Identification of a urate transporter,ABCG2, with a common functional polymorphism causing gout

Genome-wide association studies (GWAS) have successfully identified common single nucleotide polymorphisms (SNPs) associated with a wide variety of complex diseases, but do not address gene function or establish causality of disease-associated SNPs. We recently used GWAS to identify SNPs in a genomic region on chromosome 4 that associate with serum urate levels and gout, a consequence of elevated urate levels. Here we show using functional assays that human ATP-binding cassette, subfamily G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter. We further show that native ABCG2 is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion. Introduction of the mutation Q141K encoded by the common SNP rs2231142 by site-directed mutagenesis resulted in 53% reduced urate transport rates compared to wild-type ABCG2 (P < 0.001). Data from a population-based study of 14,783 individuals support rs2231142 as the causal variant in the region and show highly significant associations with urate levels [whites: P = 10⁻³⁰, minor allele frequency (MAF) 0.11; blacks P = 10⁻⁴, MAF 0.03] and gout (adjusted odds ratio 1.68 per risk allele, both races). Our data indicate that at least 10% of all gout cases in whites are attributable to this causal variant. With approximately 3 million US individuals suffering from often insufficiently treated gout, ABCG2 represents an attractive drug target. Our study completes the chain of evidence from association to causation and supports the common disease-common variant hypothesis in the etiology of gout.     

Genetics of Hyperuricemia and Gout: Implications for the Present and Future

Gout is the most common inflammatory arthropathy and occurs in the setting of elevated serum urate levels. Gout is also known to be associated with multiple comorbidities including cardiovascular disease and the metabolic syndrome. Recent advances in research have increased our understanding and improved our knowledge of the pathophysiology of gout. Genome-wide association studies have permitted the identification of several new and common genetic factors that contribute to hyperuricemia and gout. Most of these are involved with the renal urate transport system (the uric acid transportasome), generally considered the most influential regulator of serum urate homeostasis. Thus far, SCL22A12, SCL2A9, and GLUT9 have been found to have the greatest variation and most influence on serum urate levels. However, genetics are only a part of the explanation in the development of hyperuricemia and gout. As results have been mixed, the role of known urate influential genes in gout’s associated comorbidities remains unclear. Regardless, GWAS findings have expanded our understanding of the pathophysiology of hyperuricemia and gout, and will likely play a role in the development of future therapies and treatment of this ancient disease.     

Plasma Urate and Risk of a Hospital Stay with AKI: The Atherosclerosis Risk in Communities Study

Background and objectives

Higher urate levels are associated with higher risk of CKD, but the association between urate and AKI is less established. This study evaluated the risk of hospitalized AKI associated with urate concentrations in a large population-based cohort. To explore whether urate itself causes kidney injury, the study also evaluated the relationship between a genetic urate score and AKI.

Design, setting, participants, & measurements

A total of 11,011 participants from the Atherosclerosis Risk in Communities study were followed from 1996–1998 (baseline) to 2010. The association between baseline plasma urate and risk of hospitalized AKI, adjusted for known AKI risk factors, was determined using Cox regression. Interactions of urate with gout and CKD were tested. Mendelian randomization was performed using a published genetic urate score among the participants with genetic data (n=7553).

Results

During 12 years of follow-up, 823 participants were hospitalized with AKI. Overall, mean participant age was 63.3 years, mean eGFR was 86.3 ml/min per 1.73 m², and mean plasma urate was 5.6 mg/dl. In patients with plasma urate >5.0 mg/dl, there was a 16% higher risk of hospitalized AKI for each 1-mg/dl higher urate (adjusted hazard ratio, 1.16; 95% confidence interval, 1.10 to 1.23; P<0.001). When stratified by history of gout, the association between higher urate and AKI was significant only in participants without a history of gout (P for interaction=0.02). There was no interaction of CKD and urate with AKI, nor was there an association between genetic urate score and AKI.

Conclusions

Plasma urate >5.0 mg/dl was independently associated with risk of hospitalized AKI; however, Mendelian randomization did not provide evidence for a causal role of urate in AKI. Further research is needed to determine whether lowering plasma urate might reduce AKI risk.     

