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Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population.

ABSTRACT: Gout is a common inf lammatory arthritis triggered by the crystallization of uric acid in the joints. Serum uric acid levels are highly heritable, suggesting a strong genetic component. Independent studies to confirm the genetic associations with gout in various ethnic populations are warranted. We investigated the association of polymorphisms in the ABCG2 and SLC2A9 genes with gout in Korean patients and healthy individuals.We consecutively enrolled 109 patients with gout and 102 healthy controls. The diagnosis of gout was based on the preliminary criteria of the America College of Rheumatology. Genomic DNA was extracted from whole blood samples. We identified single nucleotide polymorphism (SNP) changes in the ABCG2 and SLC2A9 genes using a direct sequencing technique. rs2231142 in ABCG2 and rs6449213 and rs16890979 in SLC2A9 and nearby regions were amplified by polymerase chain reaction.Patients with gout had significantly higher A/A genotype (29.3% vs. 4.9%, respectively) and A allele (52.8% vs. 26.5%, respectively) frequencies of rs2231142 in ABCG2 than did controls (?(2) = 29.42, p < 0.001; odds ratio, 3.32; 95% confidence interval, 2.11 to 5.20). We found novel polymorphisms (c.881A>G and c.1002+78G>A) in the SLC2A9 gene. The univariate logistic regression analysis revealed that the c.881A>G and c.1002+78G>A SNPs were significantly higher in patients than in controls.We demonstrated a significant association between rs2231142 in the ABCG2 gene and gout and identified novel SNPs, c.881A>G and c.1002+78G>A, in the SLC2A9 gene that may be associated with gout in a Korean population.

SUBMITTER: Kim YS

PROVIDER: S-EPMC4642022 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population.

Kim Yun Sung YS Kim Yunsuek Y Park Geon G Kim Seong-Kyu SK Choe Jung-Yoon JY Park Byung Lae BL Kim Hyun Sook HS

The Korean journal of internal medicine 20151030 6

<h4>Background/aims</h4>Gout is a common inf lammatory arthritis triggered by the crystallization of uric acid in the joints. Serum uric acid levels are highly heritable, suggesting a strong genetic component. Independent studies to confirm the genetic associations with gout in various ethnic populations are warranted. We investigated the association of polymorphisms in the ABCG2 and SLC2A9 genes with gout in Korean patients and healthy individuals.<h4>Methods</h4>We consecutively enrolled 109 p ...[more]

PMID: 26552468

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Project description:Introduction:Genetic polymorphisms of drug transporters influence drug transporter activity and alter pharmacokinetic profiles of the drugs. Organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) are important transporters encoded by solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene and ATP-binding cassette subfamily G member 2 (ABCG2) gene, respectively. Polymorphisms in these genes are associated with increased plasma statins concentrations, statin-induced myopathy and poor response to allopurinol treatment. Purpose:We explored allele and genotype frequencies of SLCO1B1 and ABCG2 genes including their predicted phenotypes in 53 Thai participants. Of these, 17 had chronic kidney disease and were on statins. Materials and Methods:Genotyping analysis for SLCO1B1 c.521T>C (rs4149056), c.388A>G (rs2306283), g.-11187G>A (rs4149015), and ABCG2 c.421C>A (rs2231142) was done by using TaqMan® Real time PCR. All were tested for Hardy-Weinberg Equilibrium. Results:Most of the participants (80%) had normal function haplotypes SLCO1B1 (*1A and *1B) while decreased (*5, *15, and *17) and unknown (*21) function haplotypes were less observed. Four phenotypes of SLCO1B1 were observed: 69.81% had normal function (*1A/*1A,*1A/*1B, and *1B/*1B), 13.21% had intermediate function (*1A/*17, *1B/*15 and *1B/*17), 9.43% had indeterminate function (*1A/*21 and *1B/*21) and 7.55% had low function (*5/*15, *15/*15, and *15/*17). ABCG2 c.421A allele frequency was 25%. The frequency of ABCG2 c.421CA and AA phenotypes were 37.7% and 5.7%, respectively. The allele and genotype frequencies observed are consistent with reports in Asians. However, there were differences in major allele distributions between Asians and Caucasians for SLCO1B1 c.388A>G; SLCO1B1 c.388G were highly found in Asians, but c.388A were more observed in Caucasians. Conclusion:This study showed that in the Thai population, there were 4 SNPs of SLCO1B1 and ABCG2 genes. This finding may be clinically applied to minimize inter-individual variability of drugs such as statins and allopurinol. Further study with a larger sample size is needed to assess the drug profiles and responses to treatment.

