565/therapy.2026.5-s5.51-57

INTRODUCTION

Non-communicable diseases (NCDs) are the leading cause of morbidity and mortality worldwide. According to WHO data, they account for approximately 74% of all deaths globally, claiming at least 43 million lives annually, including 18 million deaths among individuals younger than 70 years [1]. Cardiovascular diseases, type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), metabolic syndrome (MetS), and rheumatic diseases frequently coexist in the same patient and share common pathogenetic mechanisms. One of the key pathways linking these conditions is dysregulation of uric acid (UA) metabolism. Hyperuricemia (HU), defined as a serum UA concentration exceeding 360–420 µmol/L, was long regarded solely as a biochemical marker of gout. However, accumulating evidence indicates that HU is also associated with arterial hypertension, coronary artery disease, CKD, insulin resistance, and obesity [2, 3]. According to the Global Burden of Disease (GBD) 2021 Study, the number of individuals with HU worldwide exceeded 800 million [4], while the age-standardized incidence of gout increased by 22.5% between 1990 and 2020 [5]. In Russia, the ESSE-RF study, which included 14,497 participants from 10 regions, showed that HU was present in 16.8% of adults, including 25.3% of men and 11.3% of women [6]. Genetic factors account for 45–73% of the interindividual variability in serum UA levels [7]. Among the genetic determinants of urate metabolism, polymorphic variants in the genes encoding two major urate transporters are of particular importance. The SLC2A9 gene encodes the high-affinity urate transporter GLUT9 (glucose transporter 9), which mediates urate reabsorption in the proximal renal tubules and is quantitatively the principal transporter responsible for returning urate to the circulation [8]. The ABCG2 gene encodes the ATP-dependent efflux transporter BCRP (breast cancer resistance protein), which is a major mediator of extrarenal, primarily intestinal, urate secretion. Its compensatory role increases as renal function declines. The ABCG2 rs2231142 variant reduces the membrane expression of the transporter by approximately 50%, resulting in impaired intestinal urate secretion and elevated serum UA levels [7]. Of particular clinical relevance is the reported association between ABCG2 rs2231142 and uric acid nephrolithiasis [9]. Reduced intestinal urate secretion in carriers of the Q141K variant leads to chronic systemic urate accumulation. In the presence of low urine volume and acidic urinary pH – conditions associated with occupational heat stress [10] – this may promote urate crystal precipitation in the renal parenchyma and collecting ducts. Despite this biologically plausible mechanism, data on the association between ABCG2 rs2231142 and urolithiasis in occupational cohorts remain limited, providing the principal rationale for the present study.

The aim of the study was to investigate the association between NCDs and disorders of UA metabolism and to evaluate the role of the ABCG2 rs2231142 (c.421C>A, p.Gln141Lys, Q141K) and SLC2A9 rs1014290 urate transporter gene variants in the development of NCDs.

METHODS

A cross-sectional clinical and genetic study was conducted in the outpatient department of the Autonomous Nonprofit Organization Central Clinical Medical and Sanitary Unit in Magnitogorsk, Russia. The study included employees of the Magnitogorsk Iron and Steel Works. The study protocol was approved by the Ethics Committee of the Medical Research and Education Institute of Lomonosov Moscow State University (Protocol No. 8/20, October 22, 2022). All participants provided written informed consent.

At the first stage, 547 plant employees (mean age, 47.2 ± 8.7 years) were screened using the validated ARTROVIS questionnaire (Cronbach’s α = 0.798), designed to identify articular symptoms and related comorbid conditions [11]. In the second stage, 492 employees with articular symptoms and/or clinically significant risk factors were invited for an in-person consultation with a rheumatologist and an extended laboratory evaluation.

Diagnoses were verified by a rheumatologist based on physical examination, medical history, and medical records. Urolithiasis was verified if at least one of the following criteria was met: a documented history of renal colic confirmed by a urologist; detection of urinary tract calculi by renal ultrasound or non-contrast computed tomography (CT); or previous surgical or interventional treatment for urolithiasis. The following biochemical parameters were assessed in all participants: serum UA, creatinine, estimated glomerular filtration rate (eGFR) calculated using the CKD-EPI equation, total cholesterol, triglycerides, fasting glucose, and rheumatoid factor.

The final study sample comprised 171 employees who met the following inclusion criteria: age ≥18 years; a verified diagnosis of an NCD; HU (serum UA ≥360 µmol/L) or ongoing urate-lowering therapy; and written inform...

O.A. Georginova, D.M. Anokhin, M.M. Masterova, L.A. Gabbasova, T.N. Krasnova, M. Jain, L.M. Samokhodskaya, M.A. Domashenko