Renal urate handling: Clinical relevance of recent advances

Urate is the major inert end product of purine degradation in higher primates in contrast to most other mammals because of the genetic silencing of hepatic oxidative enzyme uricase. The kidney plays a dominant role in urate elimination. The kidney excretes 70% of the daily urate production. Therefore, it is important to understand renal urate handling mechanism because the under excretion of urate has been implicated in the development of hyperuricemia that leads to gout. The urate transport systems exist in the proximal tubule but they are complicated because of their bidirectional transport and the species differences. Recently, we have identified the urate-anion exchanger URAT1 (SLC22A12) in the human kidney and found that defects in SLC22A12 lead to idiopathic renal hypouricemia. URAT1 is targeted by uricosuric and antiuricosuric agents that affect urate excretion. Molecular identification of urate transporting proteins will lead to the new drug development for hyperuricemia.     

New insights into renal transport of urate

PURPOSE OF REVIEW: This review focuses on recent progress in the understanding of various aspects of renal transport of urate. RECENT FINDINGS: Since the molecular cloning of the renal apical urate/anion exchanger URAT1 (SLC22A12), several membrane proteins relevant to the transport of urate have been identified. The molecular identification of two sodium-coupled monocarboxylate transporters, SMCT1(SLC5A8) and SMCT2(SLC5A12), and the emerging role of PDZ (PSD-95, DglA, and ZO-1) scaffold for renal apical transporters have led to a new concept of renal urate transport: urate-transporting multimolecular complex, or 'urate transportsome', that may form an ultimate functional unit including the sodium-coupled urate transport system by linking URAT1 and sodium-coupled monocarboxylate transporters or the coordinated apical urate uptake system by balancing reabsorptive (URAT1) and efflux (NPT1/OATv1 and MRP4) transporters. In addition, genetic variations of the URAT1 gene are associated not only with idiopathic renal hypouricemia but also with reduced renal urate excretion. SUMMARY: Although our knowledge of renal urate handling has been increased by the molecular identification of urate transport proteins and by results of genetic studies on patients with serum urate disorders, current evidence is insufficient to fully understand the precise mechanism governing the bi-directional transport of urate. Further studies are still necessary.     

A replication study of 19 GWAS-validated type 2 diabetes at-risk variants in the Lebanese population

Aim

Recent genome-wide association scans (GWAS) and replication studies have expanded the list of validated type 2 diabetes (T2DM) susceptibility loci. We replicated T2DM association of 19 SNPs from 15 candidate loci in Lebanese Arabs.

Methods

Case–control association study, comprising 995 T2DM patients and 1076 control participants. We genotyped by the allelic discrimination method 19 SNPs in/near ADAM30, NOTCH2, THADA, TMEFF2, COL8A1, ADAMTS9-AS2, WFS1, JAZF1, SLC30A8, KCNQ1, LOC387761, ALX4, TSPAN8, FTO, and HNF1.

Results

Allele frequencies of the tested SNPs were comparable with those of Caucasians. COL8A1 rs792837 (P = 2.9 × 10⁻⁹), KCNQ1 rs2237892 (P = 1.8 × 10⁻¹⁸) and rs2237895 (P = 0.002), ALX4 rs729287 (Pc = 7.5 × 10⁻⁵), and HNF1 rs4430796 (P = 0.003) were significantly associated with T2DM, with similar effect sizes to those of Europeans. While FTO rs8050136 and rs17817449, ADAMTS9 rs4607103, and WFS1 rs10010131 were initially associated with T2DM, this was lost upon multiple testing correction. The remaining variants were not associated with T2DM, possibly resulting from insufficient power to detect smaller allele effects.

Conclusion

In addition to previous findings on the association of IGF2BP2, CDKAL1, TCF7L2 variants with T2DM among Lebanese, here we extend these by validating the association of five additional loci with T2DM in Lebanese Arabs.     