Project description:BACKGROUND:The ABCG2 rs2231142 single nucleotide polymorphism (SNP) is one of the most significant genetic variants associated with hyperuricemia (HUA) in Asian populations. However, the risk of ABCG2 rs2231142 variants for HUA could interact with other important HUA risk variants and cardiovascular factors. This study investigated the effects of the combined association among ABCG2 rs2231142 and multiple HUA genetic variants or cardiovascular risk factors on HUA risk and serum uric acid (sUA) levels in an elderly Chinese population. METHODS:A total of 1206 participants over 65?years old were enrolled in this study. Physical and laboratory examinations were performed for all participants. The ABCG2 rs2231142, SLC2A9 rs3733591, and SLC22A12 rs893006 SNPs were assayed using a standardized protocol. Logistic regression analysis and liner regression were adjusted respectively to account for the association between ABCG2 rs2231142 and other genetic variants, as well as between cardiovascular risk factors and HUA risk and sUA levels. RESULTS:The prevalence of HUA was 14.71% in the elderly community-dwelling population. The ABCG2 rs2231142 risk T allele was associated with HUA risk (odds ratio (OR)?=?1.63, 95% confidence interval (CI): 1.27-2.11; p?=?1.65?×?10-?4) and with increased sUA levels (Beta?=?0.16, p?=?6.75?×?10-?9) in the whole study population. Linear regression analysis showed that the mean sUA level increased linearly with the number of risk alleles of the three candidate genetic variants (Beta?=?0.18, p?=?1.94?×?10-?12) The joint effect of the ABCG2 rs2231142 T allele and cardiovascular risk factors (obesity, hypertension and dyslipidemia) was also associated with increased HUA risk and sUA levels. Each copy of the risk T allele was significantly associated with enhanced HUA risk in patients with hypertriglyceridemia (OR?=?2.52, 95% CI: 1.33-4.60; p?=?0.003) compared to controls. CONCLUSION:Our findings reinforce the importance of the ABCG2 rs2231143 variant as a crucial genetic locus for HUA in Chinese populations and demonstrated the combined effects of multiple genetic risk variants and cardiovascular risk exposures on HUA risk and increased sUA level.

Project description:BACKGROUND:Gout is an inflammatory disease that is caused by the increased production of Interleukin-1? (IL-1?) stimulated by monosodium urate (MSU) crystals. However, some hyperuricemia patients, even gouty patients with tophi in the joints, never experience gout attack, which indicates that pathogenic pathways other than MSU participate in the secretion of IL-1? in the pathogenesis of acute gouty arthritis. The ATP-P2X7R-IL-1? axis may be one of these pathways. OBJECTIVE:This study examines the role of Adenosine triphosphate (ATP) in the pathogenesis of gout and the association of ATP receptor (P2X7R) function with single nucleotide polymorphisms and gout arthritis. METHODS:Non-synonymous single nucleotide polymorphisms (SNP) loci of P2X7R in Chinese people were screened to compare the frequencies of different alleles and genotype distribution of selective SNPs in 117 gouty patients and 95 hyperuricemia patients. Peripheral white blood cells were purified from the peripheral blood of 43 randomly selected gout patients and 36 hyperuricemia patients from the total group. Cells were cultured with MSU or MSU + ATP, and supernatants were collected for the detection of IL-1? concentrations using enzyme-linked immunosorbent assay (ELISA). RESULTS:1. Eight SNP loci, including rs1653624, rs10160951, rs1718119, rs7958316, rs16950860, rs208294, rs17525809 and rs2230912, were screened and detected, and rs1653624, rs7958316 and rs17525809 were associated with gout arthritis. 2. IL-1? concentrations in supernatants after MSU + ATP stimulation were significantly higher in gouty patients than in the hyperuricemia group [(131.08 ± 176.11) pg/ml vs. (50.84 ± 86.10) pg/ml]; Patients (including gout and hyperuricemia) carrying the susceptibility genotype AA or AT of rs1653624 exhibited significantly higher concentrations of IL-1? than patients carrying the non-susceptibility genotype TT [(104.20 ± 164.25) pg/ml vs. (21.90 ± 12.14) pg/ml]; However, no differences were found with MSU stimulation alone. CONCLUSIONS:ATP promotes the pathogenesis of gouty arthritis via increasing the secretion of IL-1 ?, and its receptor (P2X7R) function associated single nucleotide polymorphisms may be related to gouty arthritis, which indicates that ATP-P2X7R signaling pathway plays a significant regulatory role in the pathogenesis of gout.

Dataset Information

Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population.

Publications

Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population.

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