Gout: epitome of painful arthritis

Arthritic pain and disability are at or near the top of the list of reasons adult patients seek medical attention. At least 47.8 million US residents have arthritis. In Europe, the magnitude of the problem is similar, affecting 8 million in the United Kingdom and 108 million across the continent. Osteoarthritis is by far the most common form of arthritis. In a regional UK study, nearly half of adults 50 years or older reported some form of osteoarthritic knee pain over a 1-year period. Among the arthritides, gout is notable for the agonizing nature and unique pathogenesis of the pain it generates. Gout is the most common cause of inflammatory arthritis among men and postmenopausal women. Because of the atypical nature of some of its clinical manifestations, gout can present serious diagnostic challenges for practicing physicians. In recent years, knowledge about gout's pathogenesis, pathophysiology, and differential diagnosis has advanced on a broad front. Genetic variants within a newly identified transport gene, SLC2A9, have been associated with a low fractional excretion of uric acid and the presence of gout in several population samples. The SLC2A9 gene encodes glucose transporter 9—a unique hexose and high-capacity urate transporter. In addition, human ATP-binding cassette, subfamily G2 (ABCG2), encoded by the ABCG2 gene, has been found to mediate renal urate secretion. Introduction of a mutation encoded in a model system by a common single nucleotide polymorphism, rs2231142, resulted in a 53% reduction in urate transport rates compared with wild-type ABCG2. Based on a large population study, it has been estimated that at least 10% of all gout cases in white persons may be attributable to this single nucleotide polymorphism causal genetic variant. Of the various categories of arthritis, the crystal-induced arthropathies, gout and pseudogout, are manifested by acute inflammation and tissue damage arising from deposition in joints and periarticular tissues of monosodium urate (MSU), calcium pyrophosphate dehydrate, or basic calcium phosphate crystals. The innate immune system rapidly detects invading pathogenic microbes and nonmicrobial “danger signals” such as MSU crystals. When these crystals are deposited in synovial tissues, NLR proteins (NOD-like receptors) form multiprotein complexes known as inflammasomes that trigger secretion of inflammation-producing cytokines like interleukin-1β and interleukin-18. Usually, gout can be diagnosed by medical history, physical examination, and presence of hyperuricemia (urate >416 μmol/L). However, a urate concentration less than 416 does not by itself rule out gout. Confirmation of the diagnosis by identification of typical MSU crystals in aspirated synovial fluid is definitive. Analysis of joint fluid is mandatory to rule out septic arthritis, which can rapidly become lethal. Because of its special ability to identify and quantitate urate deposits in peripheral tissues, dual-energy computed tomography should prove valuable in the differential diagnosis of gout. Gout mimics a variety of illnesses; for example, spinal gout may masquerade as metastatic cancer, epidural abscess, and nerve compression syndrome.     

G109T polymorphism of SLC22A12 gene is associated with serum uric acid level, but not with metabolic syndrome

SLC22A12 gene, encoding urate transport 1, has been known to be responsible to urate metabolism. This study sought to determine the association between the novel G109T polymorphism in SLC22A12 with serum uric acid and the development of metabolic syndrome in Korean male subjects. A total of 132 healthy male subjects were enrolled in this study. Metabolic syndrome was determined using the modified guidelines for metabolic syndrome proposed by the National Cholesterol Education Program’s Third Adult Treatment Panel. Genotyping for the SLC22A12 gene was assessed using denaturing high-performance liquid chromatography analysis. Serum uric acid and fractional excretion of uric acid (FEUA) from blood and urine samples were measured. Frequencies of the 109GG, 109GT, and 109TT genotypes were 57.6, 38.6, and 3.8%, respectively. Serum uric acid levels and FEUAs were significantly different among the three genotypes of the G109T polymorphism (P?=?0.035 and P?=?0.033, respectively). In addition, subjects of genotypes with the T allele had lower uric acid levels and higher FEUAs compared to those with the 109GG genotype (P?=?0.007 and P?=?0.031, respectively). The G109T polymorphism of the SLC22A12 gene has no association with metabolic syndrome. However, a number of metabolic syndrome components were related to serum uric acid level (r?=?0.285, P?=?0.001) and also significantly different between genotype with and without T allele (P?=?0.008). The novel G109T polymorphism of the SLC22A12 gene is related to serum uric acid level, but not to the development of metabolic syndrome.     

Renal urate handling: Clinical relevance of recent advances

Urate is the major inert end product of purine degradation in higher primates in contrast to most other mammals because of the genetic silencing of hepatic oxidative enzyme uricase. The kidney plays a dominant role in urate elimination. The kidney excretes 70% of the daily urate production. Therefore, it is important to understand renal urate handling mechanism because the under excretion of urate has been implicated in the development of hyperuricemia that leads to gout. The urate transport systems exist in the proximal tubule but they are complicated because of their bidirectional transport and the species differences. Recently, we have identified the urate-anion exchanger URAT1 (SLC22A12) in the human kidney and found that defects in SLC22A12 lead to idiopathic renal hypouricemia. URAT1 is targeted by uricosuric and antiuricosuric agents that affect urate excretion. Molecular identification of urate transporting proteins will lead to the new drug development for hyperuricemia.     

Global patterns of treat-to-serum urate target care for gout: Systematic review and meta-analysis

BackgroundInternational rheumatology guidelines advocate a treat to serum urate target (T2T) approach for gout management. While individual studies have reported regional and national-level gout management, global patterns in gout care have not been synthesized. This study aimed to systematically review and meta-analyze global T2T care for patients with gout.MethodsElectronic databases were searched for studies reporting medication and serum urate testing in patients with gout. Meta-analyses were conducted to determine the pooled proportion of patients with gout achieving pre-specified T2T indicators.ResultsSixty-seven papers were included from North America (n = 31 studies), Europe (n = 22), Oceania (n = 7), Asia (n = 6), and reporting data from multiple continents (n = 1). The global pooled percentages (95% confidence interval (CI)) of patients with gout achieving T2T indicators were: 52% (45%, 59%) on urate lowering therapy (ULT), 50% (40%, 61%) on ULT receiving regular uninterrupted ULT, 53% (40%, 65%) on ULT having any serum urate testing, and 34% (28%, 41%) on ULT achieving a serum urate target.ConclusionOutside North America and Europe, there are relatively few studies about T2T care for gout management. However, available data demonstrate that a minority of people with gout receive T2T care worldwide. For those prescribed ULT, there are low rates of continuous therapy, serum urate testing, and achievement of serum urate target.     

Hepatocyte nuclear factor 4-alpha involvement in liver and intestinal inflammatory networks

Hepatocyte nuclear factor 4-alpha(HNF4-α)is a nuclear receptor regulating metabolism,cell junctions,differentiation and proliferation in liver and intestinal epithelial cells.Mutations within the HNF4A gene are associated with human diseases such as maturityonset diabetes of the young.Recently,HNF4A has also been described as a susceptibility gene for ulcerative colitis in genome-wide association studies.In addition,specific HNF4A genetic variants have been identified in pediatric cohorts of Crohn’s disease.Results obtained from knockout mice supported that HNF4-αcan protect the intestinal mucosae against inflammation.However,the exact molecular links behind HNF4-αand inflammatory bowel diseases remains elusive.In this review,we will summarize the current knowledge about the role of HNF4-αand its isoforms in inflammation.Specific nature of HNF4-αP1 and P2 classes of isoforms will be summarized.HNF4-αrole as a hepatocyte mediator for cytokines relays during liver inflammation will be integrated based on documented examples of the literature.Conclusions that can be made from these earlier liver studies will serve as a basis to extrapolate correlations and divergences applicable to intestinal inflammation.Finally,potential functional roles for HNF4-αisoforms in protecting the intestinal mucosae from chronic and pathological inflammation will be presented.     

SLC30A8 polymorphism and type 2 diabetes risk: Evidence from 27 study groups

Background and aims

Intense research has been performed to identify the genetic risk factors in type 2 diabetes, and a single nucleotide polymorphism (SNP) in SLC30A8 (rs13266634) was reported to be associated with type 2 diabetes mellitus. However, published data on the association between SLC30A8 polymorphism and the risk of type 2 diabetes were inconsistent. Therefore, we conducted this meta-analysis to derive a more precise estimation of the relationship.

Methods and results

We searched PubMed through October 2009 to identify all relevant papers. Odds ratios (ORs) and 95% confidence intervals (CIs) were extracted under an additive genetic model. In the current meta-analysis, we identified a total of 27 groups including 42,609 cases and 69,564 controls. In analyses of the case-control studies by ethnicity, the results indicated that SLC30A8 polymorphism was related to elevate risks of type 2 diabetes both in Europeans (OR = 1.15, 95% CI 1.11-1.18, P < 0.001) and Asians (OR = 1.15, 95% CI 1.11-1.19, P < 0.001). Next, we separated hospital-based case-control studies from population-based case-control studies, however, there was no apparent difference between population-based case-control study groups (OR = 1.15, 95% CI 1.12-1.17, P < 0.001) and hospital-based case-control study groups (OR = 1.16, 95% CI 1.07-1.25, P < 0.001).

Conclusion

Our present meta-analysis provided evidence that SLC30A8 (rs13266634) C allele carriers could elevate the risk of type 2 diabetes, especially in Europeans and Asians.     

What Is the Evidence for Treat-to-Target Serum Urate in Gout?

Purpose of Review

Most current clinical guidelines for gout management advocate a treat-to-target serum urate approach, although notable differences exist. Serum urate is a rational target for gout treatment given the central role of urate in disease causality, its association with key outcomes and its practicality of use in clinical practice. This review analyses the evidence for this strategy in gout.

Recent Findings

Recent studies have confirmed the efficacy of urate-lowering therapy in achieving serum urate targets, both in trials using fixed doses and those applying a treat-to-target strategy. In a limited number of long-term studies (>?12-month duration), interventions that incorporate a treat-to-target serum urate approach have been shown to promote regression of tophi, reduce the frequency of gout flares and improve MRI-detected synovitis.

Summary

A strong case can be made for a treat-to-target serum urate strategy in gout, supported by existing knowledge of disease pathophysiology, outcomes from urate-lowering therapy studies and emerging results of randomised strategy trials of sufficient duration.

     

Association between <Emphasis Type="Italic">SLC2A9</Emphasis> (<Emphasis Type="Italic">GLUT9</Emphasis>) gene polymorphisms and gout susceptibility: an updated meta-analysis

The relationship between the SLC2A9 (solute carrier family 2, member 9) gene polymorphisms and gout was still inconsistent among the individual genetic association studies. Therefore, this present research was aimed to systematically evaluate the association between SLC2A9 gene polymorphisms and gout susceptibility. Relevant studies were enrolled by searching databases systematically. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the associations. The heterogeneity between each of the studies was calculated by using the Q statistic methods, and Begg’s funnel plot and Egger’s tests were performed to evaluate publication bias. A total of 13 studies investigated four single nucleotide polymorphisms (SNPs) in SLC2A9 were included. In this study, we found that the allele C of rs3733591 was higher in patients than in controls in both all-pooled population [C vs. T: OR (95 % CI) = 1.432 (1.213–1.691)] and Asians-pooled population [C vs. T: OR (95 % CI) = 1.583 (1.365–1.835)]. The allele frequency C of s6449213 was lower in the gout patients than in controls in both all-pooled population and Caucasians-pooled population. Additionally, the allele frequency T of rs16890979 and the allele frequency C of rs1014290 were lower in gout patients than in controls. This study demonstrated that the genetic susceptibility for gout is associated with the SLC2A9 gene polymorphisms. Four of them except for the rs3733591 are protective SNPs in Caucasians, and rs16890979 and rs1014290 are protective SNPs in both Caucasians and Asians, while rs3733591 may be susceptibility SNP in Asians.     

Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways

In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity.     

Association analysis of the beta-3 adrenergic receptor Trp64Arg (<Emphasis Type="Italic">rs4994</Emphasis>) polymorphism with urate and gout

The Arg64 allele of variant rs4994 (Trp64Arg) in the β3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Māori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman^®. Māori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (β = 0.036, P = 0.004, P _Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.     

Identification and characterization of peripheral vascular color-coded DECT lesions in gout and non-gout patients: The VASCURATE study

ObjectiveTo characterize peripheral vascular plaques color-coded as monosodium urate (MSU) deposition by dual-energy computed tomography (DECT) and assess their association with the overall soft-tissue MSU crystal burden.MethodsPatients with suspected crystal arthropathies were prospectively included in the CRYSTALILLE inception cohort to undergo baseline knees and ankles/feet DECT scans; treatment-naive gout patients initiating treat-to-target urate-lowering therapy (ULT) underwent repeated DECT scans with concomitant serum urate level measurements at 6 and 12 months. We determined the prevalence of DECT-based vascular MSU-coded plaques in knee arteries, and assessed their association with the overall DECT volumes of soft-tissue MSU crystal deposition and coexistence of arterial calcifications. DECT attenuation parameters of vascular MSU-coded plaques were compared with dense calcified plaques, control vessels, control soft tissues, and tophi.ResultsWe investigated 126 gout patients and 26 controls; 17 ULT-naive gout patients were included in the follow-up study. The prevalence of DECT-based vascular MSU-coded plaques was comparable in gout patients (24.6%) and controls (23.1%; p=0.87). Vascular MSU-coded plaques were strongly associated with coexisting arterial calcifications (p<0.001), but not with soft-tissue MSU deposition. Characterization of vascular MSU-coded plaques revealed specific differences in DECT parameters compared with control vessels, control soft tissues, and tophi. During follow-up, vascular MSU-coded plaques remained stable despite effective ULT (p=0.64), which decreased both serum urate levels and soft-tissue MSU volumes (p<0.001).ConclusionOur findings suggest that DECT-based MSU-coded plaques in peripheral arteries are strongly associated with calcifications and may not reflect genuine MSU crystal deposition. Such findings should therefore not be a primary target when managing gout patients     

Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori,Pacific Island,and Caucasian case–control sample sets

Objective

To examine the role of genetic variation in the renal urate transporter SLC2A9 in gout in New Zealand sample sets of Māori, Pacific Island, and Caucasian ancestry and to determine if the Māori and Pacific Island samples could be useful for fine‐mapping.

Methods

Patients (n= 56 Māori, 69 Pacific Island, and 131 Caucasian) were recruited from rheumatology outpatient clinics and satisfied the American College of Rheumatology criteria for gout. The control samples comprised 125 Māori subjects, 41 Pacific Island subjects, and 568 Caucasian subjects without arthritis. SLC2A9 single‐nucleotide polymorphisms rs16890979 (V253I), rs5028843, rs11942223, and rs12510549 were genotyped (possible etiologic variants in Caucasians).

Results

Association of the major allele of rs16890979, rs11942223, and rs5028843 with gout was observed in all sample sets (P = 3.7 × 10⁻⁷, 1.6 × 10⁻⁶, and 7.6 × 10⁻⁵ for rs11942223 in the Māori, Pacific Island, and Caucasian samples, respectively). One 4‐marker haplotype (1/1/2/1; more prevalent in the Māori and Pacific Island control samples) was not observed in a single gout case.

Conclusion

Our data confirm a role of SLC2A9 in gout susceptibility in a New Zealand Caucasian sample set, with the effect on risk (odds ratio >2.0) greater than previous estimates. We also demonstrate association of SLC2A9 with gout in samples of Māori and Pacific Island ancestry and a consistent pattern of haplotype association. The presence of both alleles of rs16890979 on susceptibility and protective haplotypes in the Māori and Pacific Island sample is evidence against a role for this nonsynonymous variant as the sole etiologic agent. More extensive linkage disequilibrium in Māori and Pacific Island samples suggests that Caucasian samples may be more useful for fine‐mapping.

     

Association of an intronic SNP of <Emphasis Type="Italic">SLC2A9</Emphasis> gene with serum uric acid levels in the Chinese male Han population by high-resolution melting method

SLC2A9 is a novel identified urate transporter influencing uric acid metabolism. It has been suggested that the single-nucleotide polymorphisms in SLC2A9 may affect the serum UA levels. The present study was designed to investigate rs6855911 polymorphism in intron 7 of SLC2A9 in a total of 372 Chinese male subjects. We examined 166 gout patients, as well as 206 healthy male volunteers in this study. DNA was purified from peripheral blood, and the rs6855911 polymorphism was evaluated using high-resolution melting (HRM) analysis and direct sequencing. Demographic and clinical data obtained from the patients and controls among the genotype groups were analyzed. A/A and A/G genotypes were unambiguously distinguished with HRM technology. The occurrence of the homozygous type (G/G) was completely absent among the study population. The prevalence of the A/A and A/G genotype was 96.0% and 4.0%, respectively. Genotyping based on HRM was fully concordant with sequencing. The G allele frequency was significantly higher in the low-uric-acid group than in the high-uric-acid group. The genotype distribution and allele frequencies were not significantly different between gout and control subjects (p = 0.04). However, serum uric acid levels in the A/G genotype subjects were significantly lower than those with the A/A genotypes (p < 0.01). Rapid and accurate genotyping analysis of SLC2A9 can be done with HRM. The polymorphism rs6855911 in SLC2A9 may be a genetic marker to assess risk of hyperuricemia among Chinese male Han population.